Alpha 4 beta 7 integrin antagonists and uses thereof

Abstract

Described herein are α4β7 integrin inhibitors and pharmaceutical compositions containing the inhibitors. The subject compounds and compositions are useful for treating α4β7 integrin-mediated conditions, such as inflammatory bowel disease (IBD), ulcerative colitis (UC), and Crohn's disease (CD). Integrins are heterodimeric cell surface receptors composed of noncovalently associated α and β subunits and are involved in numerous cellular processes, including cell adhesion. The adhesive properties of cells can be regulated by differential expression of integrins, thus allowing different leukocyte populations to be recruited to specific organs in response to inflammatory signals.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 476,861, filed December 22, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Integrins are heterodimeric cell surface receptors composed of noncovalently associated α and β subunits and are involved in numerous cellular processes, including cell adhesion. The adhesive properties of cells can be regulated by differential expression of integrins, thus allowing distinct leukocyte populations to be recruited to specific organs in response to inflammatory signals. α4β7 integrin has been shown to be involved in lymphocyte migration throughout the gut-associated lymphoid tissue (GALT). α4β7 is expressed on leukocytes, including T and B lymphocytes, and the critical role of α4β7 in cell adhesion in GALT has been shown to be mediated through selective binding to its primary ligand, mucosal addressin cell adhesion molecule-1 (MAdCAM-1). For example, memory T lymphocytes (T( mem ) preferentially traffic to the GALT via adhesion to MAdCAM-1.

[0003] Inhibitors of integrin-ligand interactions have been used to treat a variety of diseases. For example, vedolizumab, a monoclonal antibody (mAb) with high binding affinity for α4β7, has demonstrated therapeutic efficacy in the treatment of inflammatory bowel diseases (IBD), such as Crohn's disease (CD) and ulcerative colitis (UC). However, mAbs also have certain undesirable properties for patients. Vedolizumab is administered parenterally, and mAbs generally have long half-lives, making it difficult to rapidly alter exposure. Furthermore, the formation of anti-drug antibodies can lead to loss of activity over time. Furthermore, some α4-inhibiting therapies also interfere with α4β1 integrin-ligand interactions, particularly the selective binding of α4β1 to vascular cell adhesion molecule 1 (VCAM-1), and this inhibition can result in dangerous side effects for patients. Activity against the α4β1 integrin contributes to the development of progressive multifocal leukoencephalopathy (PML), a life-threatening, progressive brain disease caused by the JC virus that is normally suppressed in patients by immune surveillance.

[0004] There remains a medical need for effective, selective, and safe oral α4β7 integrin inhibitors with improved pharmaceutical properties that target α4β7 integrin-mediated conditions such as inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD). Summary of the Invention [Means for solving the problem]

[0005] Disclosed herein are compounds of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, R 1 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 2 But hydrogen, deuterium, halogen, -L-CN, -L-OH, -L-OR a , -LS(=O)R a , -LS(=O)2R a , -LS(=O)2NR c R d , -L-NR c R d , -LC(=O)R a , -LC(=O)OR b , -LC(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, or -L-heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 3 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 4is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; L is absent or is C1-C6 alkylene; Ring A is aryl or heteroaryl; Each R 5 are independently halogen, -CN, -NO2, -OH, -OR a , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R's 5 together to form oxo, n is 0 to 4, X is -O-, -S-, -C(R 6 )2-, -NR 7 -, -[C(R 6 )2]2-, -OC(R 6 )2-, -C(R 6 )2-O-, -SC(R 6 )2-, or -C(R 6 )2-S-, Each R 6are independently hydrogen, deuterium, halogen, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or two R's 6 together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Ring B is aryl or heteroaryl; Each R 8 are independently halogen, -CN, -NO2, -OH, -OR a , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R's 8 together to form oxo, m is 0 to 4; Ring C is aryl or heteroaryl; Each R 9 are independently halogen, -CN, -NO2, -OH, -ORa , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R's 9 together to form oxo, p is 0 to 4; Each R a are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R bare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently selected from halogen, -CN, -OH, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -SC1-C3 alkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuteroalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, or heterocycloalkyl; Or two R on the same atom together form oxo.

[0006] In some embodiments of the compound of Formula (I), the compound is of Formula (Ia): [ka]

[0007] In some embodiments of the compound of Formula (I), the compound is of Formula (Ib): [ka]

[0008] In some embodiments of the compound of Formula (I), the compound is of Formula (Ic): [ka]

[0009] In some embodiments of the compound of Formula (I), the compound is of Formula (Id): [ka]

[0010] Also disclosed herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0011] Also disclosed herein are methods of treating a disease, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the disease is inflammatory bowel disease, ileoanal anastomosis, eosinophilic esophagitis, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholecititis, chronic bronchitis, chronic sinusitis, asthma, graft-versus-host disease, or chronic pulmonary inflammatory disease. In some embodiments, the disease is inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is colitis, Crohn's disease, ileitis, celiac disease, nontropical sprue, seronegative arthropathy-associated enteropathy, gastroenteritis, or pouchitis. In some embodiments, the disease is colitis. In some embodiments, the colitis is ulcerative colitis, microscopic colitis, or collagenous colitis. In some embodiments, the disease is pouchitis, where pouchitis is a result of proctocolectomy. In some embodiments, the disease is gastroenteritis. In some embodiments, the gastroenteritis is eosinophilic gastroenteritis. In some embodiments, the disease is eosinophilic esophagitis. In some embodiments, the disease is a chronic inflammatory disease of the lung. In some embodiments, the chronic inflammatory disease of the lung is interstitial fibrosis. In some embodiments, the interstitial fibrosis is hypersensitivity pneumonitis, collagen disease, or sarcoidosis.

[0012] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0013] definition In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the subject matter of the present disclosure may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout the following specification and claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," should be interpreted in an open and inclusive sense, i.e., "including, but not limited to." Furthermore, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed subject matter.

[0014] References throughout this specification to "some embodiments" or "embodiments" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally used to include "and / or" unless the content clearly dictates otherwise.

[0015] As used herein, the following terms have the following meanings unless otherwise indicated.

[0016] "Oxo" refers to =O.

[0017] "Carboxyl" refers to --COOH.

[0018] "Cyano" refers to -CN.

[0019] "Alkyl" refers to a straight- or branched-chain saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, or 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, and the like. Wherever it appears herein, a numerical range such as "C1-C6 alkyl" or "C1-6 alkyl" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is a C1- 10In some embodiments, the alkyl is an alkyl. In some embodiments, the alkyl is a C1-6 alkyl. In some embodiments, the alkyl is a C1-5 alkyl. In some embodiments, the alkyl is a C1-4 alkyl. In some embodiments, the alkyl is a C1-3 alkyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl is optionally substituted with oxo, halogen, —CN, —COOH, —COOMe, —OH, —OMe, —NH2, or —NO2. In some embodiments, the alkyl is optionally substituted with halogen, —CN, —OH, or —OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0020] "Alkenyl" refers to a straight- or branched-chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having 2 to about 10 carbon atoms, or 2 to about 6 carbon atoms. This group may be in either the cis or trans conformation about the double bond and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH), 1-propenyl (-CHCH=CH), isopropenyl [-C(CH)=CH], butenyl, 1,3-butadienyl, and the like. Wherever appearing herein, a numerical range such as "C2-C6 alkenyl" or "C2-6 alkenyl" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms; however, this definition also encompasses occurrences of the term "alkenyl" where no numerical range is specified. Unless stated otherwise specifically in the specification, an alkenyl group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, —CN, —COOH, —COOMe, —OH, —OMe, —NH, or —NO. In some embodiments, an alkenyl is optionally substituted with halogen, —CN, —OH, or —OMe. In some embodiments, an alkenyl is optionally substituted with halogen.

[0021] "Alkynyl" refers to a straight- or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having 2 to about 10 carbon atoms, or 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadinyl, and the like. Wherever it appears herein, a numerical range such as "C2-C6 alkynyl" or "C2-6 alkynyl" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms; however, this definition also encompasses occurrences of the term "alkynyl" without a numerical range specified. Unless otherwise specifically stated herein, alkynyl groups can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0022] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, alkylene groups can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkylene is optionally substituted with halogen.

[0023] "Alkoxy" means a group of the formula -OR g refers to the radical of R g is an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0024] "Amino" is -NR y R z refers to a group, wherein R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein.

[0025] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. Aryl radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems and can include fused ring systems (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is attached through an aromatic ring atom) or bridged ring systems. In some embodiments, an aryl is a 6- to 10-membered aryl. In some embodiments, an aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, an aryl is optionally substituted with halogen.

[0026] "Carboxylate" is -C(O)OR x In the formula, R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein.

[0027] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which can include fused ring systems (when fused to an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems. In some embodiments, a cycloalkyl is fully saturated. Representative cycloalkyls are those having 3 to 15 carbon atoms (C3 to C6). 15 Fully saturated cycloalkyl or C3-C 15 Cycloalkenyl), 3 to 10 carbon atoms (C3 to C 10 Fully saturated cycloalkyl or C3-C 10Examples of cycloalkyl include, but are not limited to, cycloalkyls having 3 to 8 carbon atoms (C-C fully saturated cycloalkyl or C-C cycloalkenyl), 3 to 6 carbon atoms (C-C fully saturated cycloalkyl or C-C cycloalkenyl), 3 to 5 carbon atoms (C-C fully saturated cycloalkyl or C-C cycloalkenyl), or 3 to 4 carbon atoms (C-C fully saturated cycloalkyl or C-C cycloalkenyl). In some embodiments, cycloalkyls are 3- to 10-membered fully saturated cycloalkyl or 3- to 10-membered cycloalkenyl. In some embodiments, cycloalkyls are 3- to 6-membered fully saturated cycloalkyl or 3- to 6-membered cycloalkenyl. In some embodiments, cycloalkyls are 5- to 6-membered fully saturated cycloalkyl or 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —COOH, COOMe, —CF, —OH, —OMe, —NH, or —NO.In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0028] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0029] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0030] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0031] "Aminoalkyl" refers to an alkyl radical, as defined above, substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyls include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0032] "Deuteroalkyl" refers to an alkyl radical, as defined above, that is substituted with one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyls include, for example, CD3, CHD, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0033] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl consists of 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof, and the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH, -CHCHOCH, -CHCHOCHCHOCH, -CH(CH)OCH, -CHNHCH, -CHN(CH), -CHCHNHCH, or -CHCHN(CH). Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, a heteroalkyl is optionally substituted with halogen.

[0034] "Heterocycloalkyl" refers to a 3- to 24-membered partially or fully saturated ring radical containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a heterocycloalkyl is fully saturated. In some embodiments, a heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heterocycloalkyl contains 1 to 3 nitrogens. In some embodiments, a heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, a heterocycloalkyl contains 1 nitrogen. In some embodiments, a heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless stated otherwise specifically in the specification, a heterocycloalkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and can include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical can be optionally oxidized; and the nitrogen atom can be optionally quaternized. Representative heterocycloalkyls are those having 2 to 15 carbon atoms (C2 to C6). 15 Fully saturated heterocycloalkyl or C2-C 15 heterocycloalkenyl), 2 to 10 carbon atoms (C2 to C 10 Fully saturated heterocycloalkyl or C2-C 10heterocycloalkenyl), heterocycloalkyl having 2 to 8 carbon atoms (C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), 2 to 7 carbon atoms (C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 6 carbon atoms (C2-C6 fully saturated heterocycloalkyl or C2-C6 heterocycloalkenyl), 2 to 5 carbon atoms (C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2 to 4 carbon atoms (C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, and pyrrolidinyl. Examples of heterocycloalkyl include, but are not limited to, pyrazolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes, but is not limited to, all ring forms of carbohydrates, including monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyls have 2 to 10 carbons in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring).In some embodiments, a heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl can be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, a heterocycloalkyl is optionally substituted with halogen.

[0035] "Heteroaryl" refers to a 5- to 14-membered ring system radical containing 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, a heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heteroaryl contains 1 to 3 nitrogens. In some embodiments, a heteroaryl contains 1 or 2 nitrogens. In some embodiments, a heteroaryl contains 1 nitrogen. A heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and can include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is attached through an aromatic ring atom) or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, and indolinyl. Examples of phenyl include, but are not limited to, phenyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, heteroaryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe.In some embodiments, the heteroaryl is optionally substituted with halogen.

[0036] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where the event or circumstance does not occur. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl" as defined above. Furthermore, optionally substituted groups can be unsubstituted (e.g., -CHCH), fully substituted (e.g., -CFCF), monosubstituted (e.g., -CHCHF), or substituted at any level between fully and monosubstituted (e.g., -CHCHF, -CHCF, -CFCH, -CFHCHF, etc.). Those of skill in the art will understand that with respect to any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical and / or synthetically unfeasible (e.g., a substituted alkyl can include an optionally substituted cycloalkyl group, which can continue indefinitely as defined to include an optionally substituted alkyl group). Thus, any substituent described should generally be understood to have a maximum molecular weight of up to about 1,000 daltons, more typically up to about 500 daltons.

[0037] The term "one or more" when referring to optional substituents means that the group of interest is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the group of interest is optionally substituted with one, two, three, or four substituents. In some embodiments, the group of interest is optionally substituted with one, two, or three substituents. In some embodiments, the group of interest is optionally substituted with one or two substituents. In some embodiments, the group of interest is optionally substituted with one substituent. In some embodiments, the group of interest is optionally substituted with two substituents.

[0038] An "effective amount" or "therapeutically effective amount" refers to the amount of a compound administered to a mammalian subject, either in a single dose or as part of a series, effective to produce a desired therapeutic effect.

[0039] "Treatment" of an individual (e.g., a mammal such as a human) or cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition following the onset of a pathological event or contact with a pathogen, and includes stabilization of the condition (e.g., the condition does not worsen) or alleviation of the condition.

[0040] "Synergistic" or "synergizing" refers to an effect of the combination that is greater than the additive effect of each component alone at the same dose.

[0041] As used herein, "disease or disorder associated with α4β7 integrin" or alternatively "α4β7 integrin-mediated disease or disorder" means any disease or other deleterious condition in which α4β7 integrin or a variant thereof is known or suspected to play a role.

[0042] As used herein, terms such as "α4β7," "a4B7," "a4b7," "alpha-4 beta-7," and "alpha4 beta7" all refer to α4β7.

[0043] compound Described herein are compounds, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, that are useful in the treatment of cancer.

[0044] Disclosed herein are compounds of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, R 1is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 2 But hydrogen, deuterium, halogen, -L-CN, -L-OH, -L-OR a , -LS(=O)R a , -LS(=O)2R a , -LS(=O)2NR c R d , -L-NR c R d , -LC(=O)R a , -LC(=O)OR b , -LC(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, or -L-heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 3 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 4 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; L is absent or is C1-C6 alkylene; Ring A is aryl or heteroaryl; Each R 5 are independently halogen, -CN, -NO2, -OH, -OR a , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R's 5 together to form oxo, n is 0 to 4, X is -O-, -S-, -C(R 6 )2-, -NR 7 -, -[C(R 6 )2]2-OC(R 6 )2-C(R 6 )2-O-, -SC(R 6 )2-C(R 6 )2-S-; Each R 6 are independently hydrogen, deuterium, halogen, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or two R's 6together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Ring B is aryl or heteroaryl; Each R 8 are independently halogen, -CN, -NO2, -OH, -OR a , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R's 8 together to form oxo, m is 0 to 4; Ring C is aryl or heteroaryl; Each R 9 are independently halogen, -CN, -NO2, -OH, -OR a , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R's 9 together to form oxo, p is 0 to 4; Each R a are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently selected from halogen, -CN, -OH, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -SC1-C3 alkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuteroalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, or heterocycloalkyl; Or two R on the same atom together form oxo.

[0045] In some embodiments of the compound of Formula (I), the compound is of Formula (Ia): [ka]

[0046] In some embodiments of the compound of Formula (I), the compound is of Formula (Ib): [ka]

[0047] In some embodiments of the compound of Formula (I), the compound is of Formula (Ic): [ka]

[0048] In some embodiments of the compound of Formula (I), the compound is of Formula (Id): [ka]

[0049] In some embodiments of a compound of Formula (I) or (Ia)-(Id), ring A is aryl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), ring A is phenyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), ring A is heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), ring A is a 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), ring A is a 5-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), ring A is a 6-membered heteroaryl.

[0050] In some embodiments of the compound of Formula (I), the compound is of Formula (II): [ka]

[0051] In some embodiments of the compound of Formula (I), the compound is of Formula (IIa): [ka]

[0052] In some embodiments of the compound of Formula (I), the compound is of Formula (IIb): [ka]

[0053] In some embodiments of the compound of Formula (I), the compound is of Formula (IIc): [ka]

[0054] In some embodiments of the compound of Formula (I), the compound is of Formula (IId): [ka]

[0055] In some embodiments of compounds of Formula (I) or (Ia)-(Id), each R 5 are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

[0056] In some embodiments of compounds of Formula (I) or (Ia)-(Id), each R 5is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia)-(Id), each R 5 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), each R 5 is independently halogen. In some embodiments of compounds of Formula (I) or (Ia)-(Id), each R 5 is independently C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), each R 5 is independently C1-C6 alkyl or C1-C6 haloalkyl.

[0057] In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 0 to 2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 0. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 1. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 3.

[0058] In some embodiments of compounds of Formula (I) or (Ia)-(Id), X is —O—, —S—, —C(R 6 )2- or -NR 7 In some embodiments of the compound of Formula (I) or (Ia)-(Id), X is -O-, -S-, or -NR 7In some embodiments of the compound of Formula (I) or (Ia)-(Id), X is -O-. In some embodiments of the compound of Formula (I) or (Ia)-(Id), X is -S-. In some embodiments of the compound of Formula (I) or (Ia)-(Id), X is -C(R 6 In some embodiments of compounds of Formula (I) or (Ia)-(Id), X is —NR 7 -It is.

[0059] In some embodiments of the compound of Formula (I), the compound is of Formula (Ie): [ka]

[0060] In some embodiments of the compound of Formula (I), the compound is of Formula (IIe): [ka]

[0061] In some embodiments of compounds of Formula (I) or (Ia)-(Id), each R 6 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), each R 6 is independently hydrogen, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), each R 6 is hydrogen.

[0062] In some embodiments of compounds of Formula (I) or (Ia)-(Id), two R 6 together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R.

[0063] In some embodiments of the compound of Formula (I), the compound is of Formula (If): [ka]

[0064] In some embodiments of the compound of Formula (I), the compound is of Formula (Ig): [ka]

[0065] In some embodiments of the compound of Formula (I), the compound is of Formula (IIf): [ka]

[0066] In some embodiments of the compound of Formula (I), the compound is of Formula (IIg): [ka]

[0067] In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 7 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 7 is hydrogen.

[0068] In some embodiments of a compound of Formula (I) or (Ia)-(Id), ring B is aryl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), ring B is phenyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), ring B is heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), ring B is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), ring B is 5-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), ring B is 6-membered heteroaryl.

[0069] In some embodiments of compounds of Formula (I) or (Ia)-(Id), each R 8 are independently halogen, -CN, -NO2, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

[0070] In some embodiments of compounds of Formula (I) or (Ia)-(Id), each R 8 is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0071] In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 0 to 2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 0. In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 1. In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 3.

[0072] In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring C is aryl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring C is phenyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring C is heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring C is a 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring C is a 5-membered heteroaryl.

[0073] In some embodiments of compounds of Formula (I) or (Ia)-(Id), each R 9 are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia)-(Id), each R 9 are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), each R 9 is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0074] In some embodiments of a compound of Formula (I) or (Ia)-(Id), p is 0 to 2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), p is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), p is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia)-(Id), p is 0. In some embodiments of a compound of Formula (I) or (Ia)-(Id), p is 1. In some embodiments of a compound of Formula (I) or (Ia)-(Id), p is 2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), p is 3.

[0075] In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 1 is hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, wherein alkyl is optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 1 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 1 is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 1 is hydrogen.

[0076] In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 3 is hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, wherein alkyl is optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 3 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 3 is hydrogen or C1-C6 haloalkyl.

[0077] In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 4 is hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, wherein alkyl is optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 4 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 4 is hydrogen or C1-C6 haloalkyl.

[0078] In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 2 -L-CN, -L-OH, -L-OR a , -L-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 2 -L-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, -L-cycloalkyl, or -L-heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 2 -L-NR c R d or -L-heterocycloalkyl, wherein heterocycloalkyl is optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 2 -L-NR c R d In some embodiments of compounds of Formula (I) or (Ia)-(Id), R2 is -L-heterocycloalkyl.

[0079] In some embodiments of the compound of Formula (I), the compound is of Formula (Ih): [ka]

[0080] In some embodiments of the compound of Formula (I), the compound is of Formula (Ij): [ka]

[0081] In some embodiments of the compound of Formula (I), the compound is of Formula (IIh): [ka]

[0082] In some embodiments of the compound of Formula (I), the compound is of Formula (IIj): [ka]

[0083] In some embodiments of a compound of Formula (I) or (Ia)-(Id), L is absent. In some embodiments of a compound of Formula (I) or (Ia)-(Id), L is C1-C6 alkylene. In some embodiments of a compound of Formula (I) or (Ia)-(Id), L is C1-C3 alkylene. In some embodiments of a compound of Formula (I) or (Ia)-(Id), L is C1-C2 alkylene. In some embodiments of a compound of Formula (I) or (Ia)-(Id), L is C1 alkylene.

[0084] In some embodiments of the compounds disclosed herein, each R ais independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl), or C1-C6 alkylene(heterocycloalkyl), where each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, and each alkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R a is independently C1 to C6 alkyl.

[0085] In some embodiments of the compounds disclosed herein, R c and R dare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl), or C1-C6 alkylene(heterocycloalkyl), and each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, and each alkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R c and R d and R are each hydrogen. In some embodiments of the compounds disclosed herein, R c and Rd are each independently C1 to C6 alkyl.

[0086] In some embodiments of the compounds disclosed herein, R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more R.

[0087] In some embodiments of the compounds disclosed herein, each R is independently halogen, —CN, —OH, —OC-C alkyl, —OC-C haloalkyl, —NH, —NHC alkyl, —N(C-C alkyl), —C(═O)C alkyl, —C(═O)OH, —C(═O)OC alkyl, —C(═O)NH, —C(═O)NHC alkyl, —C(═O)N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C cycloalkyl, or heterocycloalkyl, or two R on the same atom together form oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, —CN, —OH, —O—C alkyl, —O—C haloalkyl, —NH, —NHC alkyl, —N(C alkyl), C alkyl, C haloalkyl, C deuteroalkyl, C hydroxyalkyl, C aminoalkyl, C heteroalkyl, C cycloalkyl, or heterocycloalkyl, or two R on the same atom together form oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC-C alkyl, -OC-C haloalkyl, -NH, -NHC-C alkyl, -N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C cycloalkyl, or heterocycloalkyl, or two R on the same atom together form oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC-C alkyl, -NH, C-C alkyl, or C-C haloalkyl, or two R on the same atom together form oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC-C alkyl, -NH, C-C alkyl, or C-C haloalkyl, or two R on the same atom together form oxo.In some embodiments of the compounds disclosed herein, each R is independently halogen or C1-C3 alkyl, or two R on the same atom together form oxo.

[0088] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0089] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is selected from the compounds found in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20] [Table 1-21] [Table 1-22] [Table 1-23]

[0090] The absolute label (abs) is added to the chiral center to indicate that it is a pure sample of the specifically drawn stereoisomer.

[0091] The OR label (or) indicates a pure substance, but the absolute configuration of the stereochemical centers is unknown. After chiral separation with isolated pure structures, multiple OR labels with the same numerical value (OR indicates purity) indicate that the sample is one of a pair of pure enantiomers (but the absolute configuration of the stereochemical centers is unknown).

[0092] The AND symbol (and) indicates that both isomers are present at the depicted stereochemical center. Assigning different numerical values ​​to the AND symbols indicates that they are independent of each other. Use of AND symbols with the same value indicates that the two stereocenters are relative to each other and can only change in unison.

[0093] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is selected from the compounds found in Table 2. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 Table 2-21 Table 2-22 Table 2-23 Table 2-24 Table 2-25 Table 2-26 Table 2-27 Table 2-28 Table 2-29 Table 2-30 Table 2-31 Table 2-32 Table 2-33 Table 2-34 Table 2-35 Table 2-36 Table 2-37 Table 2-38 Table 2-39 Table 2-40 Table 2-41 Table 2-42 Table 2-43 Table 2-44 Table 2-45 Table 2-46 Table 2-47 [Table 2-48] [Table 2-49] [Table 2-50] [Table 2-51] [Table 2-52] [Table 2-53] [Table 2-54]

[0094] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is [ka] [ka] [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0095] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds described herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as their corresponding mixtures. In some circumstances, the compounds described herein possess one or more chiral centers, with each center existing in either the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, as well as their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers obtained from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, diastereomers are separated by chiral chromatography, for example, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomers are then recovered, along with the resolving agent, by any practical means that does not result in racemization.

[0096] labeled compound In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those listed herein, except for the fact that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. l5 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Compounds described herein, and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically labeled compounds, e.g., 3 H and 14 Those in which a radioactive isotope such as 3C is incorporated are useful in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred for their ease of preparation and detectability. Additionally, heavy isotopes such as deuterium, i.e., 2 Substitution with, for example, H may confer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements.

[0097] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0098] pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt as a pharmaceutical composition.

[0099] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or solvates or stereoisomers thereof, or by separately reacting the purified compounds in free form with a suitable acid or base and isolating the salt thus formed.

[0100] Examples of pharmaceutically acceptable salts include salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, Digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate Examples of suitable salts include mandelatemetaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate undeconate, and xylenesulfonate.

[0101] Additionally, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compounds with a pharmaceutically acceptable inorganic or organic acid, including inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, and the like. Examples of suitable pharmaceutically acceptable acids include, but are not limited to, aromatic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, are used in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, their solvates, or stereoisomers, and their pharmaceutically acceptable acid addition salts.

[0102] In some embodiments, compounds described herein containing free acid groups are reacted with a suitable base, such as a hydroxide, carbonate, bicarbonate, or sulfate salt of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1~4 alkyl)4.

[0103] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water- or oil-soluble or dispersible products are obtained by such quaternization.

[0104] solvate In some embodiments, the compounds described herein exist as solvates. The present disclosure provides methods of treating diseases by administering such solvates. The present disclosure further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0105] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and, in some embodiments, are formed using pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from aqueous / organic solvent mixtures using organic solvents, including, but not limited to, dioxane, tetrahydrofuran, or methanol. Furthermore, the compounds provided herein can exist in unsolvated and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0106] tautomers In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can be interconverted by the migration of a hydrogen atom, accompanied by the switching of a single bond and an adjacent double bond. In bonding configurations where tautomerization is possible, a chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0107] Treatment method Disclosed herein are methods for treating diseases in which inhibition of α4β7 integrin is beneficial, the methods comprising administering a compound disclosed herein. Compounds that inhibit α4β7 are useful for the development of pharmaceuticals for treating ulcerative colitis (UC) and Crohn's disease (CD). Inflammatory bowel diseases, such as UC and CD, are inflammatory diseases of the digestive tract and involve the inhibition of CD4 + Memory T cells contribute to the pathogenesis of these diseases through their ability to secrete pro-inflammatory effector cytokines into the intestine and affect surrounding immune cells and tissues. The progression and relapse of these diseases are thought to involve extravasation, where T cells enter intestinal tissues via integrin-mediated mechanisms, resulting in inflammation. Inhibition of α4β7 can disrupt T cell localization to intestinal tissues, and the α4β7-targeting mAb vedolizumab has been shown to be effective in treating UC and CD. T cell homing to the intestine requires surface expression of the integrin α4β7 and the chemokine receptor CCR9. While CCR9 is utilized by cells to migrate toward a gradient of CCL25 expressed in the small intestine, α4β7 is a tethering molecule that binds to its ligand, the mucosal addressin cell adhesion molecule 1 (MAdCAM-1). Integrin α4β7 binds to MAdCAM-1 with high affinity, promoting cell rolling and firm adhesion, followed by extravasation into tissues.

[0108] In some embodiments, the disease is inflammatory bowel disease, ileoanal anastomosis, eosinophilic esophagitis, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholecititis, chronic bronchitis, chronic sinusitis, asthma, graft-versus-host disease, or chronic inflammatory disease of the lung.

[0109] In some embodiments, the disease is inflammatory bowel disease (IBD). In some embodiments, the inflammatory bowel disease is ulcerative colitis (UC) or Crohn's disease (CD).

[0110] In some embodiments, the inflammatory bowel disease is colitis, Crohn's disease, ileitis, celiac disease, non-tropical sprue, seronegative arthropathy-associated enteropathy, gastroenteritis, or pouchitis.

[0111] In some embodiments, the disease is colitis, hi some embodiments, the colitis is ulcerative colitis, microscopic colitis, or collagenous colitis.

[0112] In some embodiments, the disease is pouchitis, and the pouchitis is a result of a proctocolectomy.

[0113] In some embodiments, the disease is gastroenteritis, hi some embodiments, the gastroenteritis is eosinophilic gastroenteritis.

[0114] In some embodiments, the disease is eosinophilic esophagitis.

[0115] In some embodiments, the disease is a chronic inflammatory disease of the lung. In some embodiments, the chronic inflammatory disease of the lung is interstitial fibrosis.

[0116] In some embodiments, the interstitial fibrosis is hypersensitivity pneumonitis, collagen disease, or sarcoidosis.

[0117] Administration In certain embodiments, compositions containing the compounds described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest at least one symptom of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous medications, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0118] In certain embodiments where the patient's condition does not improve, at the physician's discretion, administration of the compound is administered chronically, i.e., for an extended period of time, including the entire lifespan of the patient, to alleviate or otherwise control or limit the symptoms of the patient's disease or condition.

[0119] Once the patient's condition has improved, a maintenance dose is administered as needed. Thereafter, in specific embodiments, the dosage or frequency of administration, or both, is reduced, depending on the symptoms, to a level at which the improved disease, disorder, or condition is maintained. However, in certain embodiments, the patient requires long-term, intermittent, or daily treatment upon any recurrence of symptoms.

[0120] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, but will nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0121] The toxicity and therapeutic efficacy of such treatment regimens are discussed in detail below. 10 and ED 90 The dose ratio between toxic and therapeutic effects is the therapeutic index, and is known as the LD50 and ED 50 In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating therapeutically effective daily dosage ranges and / or therapeutically effective unit dosages for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein is such that the ED 50 In certain embodiments, the daily dosage range and / or unit dosage amount varies within this range depending on the dosage form employed and the route of administration utilized.

[0122] Route of administration Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. Further, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intrathecal injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0123] In certain embodiments, the compounds described herein are administered in a local rather than systemic manner, for example, via direct injection of the compound into an organ, often in a depot or sustained-release formulation. In specific embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome targets and is selectively taken up by the organ. In still other embodiments, the compounds described herein are provided in the form of an immediate-release formulation, an extended-release formulation, or an intermediate-release formulation. In still other embodiments, the compounds described herein are administered locally.

[0124] Pharmaceutical Compositions / Formulations The compounds described herein are administered to a subject in need thereof, according to standard pharmaceutical practice, either alone or in a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, excipient, or diluent. In one embodiment, the compounds of the present disclosure can be administered to animals. The compounds can be administered orally or parenterally, including intravenously, intramuscularly, intraperitoneally, subcutaneously, rectally, and topically.

[0125] In another aspect, provided herein is a pharmaceutical composition comprising the compound described herein or its pharmaceutically acceptable salt, solvate or stereoisomer and at least one pharmaceutically acceptable excipient.The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutical preparation.The appropriate formulation depends on the selected route of administration. A summary of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0126] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, coloring agents, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, and any combination thereof.

[0127] The pharmaceutical compositions described herein are administered to a subject by any suitable route of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes. Pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate-release formulations, controlled-release formulations, fast-melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed-release formulations, extended-release formulations, pulsatile-release formulations, multiparticulate formulations, and combined immediate- and controlled-release formulations.

[0128] Pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are manufactured by conventional means such as, by way of example only, conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compressing processes.

[0129] Pharmaceutical compositions for oral use can be prepared by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and then processing the granulated mixture to obtain tablets or dragee cores, if desired, after adding suitable additives. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or others, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrants such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, can be added. In some embodiments, dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0130] Orally administered pharmaceutical compositions include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules contain the active ingredient in a mixture of fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound is dissolved or suspended in a suitable liquid (e.g., fatty oils, liquid paraffin, or liquid polyethylene glycol). In some embodiments, stabilizers are added.

[0131] Pharmaceutical compositions for parenteral use are formulated for infusion or injection. In some embodiments, pharmaceutical compositions suitable for injection or infusion comprise a sterile aqueous solution or dispersion, or a sterile powder, containing a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the pharmaceutical composition comprises a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium, including, for example, water, saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and any combination thereof. In some embodiments, the pharmaceutical composition further comprises a preservative to prevent the growth of microorganisms.

[0132] combination Disclosed herein are methods of treating cancer using the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, in combination with an additional therapeutic agent.

[0133] In some embodiments, the additional therapeutic agent is administered simultaneously with the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered before administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after administration of the compound disclosed herein. [Example]

[0134] Compound synthesis The compounds can be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent in light of the disclosure herein and methods well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods may also be used. The synthesis of exemplary compounds described herein can be achieved as illustrated in the following examples. Where available, reagents and starting materials may be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers.

[0135] Where typical process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, it will be understood that other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0136] Additionally, conventional protecting groups ("protecting groups") may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting particular functional groups, are well known in the art. For example, Wuts, PGM, Greene, TW, & Greene, TW (2006). Greene's protective groups in organic synthesis. Hoboken, NJ, Wiley-Interscience, and references cited therein, describe numerous protecting groups. For example, protecting groups for alcohols such as hydroxy include silyl ethers (such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers), which can be removed by acid or fluoride ion, such as NaF, tetra-n-butylammonium fluoride (TBAF), HF-Py, or HF-NEt3. Other protecting groups for alcohols include acetyl, which is removed by acid or base; benzoyl, which is removed by acid or base; benzyl, which is removed by hydrogenation; methoxyethoxymethyl ether, which is removed by acid; dimethoxytrityl, which is removed by acid; methoxymethyl ether, which is removed by acid; tetrahydropyranyl or tetrahydrofuranyl, which is removed by acid; and trityl, which is removed by acid.Examples of amine protecting groups include carbobenzyloxy, which is removed by hydrogenolysis; p-methoxybenzylcarbonyl, which is removed by hydrogenolysis; tert-butyloxycarbonyl, which is removed by concentrated strong acid (such as HCl or CF3COOH) or by heating above about 80°C; 9-fluorenylmethyloxycarbonyl, which is removed by base such as piperidine; acetyl, which is removed by treatment with base; benzoyl, which is removed by treatment with base; benzyl, which is removed by hydrogenolysis; and carbamate, which is removed by acid and mild heating. p-Methoxyphenyl, which is removed by cerium(IV) ammonium nitrate; tosyl, which is removed by concentrated acid (such as HBr or H2SO4) and strong reducing agents (sodium in liquid ammonia or sodium naphthalenide); troc (trichloroethyl chloroformate), which is removed by Zn insertion in the presence of acetic acid; and sulfonamides (Nosyl & Nps), which are removed by samarium iodide or tributyltin hydride.

[0137] Furthermore, compounds of the present disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure. Pure stereoisomers (or enriched mixtures) may be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, etc.

[0138] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chem or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures or obvious modifications thereof described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0139] General Synthesis Scheme I illustrates a general method that can be used to synthesize the compounds described herein, and includes n, m, p, X, ring A, ring B, ring C, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , and R 9 are each independently as defined herein, LG is independently a leaving group (e.g., halo, -OTf, etc.), and PG is a suitable protecting group (e.g., alkyl, such as methyl, ethyl, tert-butyl, etc.). [ka]

[0140] In Scheme 1, compounds of formula (I) can be prepared by contacting compound I-1 with compound I-2 under appropriate conditions, such as in the presence of a coupling agent (such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1-hydroxybenzotriazole (HOBT), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU)), and optionally a base, to provide compound I-3.

[0141] Compound I-3 can then be cyclized in the presence of a catalyst (e.g., copper iodide, sodium iodide, etc.) and a base (e.g., potassium carbonate, sodium carbonate, cesium carbonate, etc.), followed by deprotection of the carboxylic acid to give compounds of formula (I) where X is —O—.

[0142] Alternatively, compound I-3 can further undergo Stille coupling in the presence of an organotin reagent (e.g., (tributyltin)methanol) and a palladium catalyst to give compound I-4. Compound I-4 can then undergo dehydration to cyclize at elevated temperatures of about 50-120°C in a suitable solvent (e.g., toluene), where X becomes -C(R 6 )2O-, a compound of formula (I) can be obtained.

[0143] After each reaction is complete, each intermediate or final compound can be recovered and optionally purified by conventional techniques, such as neutralization, extraction, precipitation, chromatography, filtration, and the like. [ka]

[0144] Alternatively, compounds of formula (I) can be prepared by the route shown in Scheme 2, wherein n, m, p, X, Ring A, Ring B, Ring C, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , and R 9 are each independently as defined herein, and PG and PG 1 is a suitable protecting group (e.g., alkyl, such as methyl, ethyl, tert-butyl, etc.), provided that PG and PG 1 are different, LG is a suitable leaving group (e.g., mesylate, tosylate, triflate, etc.), and each R 50 are independently -OH, -O-alkyl, or together with the boron atom to which they are attached form a cyclic boronate.

[0145] In Scheme 2, compounds of formula (I) can be prepared by first contacting compound I-5 with compound I-6 under suitable Suzuki coupling conditions (i.e., in the presence of a palladium catalyst such as XPhos Pd G3 and a base such as potassium carbonate, sodium carbonate, cesium carbonate, etc.) to give compound I-7.

[0146] Compound I-7 can then undergo deprotection under acidic or basic conditions to give the amine, followed by amide coupling in the presence of a suitable coupling reagent, such as chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) and 1-methylimidazole (NMI), to give compound I-8.

[0147] The ketone in compound I-8 can then be converted to an alcohol in the presence of a suitable reducing agent (e.g., sodium borohydride, lithium aluminum hydride, etc.) The alcohol can then be converted to a suitable leaving group by contact with a suitable reagent such as mesyl chloride, tosyl chloride, etc. to provide compound I-9.

[0148] Finally, compound I-9 is contacted with compound I-10 in the presence of a base (e.g., potassium carbonate, sodium carbonate, or cesium carbonate), followed by deprotection under acidic or basic conditions to convert X to —C(R 6 )2- to obtain a compound of formula (I).

[0149] After each reaction is complete, each intermediate or final compound can be recovered and optionally purified by conventional techniques, such as neutralization, extraction, precipitation, chromatography, filtration, and the like.

[0150] The reagents and starting materials used in Scheme I and Scheme 2 can be purchased from commercial sources or prepared according to methods known to those skilled in the art. Synthesis of intermediates Intermediate 1 [ka]

[0151] Step 1: Preparation of 5-bromo-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one: To a stirred mixture of 5-bromo-4-(trifluoromethyl)-1H-pyridin-2-one (50.00 g, 206.61 mmol, 1.00 equiv.) and PMBCl (48.00 g, 309.92 mmol, 1.50 equiv.) in DMF (600 mL) was added CsCO (134.00 g, 413.23 mmol, 2.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60° C. under a nitrogen atmosphere overnight and then cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOAc (800 mL). The resulting mixture was extracted with water (3×900 mL). The combined organic layers were washed with brine (2×800 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (20-40%, 25 min) to give 5-bromo-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one (50 g, 66.8%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =362.1; 1 H NMR (300MHz, DMSO-d6) δ 8.48 (s, 1H), 7.42-7.27 (m, 2H), 6.97-6.84 (m, 3H), 5.04 (s, 2H), 3.73 (s, 3H). 19 F NMR(300MHz,DMSO-d6)δ-64.13.

[0152] Step 2: Preparation of 5-[(E)-2-ethoxyethenyl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one: To a stirred mixture of 5-bromo-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one (50.00 g, 138.06 mmol, 1.00 equiv.) and 2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (30.00 g, 151.87 mmol, 1.10 equiv.) in 1,4-dioxane (600 mL) and HO (30 mL), Pd(dppf)Cl (5.00 g, 6.90 mmol, 0.05 equiv.) and CsCO (134.00 g, 414.19 mmol, 3.00 equiv.) were added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 70 °C under a nitrogen atmosphere overnight and then cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOAc (800 mL). The resulting mixture was extracted with water (3 × 900 mL). The combined organic layers were washed with brine (2 × 800 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (20% to 40%, 30 min) to give 5-[(E)-2-ethoxyethenyl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one (25 g, 51.2%) as a yellow oil. LC-MS: (ES+H, m / z): [M+H] + =354.1; 1 H NMR(400MHz,DMSO-d6)δ8.06(d,J=6.7Hz,1H),7.39-7.27(m,2H),6.96-6.74(m,4H),5.56- 5.49(m,1H),5.07(d,J=10.0Hz,2H),3.86(q,J=7.0Hz,2H),3.73(s,3H),1.27-1.16(m,3H). 19 F NMR (300MHz, DMSO-d6) δ-62.96.

[0153] Step 3: Preparation of 2-{1-[(4-methoxyphenyl)methyl]-6-oxo-4-(trifluoromethyl)pyridin-3-yl}acetaldehyde: To a stirred mixture of 5-[(E)-2-ethoxyethenyl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one (25.00 g, 70.75 mmol, 1.00 equiv.) in CHCl (80 mL) was added TFA (80 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with CHCl (300 mL). The resulting mixture was washed with NaHCO (aq., 3×300 mL). The combined organic layers were washed with brine (2 x 300 mL), dried over anhydrous NaSO, filtered, and concentrated to give 2-{1-[(4-methoxyphenyl)methyl]-6-oxo-4-(trifluoromethyl)pyridin-3-yl}acetaldehyde as a red oil. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =326.1.

[0154] Step 4: Preparation of 5-[2-(3-fluoroazetidin-1-yl)ethyl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one: To a stirred mixture of 2-{1-[(4-methoxyphenyl)methyl]-6-oxo-4-(trifluoromethyl)pyridin-3-yl}acetaldehyde (25.00 g, 76.85 mmol, 1.00 equiv., crude) and 3-fluoroazetidine (7.50 g, 99.91 mmol, 1.30 equiv.) in EtOH (400 mL) was added CHCOOH (461 mg, 7.68 mmol, 0.10 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. To the above mixture was added NaBHCN (9.66 g, 153.71 mmol, 2.00 equiv.) in portions over 10 minutes at room temperature. The resulting mixture was stirred at room temperature for an additional 4 hours. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The reaction was quenched by adding water / ice (500 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 600 mL), and the combined organic layers were washed with brine (2 × 500 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by silica gel column chromatography eluting with CHCl / MeOH (0–10%, 25 min) to give 5-[2-(3-fluoroazetidin-1-yl)ethyl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one (15 g, 50.7%) as a yellow oil. LC-MS: (ES+H, m / z): [M+H] + =385.1; 1 H NMR(300MHz,DMSO-d6)δ7.96(s,1H),7.36-7.29(m,2H),6.95-6.87(m,2H),6.74(s,1H),5.25-5.15(m,1H),5 .04(s,2H),3.73(s,3H),3.60-3.48(m,2H),3.15-2.99(m,2H),2.57(t,J=7.3Hz,2H),2.42(t,J=7.3Hz,2H). 19 F NMR (300MHz, DMSO-d6) δ-62.51,-177.55.

[0155] Step 5: Preparation of 5-[2-(3-fluoroazetidin-1-yl)ethyl]-4-(trifluoromethyl)-1H-pyridin-2-one: A stirred mixture of 5-[2-(3-fluoroazetidin-1-yl)ethyl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one (15.00 g, 39.02 mmol, 1.00 equiv) in TFA (80 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. Upon completion, the mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography (C18; MeOH / water (10 mM NH4HCO3), 10% to 50%, UV 254 nm) to afford 5-[2-(3-fluoroazetidin-1-yl)ethyl]-4-(trifluoromethyl)-1H-pyridin-2-one (6 g, 58.1%) as an off-white solid. LC-MS: (ES+H, m / z): [M+H] + =265.1; 1 H NMR(400MHz,DMSO-d6)δ12.12(s,1H),7.53(s,1H),6.67(s,1H),5.25-5.03(m,1H), 3.63-3.50(m,2H),3.15-3.01(m,2H),2.57(t,J=7.4Hz,2H),2.42(t,J=7.4Hz,2H). 19 F NMR (400MHz, DMSO-d6) δ-62.61,-177.61. Intermediate 2 [ka]

[0156] Step 1: Preparation of tert-butyl 2-(3-bromophenyl)-2-hydroxyacetate: To a stirred solution of (3-bromophenyl)(hydroxy)acetic acid (5.00 g, 21.64 mmol, 1.00 equiv.) in tetrahydrofuran (100 mL) was added N,N'-diisopropyl tert-butoxymethaneimidamide (13.01 g, 64.92 mmol, 3.00 equiv.) dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C under a nitrogen atmosphere for 3 hours. The reaction was monitored by TLC (PE / EA = 5 / 1). Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (0% to 20% gradient in 30 min) to afford tert-butyl 2-(3-bromophenyl)-2-hydroxyacetate (5 g, 80.4%) as a colorless oil. 1 H NMR(300MHz,CDCl3)δ7.59(t,J=1.9Hz,1H),7.46-7.42(m,1H),7.38-7.33(m,1H) ),7.22(t,J=7.8Hz,1H),5.01(d,J=3.3Hz,1H),3.63-3.47(m,1H),1.42(s,9H).

[0157] Step 2: Preparation of tert-butyl 2-(3-bromophenyl)-2-(methanesulfonyloxy)acetate: To a stirred solution of tert-butyl 2-(3-bromophenyl)-2-hydroxyacetate (4.00 g, 13.93 mmol, 1.00 equiv.) and EtN (2.26 g, 22.33 mmol, 1.60 equiv.) in DCM (6 mL) was added MsCl (2.07 g, 18.07 mmol, 1.30 equiv.) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred from 0 °C to room temperature under a nitrogen atmosphere for 5 h. The reaction was monitored by TLC (PE / EA = 10 / 1). The resulting mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA (0% to 20% gradient in 30 min)) to give tert-butyl 2-(3-bromophenyl)-2-(methanesulfonyloxy)acetate (4 g, 78.6%) as a white solid. 1H NMR (300MHz, CDCl3) δ7.60(d,J=1.9Hz,1H),7.57-7.51(m,1H),7.40-7.37(m,1H),7.29(d,J=7.8Hz,1H),5.76(s,1H),3.15(s,3H),1.44(s,9H).

[0158] Step 3: Preparation of tert-butyl 2-(3-bromophenyl)-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate: To a stirred mixture of tert-butyl 2-(3-bromophenyl)-2-(methanesulfonyloxy)acetate (5.00 g, 13.69 mmol, 1.29 equiv.) and 5-[2-(3-fluoroazetidin-1-yl)ethyl]-4-(trifluoromethyl)-1H-pyridin-2-one (2.80 g, 10.59 mmol, 1.00 equiv.) in CHCN (200 mL) was added KCO (4.39 g, 31.79 mmol, 3.00 equiv.) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 6 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature and concentrated. The resulting mixture was diluted with EtOAc (500 mL), washed with water (2×50 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE / EA (0% to 30%)) to give tert-butyl 2-(3-bromophenyl)-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (3 g, 53.0%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =533.1; 1 H NMR(300MHz,DMSO-d6)δ7.74-7.66(m,2H),7.52-7.42(m,3H),6.85(s,1H),6.27(s,1H),5.15-4.89( m,1H),3.46-3.36(m,2H),3.03-2.88(m,2H),2.51-2.46(m,2H),2.39(t,J=6.6Hz,2H),1.41(s,9H).

[0159] Step 4: Preparation of (3-bromophenyl)({5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl})acetic acid: To a stirred solution of tert-butyl 2-(3-bromophenyl)-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (3.00 g, 5.62 mmol, 1.00 equiv) in DCM (15 mL) was added TFA (15 mL) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by reverse-phase flash chromatography (C18 gel; MeCN / water (0.1% NH3.HO), 0% to 70% gradient in 40 min; UV 254 nm) to give (3-bromophenyl)({5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl})acetic acid (1.8 g, 67.0%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =477.1; 1 H NMR(400MHz,DMSO-d6)δ7.76-7.66(m,2H),7.63-7.60(m,1H),7.46-7.35(m,2H),6.83(s,1H) ,6.35(s,1H),5.19-5.00(m,1H),3.70-3.61(m,4H),2.73-2.65(m,2H),2.47(d,J=7.2Hz,2H). Intermediate 3 [ka]

[0160] Step 1: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4-fluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate: To a stirred solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (prepared according to WO 2021076890) (1.00 g, 2.21 mmol, 1.00 equiv.) and 2-bromo-3-methylphenol (0.50 g, 2.65 mmol, 1.20 equiv.) in dioxane (10 mL), Pd(PPh) (256 mg, 0.22 mmol, 0.10 equiv.) and KHPO (1.16 g, 6.64 mmol, 3.00 equiv.) were added dropwise under a nitrogen atmosphere at room temperature. The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere and then cooled to room temperature. The resulting mixture was diluted with EtOAc (200 mL), washed with water (2 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by reverse-phase flash chromatography (C18; mobile phase, MeCN / water (0.1% NH.H.sub.2O), 0% to 60% gradient in 40 min; detector: UV 254 nm) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4-fluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate (600 mg, 62.7%) as a colorless oil. LC-MS: (ES+H, m / z): [M+H] + =432.2; 1 H NMR(300MHz,DMSO-d6)δ9.09(s,1H),7.51(d,J=9.1Hz,2H),7.03(t,J=7.6Hz,2H),6.73(t,J=8.6Hz,2H),5.28(d,J=8.4Hz, 1H),4.06-4.01(m,2H),2.66(d,J=7.3Hz,2H),2.24(d,J=2.1Hz,3H),1.95(s,3H),1.35(d,J=4.5Hz,9H),1.18-1.13(m,3H).

[0161] Step 2: Preparation of ethyl (3S)-3-amino-3-{4-fluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate: To a stirred solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4-fluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate (600 mg, 1.39 mmol, 1 equiv.) in DCM (6 mL) was added dropwise HCl (gas) in 1,4-dioxane (3 mL, 4 M) under a nitrogen atmosphere at 0°C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. Upon completion, the resulting mixture was concentrated under reduced pressure to give ethyl (3S)-3-amino-3-{4-fluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate (600 mg, crude). LC-MS: (ES+H, m / z): [M+H] + =332.1. Intermediate 4 [ka]

[0162] Step 1: Preparation of tert-butyl 2-(3-methylphenyl)-2-oxoacetate: To a stirred solution of tert-butyl ethyl oxalate (10.00 g, 57.40 mmol, 1.00 equiv.) in THF (100 mL) was added bromo(3-methylphenyl)magnesium (68 mL, 68.88 mmol, 1.20 equiv., 1 M / L in THF) dropwise at −78° C. under a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 3 hours under a nitrogen atmosphere. The reaction was monitored by TLC (PE / EA=20 / 1, r=0.5). The reaction was quenched at −78° C. by the addition of saturated NH4Cl(aq.) (10 mL). The resulting mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA (gradient from 0% to 5% in 20 min)) to give tert-butyl 2-(3-methylphenyl)-2-oxoacetate (6.00 g, 45.1%) as a yellow oil. 1 H NMR (300MHz, DMSO-d6) δ7.72-7.65(m,2H), 7.63-7.49(m,2H), 2.41(s,3H), 1.59(s,9H).

[0163] Step 2: Preparation of tert-butyl 2-[3-(bromomethyl)phenyl]-2-oxoacetate: To a stirred solution of tert-butyl 2-(3-methylphenyl)-2-oxoacetate (6.00 g, 27.24 mmol, 1.00 equiv.) and NBS (5.82 g, 32.68 mmol, 1.20 equiv.) in MeCN (50 mL) was added AIBN (0.45 g, 2.72 mmol, 0.10 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 60 °C under a nitrogen atmosphere. The reaction was monitored by TLC (PE / EA = 20 / 1, r = 0.7). The resulting mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA (0% to 5% gradient in 20 min)) to give tert-butyl 2-[3-(bromomethyl)phenyl]-2-oxoacetate (4.00 g, 46.6%) as a yellow oil. 1 H NMR (300MHz, DMSO-d6) δ 8.01-7.96 (m, 1H), 7.88-7.81 (m, 2H), 7.67-7.56 (m, 1H), 4.84 (s, 2H), 1.59 (s, 9H).

[0164] Step 3: Preparation of tert-butyl 2-oxo-2-{3-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]phenyl}acetate: To a stirred solution of tert-butyl 2-[3-(bromomethyl)phenyl]-2-oxoacetate (8.00 g, 26.74 mmol, 1.00 equiv.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (8.15 g, 32.08 mmol, 1.20 equiv.) in dioxane (80 mL), KOAc (7.87 g, 80.22 mmol, 3.00 equiv.) and Pd(dppf)Cl-CHCl (2.18 g, 2.67 mmol, 0.10 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was then heated to 100 °C under a nitrogen atmosphere. After 3 h, the reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA (0% to 10% gradient over 30 min)) to give tert-butyl 2-oxo-2-{3-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]phenyl}acetate (6.00 g, 61.6%) as a yellow oil. 1 H NMR (300MHz, DMSO-d6) δ7.69-7.63(m,2H),7.56-7.44(m,2H),2.35(s,2H),1.59(s,9H),1.17(s,12H). Intermediate 5 [ka]

[0165] Step 1: Preparation of ethyl (3S)-3-{2'-bromo-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(tert-butoxycarbonyl)amino]propanoate: To a stirred mixture of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (2.00 g, 4.43 mmol, 1.00 equiv.) and 1-bromo-2-iodo-3-methylbenzene (1.45 g, 4.87 mmol, 1.10 equiv.) in dioxane (20 mL) and HO (2 mL), KCO (1.84 g, 13.29 mmol, 3.00 equiv.) and Pd(dppf)Cl (0.32 g, 0.44 mmol, 0.10 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature and then concentrated. The crude product was purified by silica gel column chromatography (PE / EA (0% to 20% gradient over 25 min)) to give ethyl (3S)-3-{2'-bromo-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(tert-butoxycarbonyl)amino]propanoate (1.4 g, 63.9%) as a pale yellow oil. LC-MS: (ES+H, m / z): [M+H] + =494.1; 1 H NMR(400MHz,DMSO-d6)δ7.57-7.47(m,2H),7.35-7.29(m,1H),7.21(t,J=7.6Hz,1H),7.08-6.96(m,2H),5.28(h,J=8.2,7.3Hz,1H),4.0 7-3.99(m,2H),2.67(t,J=7.5Hz,2H),2.26(t,J=1.3Hz,3H),2.01(d,J=8.5Hz,3H),1.33(d,J=2.9Hz,9H),1.12(td,J=7.1,4.5Hz,3H). 19 F NMR (377MHz, DMSO-d6) δ-125.96. Intermediate 6 [ka]

[0166] Step 1: Preparation of (3-bromo-5-chlorophenyl)(oxo)acetic acid: To a stirred mixture of 1-(3-bromo-5-chlorophenyl)ethanone (10.00 g, 42.82 mmol, 1.00 equiv.) in pyridine (100 mL) was added SeO (7.13 g, 64.24 mmol, 1.50 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was then cooled to room temperature and acidified to pH 5 with concentrated HCl. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (1 × 500 mL), dried over anhydrous NaSO, filtered, and concentrated to give (3-bromo-5-chlorophenyl)(oxo)acetic acid (12 g, crude) as a yellow solid. LC-MS: (ES-H, m / z): [MH] - =260.8; 1 H NMR (400MHz, DMSO-d6) δ8.15 (t, J = 1.9 Hz, 1H), 8.05 (t, J = 1.6 Hz, 1H), 7.97 (t, J = 1.7 Hz, 1H).

[0167] Step 2: Preparation of tert-butyl 2-(3-bromo-5-chlorophenyl)-2-oxoacetate: To a stirred mixture of (3-bromo-5-chlorophenyl)(oxo)acetic acid (11.00 g, 41.75 mmol, 1.00 equiv.) in DCM (200 mL) was added (Z)-N,N'-diisopropyl tert-butoxymethaneimidamide (16.73 g, 83.50 mmol, 2.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 500 mL). The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / CHCl (0% to 10% gradient in 30 min)) to afford tert-butyl 2-(3-bromo-5-chlorophenyl)-2-oxoacetate (7 g, 52.4%) as a yellow oil. 1H NMR (400MHz, DMSO-d6) δ8.21(dq,J=2.4,1.5Hz,1H),8.06(q,J=1.7Hz,1H),7.97(q,J=1.8Hz,1H),1.63(s,9H).

[0168] Step 3: Preparation of tert-butyl 2-(3-bromo-5-chlorophenyl)-2-hydroxyacetate: To a stirred mixture of tert-butyl 2-(3-bromo-5-chlorophenyl)-2-oxoacetate (2.40 g, 7.51 mmol, 1.00 equiv.) and CHCOH (1.5 mL) in CHCHOH (15 mL) was added NaBHCN (519 mg, 8.26 mmol, 1.10 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The reaction was quenched with water (200 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×250 mL). The combined organic layers were washed with brine (1×200 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / CHCl (gradient of 0% to 50% in 30 min) to give tert-butyl 2-(3-bromo-5-chlorophenyl)-2-hydroxyacetate (1.6 g, 66.2%) as a white solid. LC-MS: (ES-H, m / z): [MH] - =318.9; 1 H NMR(300MHz,DMSO-d6)δ7.68(t,J=1.9Hz,1H),7.57-7.52(m,1H),7.46(ddd,J= 2.0,1.4,0.6Hz,1H),6.25(d,J=5.8Hz,1H),5.08(d,J=5.8Hz,1H),1.36(s,9H).

[0169] Step 4: Preparation of tert-butyl 2-(3-bromo-5-chlorophenyl)-2-(methanesulfonyloxy)acetate: To a stirred mixture of tert-butyl 2-(3-bromo-5-chlorophenyl)-2-hydroxyacetate (1.60 g, 4.97 mmol, 1.00 equiv.) and NEt (755 mg, 7.46 mmol, 1.50 equiv.) in DCM (15 mL) was added MsCl (684 mg, 5.97 mmol, 1.20 equiv.) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (1 × 400 mL), dried over anhydrous NaSO, filtered, and concentrated to give tert-butyl 2-(3-bromo-5-chlorophenyl)-2-(methanesulfonyloxy)acetate (2 g, crude) as a white solid. LC-MS: (ES-H, m / z): [MH] - =396.9;

[0170] Step 5: Preparation of tert-butyl 2-(3-bromo-5-chlorophenyl)-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate: To a stirred mixture of tert-butyl 2-(3-bromo-5-chlorophenyl)-2-(methanesulfonyloxy)acetate (1.82 g, 4.54 mmol, 1.20 equiv.) and 5-[2-(3-fluoroazetidin-1-yl)ethyl]-4-(trifluoromethyl)-1H-pyridin-2-one (1.00 g, 3.78 mmol, 1.00 equiv.) in MeCN (10 mL), KCO (1.05 g, 7.57 mmol, 2.00 equiv.) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 80° C. under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3×500 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18; mobile phase, MeCN / water (0.1% HCOH), 0% to 30% gradient in 10 min; detector: UV 220 nm) to give tert-butyl 2-(3-bromo-5-chlorophenyl)-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (1.1 g, 51.1%) as a colorless oil. LC-MS: (ES+H, m / z): [M+H] + =567.1.

[0171] Step 6: Preparation of (3-bromo-5-chlorophenyl)({5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl})acetic acid: To a stirred mixture of tert-butyl 2-(3-bromo-5-chlorophenyl)-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (1.00 g, 1.76 mmol, 1.00 equiv.) in DCM (4 mL) was added TFA (4 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18; mobile phase, MeCN / water (0.1% NH3.HO), 0% to 20% gradient in 30 min; detector: UV 220 nm) to give (3-bromo-5-chlorophenyl)({5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl})acetic acid (800 mg, 88.7%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =511.0; 1 H NMR(300MHz,DMSO-d6)δ7.85(s,1H),7.75(t,J=1.8Hz,1H),7.65(t,J=1.6Hz,1H),7.56(q,J=2.1,1.7Hz,1H),6.82(d ,J=5.2Hz,1H),6.30(s,1H),5.31-5.04(m,2H),3.46(d,J=23.4Hz,4H),2.82(d,J=7.3Hz,2H),2.55(t,J=3.5Hz,2H). 19 F NMR(282MHz,DMSO-d6)δ-62.20,-177.84. Intermediates 7 and 8 [ka]

[0172] Step 1: Preparation of ethyl (3S)-3-amino-3-[5-bromo-2-fluoro-3-(trifluoromethyl)phenyl]propanoate hydrochloride: To a stirred solution of ethyl (3S)-3-[5-bromo-2-fluoro-3-(trifluoromethyl)phenyl]-3-{[(S)-2-methylpropane-2-sulfinyl]amino}propanoate (prepared according to WO 2021076890) (10.00 g, 21.63 mmol, 1.00 equiv.) in DCM (15 mL) was added dropwise HCl (gas) in 1,4-dioxane (30 mL, 4 M) under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature for an additional 1.5 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give crude ethyl (3S)-3-amino-3-[5-bromo-2-fluoro-3-(trifluoromethyl)phenyl]propanoate hydrochloride (11.50 g) as a yellow oil. The crude product mixture was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =359.9.

[0173] Step 2: Preparation of ethyl (3S)-3-[5-bromo-2-fluoro-3-(trifluoromethyl)phenyl]-3-[(tert-butoxycarbonyl)amino]propanoate: To a stirred solution of ethyl (3S)-3-amino-3-[5-bromo-2-fluoro-3-(trifluoromethyl)phenyl]propanoate hydrochloride (11.50 g, estimated 100% yield, 32.11 mmol, 1.00 equiv.) in DCM (100 mL) was added dropwise DIEA (16.64 g, 128.76 mmol, 4.01 equiv.) and BocO (14.02 g, 64.22 mmol, 2.00 equiv.) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL) and extracted with CHCl (3 × 120 mL). The combined organic layers were washed with brine (2 × 40 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE / EA (5% to 25% gradient in 20 min)) to give ethyl (3S)-3-[5-bromo-2-fluoro-3-(trifluoromethyl)phenyl]-3-[(tert-butoxycarbonyl)amino]propanoate (3.80 g, 38.7%, in two steps) as a white solid. LC-MS: (ES+H, m / z): [M+H-tBu] + =404.1; 1 H NMR(300MHz,CDCl3):δ7.69(dd,J=6.1,2.5Hz,1H),7.64(dd,J=6.0,2.5Hz,1H),5.76(s,1H), 5.30(s,1H),4.10(q,J=7.1Hz,2H),2.85(d,J=5.8Hz,2H),1.43(s,9H),1.19(t,J=7.1Hz,3H). 19 F NMR (282MHz, CDCl3) δ-61.41,-121.99.

[0174] Step 3: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl]propanoate: To a stirred solution of ethyl (3S)-3-[5-bromo-2-fluoro-3-(trifluoromethyl)phenyl]-3-[(tert-butoxycarbonyl)amino]propanoate (6.60 g, 14.40 mmol, 1.00 equiv.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.66 g, 14.40 mmol, 1.00 equiv.) in 1,4-dioxane (80 mL), KOAc (4.24 g, 43.20 mmol, 3.00 equiv.) and Pd(dppf)Cl.CHCl (1.17 g, 1.44 mmol, 0.10 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 110 °C for an additional 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3×30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10% to 30% gradient in 20 min) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl]propanoate (6.2 g, 85.1%) as a yellow oil. LC-MS: (ES+H, m / z): [M+Na] + =528.4; 1 H NMR (400MHz, CDCl3): δ7.96(d,J=3.1Hz,1H),7.95(d,J=3.2Hz,1H),5.58(s,1H),5.37(s,1H),4.08(q ,J=7.1Hz,2H),2.83(q,J=8.9,8.3Hz,2H),1.43(s,9H),1.34(d,J=1.6Hz,12H),1.18(t,J=7.1Hz,3H). 19 F NMR (377MHz, CDCl3) δ-61.09,-116.29.

[0175] Step 4: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-fluoro-2'-hydroxy-4',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate: To a stirred solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl]propanoate (750 mg, 1.48 mmol, 1.00 equiv.) and 2-bromo-3,5-dimethylphenol (298 mg, 1.48 mmol, 1.00 equiv.) in 1,4-dioxane (10 mL) and HO (0.5 mL), Pd(dppf)Cl.CHCl (120 mg, 0.14 mmol, 0.10 equiv.) and KCO (615 mg, 4.45 mmol, 3.00 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for an additional 2 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (1 × 8 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE / EA (10% to 40% gradient in 10 min)) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-fluoro-2'-hydroxy-4',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate (510 mg, 68.7%) as a pale yellow oil. LC-MS: (ES+H, m / z): [M+H] + =500.2; 1 H NMR(400MHz,CDCl3)δ7.50(d,J=6.4Hz,1H),7.44(d,J=6.3Hz,1H),6.69(s,1H),6.65(s,1H),5.79(s,1H),5.39(s,1H) ,4.65(s,1H),4.07(dd,J=12.9,5.6Hz,2H),2.90(s,2H),2.31(s,3H),2.00(s,3H),1.41(s,9H),1.18(t,J=6.9Hz,3H).

[0176] Step 5: Preparation of ethyl (3S)-3-amino-3-[4-fluoro-2'-hydroxy-4',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate hydrochloride: To a stirred solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-fluoro-2'-hydroxy-4',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate (480 mg, 0.96 mmol, 1.00 equiv.) in DCM (7 mL) was added dropwise HCl (gas) in 1,4-dioxane (5 mL, 4 M) under a nitrogen atmosphere at 0°C. The resulting mixture was stirred at room temperature for an additional 1 hour. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure to give ethyl (3S)-3-amino-3-[4-fluoro-2'-hydroxy-4',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate hydrochloride (510 mg, crude) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] += 400.1. Intermediate 9 [ka]

[0177] Step 1: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-fluoro-2'-hydroxy-6'-methyl-4',5-bis(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate: A mixture of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl]propanoate (750 mg, 1.48 mmol, 1.00 equiv), 2-iodo-3-methyl-5-(trifluoromethyl)phenol (471 mg, 1.56 mmol, 1.05 equiv), Pd(dppf)Cl (109 mg, 0.15 mmol, 0.10 equiv) and KCO (410 mg, 2.97 mmol, 2.00 equiv) in dioxane (10 mL) and HO (0.5 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 h and then cooled to room temperature. The residue was purified by silica gel column chromatography (PE / EA (0% to 30% in 20 min)) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-fluoro-2'-hydroxy-6'-methyl-4',5-bis(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate (580 mg, 70.6%) as an off-white solid. LC-MS: (ES+H, m / z): [M+H] + =554.25; 1 H NMR(300MHz,CDCl3)δ7.51(d,J=6.4Hz,1H),7.45(dd,J=6.5,2.1Hz,1H),7.10(d,J=7.9Hz,2H),5.84(s,1H),5. 39(d,J=6.8Hz,1H),4.19-4.06(m,2H),2.94(d,J=5.7Hz,2H),2.09(s,3H),1.43(s,9H),1.21(t,J=7.1Hz,3H). 19 F NMR (282MHz, CDCl3) δ-61.14,-61.19,-62.99,-120.65.

[0178] Step 2: Preparation of ethyl (3S)-3-amino-3-[4-fluoro-2'-hydroxy-6'-methyl-4',5-bis(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate: A solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-fluoro-2'-hydroxy-6'-methyl-4',5-bis(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate (500 mg, 0.90 mmol, 1.00 equiv.) and HCl (gas) in 1,4-dioxane (4 M, 5 mL) in DCM (5 mL) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give ethyl (3S)-3-amino-3-[4-fluoro-2'-hydroxy-6'-methyl-4',5-bis(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate (500 mg, crude) as a colorless oil. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =454.10. Intermediate 10 [ka]

[0179] Step 1: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-fluoro-2'-hydroxy-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate: To a stirred solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl]propanoate (1.80 g, 3.56 mmol, 1.00 equiv.) and 2-bromo-3-methylphenol (0.80 g, 4.27 mmol, 1.20 equiv.) in dioxane (50 mL) was added dropwise Pd(PPh) (0.41 g, 0.36 mmol, 0.10 equiv.) and KHPO (1.86 g, 10.68 mmol, 3.00 equiv.) in HO (5 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (200 mL) and washed with water (2 × 30 mL). The combined organic layers were washed with brine (1 × 30 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by reverse-phase flash chromatography (C18; mobile phase, MeCN / water (0.1% NH.H.O), 0% to 70% gradient in 40 min; detector: UV 220 nm) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-fluoro-2'-hydroxy-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate (0.8 g, 46.2%) as a brown solid. LC-MS: (ES-H, m / z): [MH] -= 484.1; 1 H NMR(300MHz,DMSO-d6)δ9.55(s,1H),7.77-7.53(m,2H),7.43(dd,J=6.6,2.1Hz,1H),7.09(t,J=7.8Hz,1H),6.87(d,J=8.1Hz,1H),6 .75(d,J=7.5Hz,1H),5.33(q,J=7.9Hz,1H),4.08-3.97(m,2H),2.86-2.65(m,2H),1.98(s,3H),1.34(s,9H),1.11(t,J=7.1Hz,3H).

[0180] Step 2: Preparation of ethyl (3S)-3-amino-3-[4-fluoro-2'-hydroxy-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate: To a stirred solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-fluoro-2'-hydroxy-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate (0.80 g, 1.65 mmol, 1.00 equiv.) in CHCl (4 mL) was added dropwise at room temperature under a nitrogen atmosphere with HCl (gas) in 1,4-dioxane (8 mL, 4 M). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The crude product, ethyl (3S)-3-amino-3-[4-fluoro-2'-hydroxy-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate (800 mg, crude), was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =386.1. Intermediate 11 [ka]

[0181] Step 1: Preparation of (5-bromo-2-fluorophenyl)(oxo)acetic acid: A mixture of 1-(5-bromo-2-fluorophenyl)ethanone (10.00 g, 46.07 mmol, 1.00 equiv.) and SeO (10.23 g, 92.15 mmol, 2.00 equiv.) in pyridine (20 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by TLC (CHCl:MeOH = 10:1). The resulting mixture was diluted with 1 N HCl (aq.) (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (CHCl / MeOH (gradient from 0% to 10% over 20 min)) to give (5-bromo-2-fluorophenyl)(oxo)acetic acid (5.4 g, 47.5%) as a yellow oil.1 H NMR (300MHz, DMSO-d6) δ7.95-7.80 (m, 2H), 7.35 (t, J = 9.3Hz, 1H).

[0182] Step 2: Preparation of tert-butyl 2-(5-bromo-2-fluorophenyl)-2-oxoacetate: To a stirred solution of (5-bromo-2-fluorophenyl)(oxo)acetic acid (1.40 g, 5.66 mmol, 1.00 equiv.) in tetrahydrofuran (10 mL), N,N'-diisopropyl tert-butoxymethaneimidamide (3.97 g, 19.83 mmol, 3.50 equiv.) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C under a nitrogen atmosphere for 3 hours. The reaction was monitored by TLC (PE / EtOAc = 5 / 1). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (0% to 20% gradient in 30 min) to afford tert-butyl 2-(5-bromo-2-fluorophenyl)-2-oxoacetate (1.3 g, 75.7%) as a colorless oil. 1 H NMR (300MHz, DMSO-d6) δ8.08-7.94 (m, 2H), 7.48 (dd, J=10.6, 8.8Hz, 1H), 1.54 (s, 9H).

[0183] Step 3: Preparation of tert-butyl 2-(5-bromo-2-fluorophenyl)-2-hydroxyacetate: A mixture of tert-butyl 2-(5-bromo-2-fluorophenyl)-2-oxoacetate (900 mg, 2.96 mmol, 1.00 equiv.) and NaBHCN (205 mg, 3.26 mmol, 1.10 equiv.) in (EtOH:HCOOH=8:1) was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by TLC (PE / EtOAc=5:1). The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (1×50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 2-(5-bromo-2-fluorophenyl)-2-hydroxyacetate (864 mg, 95.4%) as a yellow oil. 1 H NMR (300MHz, DMSO-d6) δ7.61(dd,J=6.4,2.6Hz,1H),7.56(ddd,J=8.7,4.6,2.6Hz,1H),7.31-7.15(m,1H),5.18(s,1H),1.35(s,9H).

[0184] Step 5: Preparation of tert-butyl 2-(5-bromo-2-fluorophenyl)-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate To a stirred mixture of tert-butyl 2-(5-bromo-2-fluorophenyl)-2-(methanesulfonyloxy)acetate (942 mg, 2.46 mmol, 1.30 equiv.) and 5-[2-(3-fluoroazetidin-1-yl)ethyl]-4-(trifluoromethyl)-1H-pyridin-2-one (500 mg, 1.89 mmol, 1.00 equiv.) in CHCN (10 mL) was added KCO (784 mg, 5.67 mmol, 3.00 equiv.) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 6 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0% to 30% gradient in 40 min)) to give tert-butyl 2-(5-bromo-2-fluorophenyl)-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (720 mg, 69.0%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =551.1; 1 H NMR(300MHz,DMSO-d6)δ7.74(ddd,J=8.8,4.6,2.5Hz,1H),7.68-7.59(m,2H),7.37(dd,J=10.1,8.8Hz,1H),6.87(s,1H),6.51(s ,1H),5.16-4.89(m,1H),3.44(ddd,J=15.5,8.5,5.9Hz,2H),2.98(ddt,J=24.1,8.8,4.5Hz,2H),2.58-2.38(m,4H),1.41(s,9H).

[0185] Step 6: Preparation of (5-bromo-2-fluorophenyl)({5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl})acetic acid: To a stirred solution of tert-butyl 2-(5-bromo-2-fluorophenyl)-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (600 mg, 1.08 mmol, 1.00 equiv.) in CHCl (15 mL) was added TFA (15 mL) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 gel; mobile phase, MeCN / water (0.1% NH3.HO), 0% to 30% gradient in 25 min; detector: UV 254 nm) to give (5-bromo-2-fluorophenyl)({5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl})acetic acid (511 mg, 94.8%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =495.0. Intermediates 12 and 13 [ka]

[0186] Step 1: Preparation of 4-chloro-2-cyclopropyl-1-fluorobenzene: To a stirred solution of 4-chloro-1-fluoro-2-iodobenzene (50.00 g, 194.97 mmol, 1.00 equiv.) and cyclopropylboronic acid (25.12 g, 292.46 mmol, 1.50 equiv.) in PhCH (800 mL), Pd(OAc) (4.38 g, 19.49 mmol, 0.10 equiv.), tricyclohexylphosphane (10.94 g, 38.99 mmol, 0.20 equiv.), and CsCO (127.05 g, 389.95 mmol, 2.00 equiv.) in HO (80 mL) were added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 6 h and then cooled to room temperature. The resulting mixture was diluted with EtOAc (500 mL). The resulting mixture was washed with water (2 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (0% to 10% gradient over 30 min) to give 4-chloro-2-cyclopropyl-1-fluorobenzene (30 g, crude) as a tan oil. 1 H NMR(300MHz,CDCl3)δ7.40-7.06(m,1H),6.95(dd,J=9.6,8.7Hz,1H),6.86(dd ,J=6.6,2.6Hz,1H),2.13-2.03(m,1H),1.07-0.99(m,2H),0.77-0.71(m,2H).

[0187] Step 2: Preparation of 5-chloro-3-cyclopropyl-2-fluorobenzaldehyde: To a stirred solution of 4-chloro-2-cyclopropyl-1-fluorobenzene (15.00 g, 87.92 mmol, 1.00 equiv) in THF (150 mL) was added LDA (66 mL, 131.88 mmol, 1.50 equiv, 2 M in THF) dropwise at −78° C. under a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 1 hour under a nitrogen atmosphere. To the above mixture was added DMF (22.5 mL) dropwise at −78° C. The resulting mixture was stirred at −78° C. for an additional 3 hours. The reaction was monitored by LCMS. The reaction was quenched by adding water (10 mL) at −60° C. The resulting mixture was stirred at −60° C. for 15 hours. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (0% to 5% gradient in 30 min) to give 5-chloro-3-cyclopropyl-2-fluorobenzaldehyde (12 g, 65.5%) as a yellow solid. 1 H NMR (300MHz, CDCl3) δ10.34(s,1H),7.63-7.50(m,1H),7.10(dd,J=6.4,2.7Hz,1H),2.14-2.12(m,1H),1.15-1.08(m,2H),0.81-0.76(m,2H).

[0188] Step 3: Preparation of (S)—N-[(1E)-(5-chloro-3-cyclopropyl-2-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide: To a stirred solution of 5-chloro-3-cyclopropyl-2-fluorobenzaldehyde (12.00 g, 60.41 mmol, 1.00 equiv.) and (R)-2-methylpropane-2-sulfinamide (8.79 g, 72.50 mmol, 1.20 equiv.) in THF (150 mL) was added titanium(IV) isopropoxide (25.76 g, 90.62 mmol, 1.50 equiv.) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (20 mL). The reaction was quenched by adding water (20 mL) at room temperature. The resulting mixture was stirred at room temperature for 5 minutes. The precipitated solid was collected by filtration. The resulting mixture was diluted with water (150 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by silica gel column chromatography eluting with PE / EtOAc (0% to 10% gradient in 30 min) to give (S)—N-[(1E)-(5-chloro-3-cyclopropyl-2-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide (15 g, 78.1%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =302.0. 1 H NMR(300MHz,DMSO-d6)δ8.65(s,1H),7.71(dd,J=5.6,2.7Hz,1H),7.29(dd,J=6.5,2.7H z,1H),2.15-2.06(m,1H),1.19(d,J=1.5Hz,9H),1.06-1.02(m,2H),0.87-0.84(m,2H).

[0189] Step 4: Preparation of ethyl (3S)-3-(5-chloro-3-cyclopropyl-2-fluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate: To a stirred solution of Zn (5.80 g, 88.69 mmol, 6.00 equiv.) and TMSCl (0.80 g, 7.39 mmol, 0.50 equiv.) in THF (50 mL) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60° C. for 1 hour under a nitrogen atmosphere. To the above mixture, 2-bromoethyl acetate (7.41 g, 44.34 mmol, 3.00 equiv.) was added dropwise at room temperature. The resulting mixture was stirred at 60° C. for an additional 1 hour. To the above mixture, (S)—N-[(1E)-(5-chloro-3-cyclopropyl-2-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide (5.00 g, 16.56 mmol, 1.00 equiv.) was added at 0° C. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (10 mL). The reaction was quenched by adding water (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 5 minutes. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (2 × 150 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (0% to 10% gradient in 30 minutes) to give ethyl (3S)-3-(5-chloro-3-cyclopropyl-2-fluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate (4.2 g, 69.23%) as a yellow oil. LC-MS: (ES+H, m / z): [M+H] + =390.1. 1 H NMR(300MHz,DMSO-d6)δ7.32(dd,J=5.9,2.6Hz,1H),6.93(dd,J=6.3,2.6Hz,1H),5.76(d,J=7.0Hz,1H),4.95-4.93(m,1H),4.05-4.01(m,2H),2.98 (dd,J=15.5,7.3Hz,1H),2.83(dd,J=15.5,7.4Hz,1H),2.07-1.98(m,1H), 1.11(t,J=7.1Hz,3H),1.05(s,9H),0.98-0.97(m,2H),0.77-0.75(m,2H).

[0190] Step 5: Preparation of ethyl (3S)-3-amino-3-(5-chloro-3-cyclopropyl-2-fluorophenyl)propanoate: To a stirred solution of ethyl (3S)-3-(5-chloro-3-cyclopropyl-2-fluorophenyl)-3-{[(S)-2-methylpropane-2-sulfinyl]amino}propanoate (4.20 g, 10.77 mmol, 1.00 equiv.) in CHCl (5 mL) was added dropwise at room temperature HCl (gas) in 1,4-dioxane (30 mL, 4 M). The resulting mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18; mobile phase, MeCN / water (0.1% NH3.HO), 10% to 60% gradient in 30 min; detector: UV 254 nm) to give ethyl (3S)-3-amino-3-(5-chloro-3-cyclopropyl-2-fluorophenyl)propanoate (2.3 g, 71.0%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =286.0. 1 H NMR(300MHz,DMSO-d6)δ7.38(dd,J=6.0,2.7Hz,1H),6.87(dd,J=6.3,2.7Hz,1H),4.45(dd,J=7.8,6.2Hz,1H),4.03( q,J=7.1Hz,2H),2.64-2.54(m,3H),2.07-1.98(m,1H),1.13(t,J=7.1Hz,3H),0.99-0.96(m,2H),0.76-0.73(m,2H).

[0191] Step 6: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-(5-chloro-3-cyclopropyl-2-fluorophenyl)propanoate: To a stirred solution of ethyl (3S)-3-amino-3-(5-chloro-3-cyclopropyl-2-fluorophenyl)propanoate (2.30 g, 8.04 mmol, 1.00 equiv.) and BocO (2.64 g, 12.07 mmol, 1.50 equiv.) in CHCl (30 mL) was added DIEA (3.12 g, 24.14 mmol, 3.00 equiv.) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with CHCl (3×200 mL). The combined organic layers were washed with brine (1×200 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by silica gel column chromatography eluting with PE / EtOAc (0% to 10% gradient in 30 min) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-(5-chloro-3-cyclopropyl-2-fluorophenyl)propanoate (2.6 g, 79.5%) as a white solid. LC-MS: (ES-H, m / z): [MH] - =384.0. 1 H NMR(300MHz,DMSO-d6)δ7.58(d,J=8.8Hz,1H),7.23(dd,J=6.0,2.6Hz,1H),6.92(dd,J=6.2,2.6Hz,1H),5.26-5.18(m,1H),4.06- 4.02(m,2H),2.69-2.65(m,2H),2.05-2.02(m,1H),1.36(s,9H),1.13(t,J=7.1Hz,3H),1.01-0.97(m,2H),0.77(t,J=5.1Hz,2H).

[0192] Step 7: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[3-cyclopropyl-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate: To a stirred solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-(5-chloro-3-cyclopropyl-2-fluorophenyl)propanoate (2.60 g, 6.73 mmol, 1.00 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.05 g, 8.08 mmol, 1.20 equiv) in dioxane (40 mL) was added XPhos Pd G3 (0.57 g, 0.67 mmol, 0.10 equiv), XPhos (0.64 g, 1.34 mmol, 0.20 equiv) and KOAc (1.98 g, 20.21 mmol, 3.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3×200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (0% to 30% gradient in 30 minutes) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[3-cyclopropyl-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (3 g, 74.6%) as a red oil. LC-MS: (ES+H, m / z): [M+H-tBu] + =422.2. 1 H NMR(300MHz,DMSO-d6)δ7.67-7.51(m,2H),7.15-7.04(m,1H),5.27-5.19(m,1H),4.07-3.99(m,2H),2.75-2.58(m,2H) ),2.08-2.00(m,1H),1.28(d,J=2.0Hz,12H),1.12(d,J=7.1Hz,3H),1.07(s,9H),0.99-096(m,2H),0.71-0.63(m,2H).

[0193] Step 8: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{5-cyclopropyl-4-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl}propanoate: To a stirred solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[3-cyclopropyl-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (1.40 g, 2.93 mmol, 1.00 equiv.) and 2-bromo-3-methylphenol (0.66 g, 3.52 mmol, 1.20 equiv.) in dioxane (15 mL) and HO (1.5 mL), Pd(dppf)Cl.CHCl (0.21 g, 0.29 mmol, 0.10 equiv.) and KCO (1.22 g, 8.78 mmol, 3.00 equiv.) were added portionwise at room temperature. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3×100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (0% to 30% gradient in 30 min) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{5-cyclopropyl-4-fluoro-2′-hydroxy-6′-methyl-[1,1′-biphenyl]-3-yl}propanoate (760 mg, 53.8%) as a red oil. LC-MS: (ES+H, m / z): [M+H] + =458.2. 1 H NMR(300MHz,DMSO-d6)δ9.10(s,1H),7.53(d,J=8.9Hz,1H),7.06-6.95(m,2H ),6.72(t,J=7.8Hz,2H),6.62(dd,J=7.1,2.1Hz,1H),5.30(d,J=8.2Hz,1H), 4.12-4.00(m,2H),2.66(d,J=7.5Hz,2H),2..11-2.04(m,1H),1.93(s,3H),1 .34(s,9H),1.14(t,J=7.1Hz,3H),1.00-0.92(m,2H),0.69(t,J=4.1Hz,2H).

[0194] Step 9: Preparation of ethyl (3S)-3-amino-3-{5-cyclopropyl-4-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl}propanoate: To a stirred solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{5-cyclopropyl-4-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl}propanoate (660 mg, 1.44 mmol, 1.00 equiv.) in CHCl (5 mL, 103.78 mmol, 71.97 equiv.), HCl (gas) in 1,4-dioxane (40 mL, 4 M) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give ethyl (3S)-3-amino-3-{5-cyclopropyl-4-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl}propanoate (540 mg, crude) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =358.10. Intermediate 14 [ka]

[0195] Step 1: Preparation of 3-cyclopropyl-5-methylphenol: To a stirred mixture of 3-bromo-5-methylphenol (10.00 g, 53.47 mmol, 1.00 equiv.) and cyclopropylboronic acid (6.89 g, 80.20 mmol, 1.50 equiv.) in toluene (400 mL) and HO (40 mL), Pd(OAc) (1.20 g, 5.35 mmol, 0.10 equiv.), PCy (3.00 g, 10.69 mmol, 0.20 equiv.), and KPO (34.05 g, 160.40 mmol, 3.00 equiv.) were added at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The mixture was allowed to cool to room temperature and concentrated. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (0-20% gradient in 30 min) to give 3-cyclopropyl-5-methylphenol (3.5 g, 44.1%) as a yellow liquid. LC-MS: (ES-H, m / z): [MH] - =147.0. 1 H NMR(300MHz,CDCl3)δ6.52(tt,J=1.4,0.7Hz,1H),6.46(tt,J=1.5,0.7Hz,1H),6.36(t,J=2.0Hz,1H), 4.64(s,1H),2.29(d,J=0.8Hz,3H),1.83(tt,J=8.4,5.1Hz,1H),1.00-0.89(m,2H),0.74-0.63(m,2H).

[0196] Step 2: Preparation of 5-cyclopropyl-2-iodo-3-methylphenol: To a stirred solution of 3-cyclopropyl-5-methylphenol (3.50 g, 23.62 mmol, 1.00 equiv) in toluene (200 mL) was added NaH (1.89 g, 47.23 mmol, 2.00 equiv, 60%) portionwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 30 minutes under a nitrogen atmosphere. To the above mixture was added iodine (5.99 g, 23.62 mmol, 1.00 equiv) portionwise at 0° C. The resulting mixture was stirred at 0° C. for an additional 1 hour. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (100 mL). The mixture was acidified to pH 5 with HCl (aq, 1N). The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (3 x 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / CHCl2 (0-20% gradient in 30 min) to give 5-cyclopropyl-2-iodo-3-methylphenol (1.50 g, 23.1%) as a white liquid. LCMS: (ES-H, m / z): [MH] - =272.9. 1 H NMR(300MHz,CDCl3)δ6.58(d,J=2.1Hz,1H),6.52(d,J=2.1Hz,1H),5.34(s,1H),2.39 (t,J=0.7Hz,3H),1.79(tt,J=8.4,5.0Hz,1H),0.99-0.91(m,2H),0.71-0.61(m,2H).

[0197] Step 3: Preparation of (S)-ethyl 3-((tert-butoxycarbonyl)amino)-3-(4'-cyclopropyl-4-fluoro-2'-hydroxy-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate: To a stirred mixture of (S)-ethyl 3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl)propanoate (1.00 g, 1.98 mmol, 1.00 equiv.) and 5-cyclopropyl-2-iodo-3-methylphenol (0.65 g, 2.38 mmol, 1.20 equiv.) in 1,4-dioxane (20 mL) and HO (1 mL), Pd(dppf)Cl.CHCl (0.14 g, 0.20 mmol, 0.10 equiv.) and KCO (0.55 g, 3.96 mmol, 2.00 equiv.) were added at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (3×200 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by silica gel column chromatography eluting with PE / EtOAc (0-20% gradient in 30 min) to give the crude product (490 mg), which was further purified by preparative SFC (column: NB_CHIRALPAK AD-H Purification using a 3 × 25 cm, 5 μm column; mobile phase A: CO₂, mobile phase B: EtOH; flow rate: 100 mL / min; gradient: isocratic 25% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220 / 202 nm; RT1 (min): 3.03; RT2 (min): 7.18; sample solvent: EtOH; injection volume: 4 mL gave ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-cyclopropyl-4-fluoro-2'-hydroxy-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate (350 mg, 33.6%) as a white solid. LC-MS: (ES-H, m / z): [MH] - =524.2. 1H NMR(300MHz,CD3OD)δ7.47(dd,J=6.7,2.2Hz,1H),7.39(dd,J=6.7,2.2Hz,1H),6.52(d,J=1.7Hz,1H),6.44(d,J=1.7Hz,1H),5.40(s,1H),4.10(qd,J=7 .2,1.1Hz,2H),2.90-2.70(m,2H),1.98(s,3H),1.81(tt,J=8.3,5.0Hz,1H) ,1.40(s,9H),1.20(t,J=7.1Hz,3H),1.00-0.87(m,2H),0.77-0.62(m,2H).

[0198] Step 4: Preparation of (S)-3-amino-3-(4'-cyclopropyl-4-fluoro-2'-hydroxy-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate ethyl hydrochloride: To a stirred solution of (S)-ethyl 3-((tert-butoxycarbonyl)amino)-3-(4'-cyclopropyl-4-fluoro-2'-hydroxy-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate (350 mg, 0.67 mmol, 1.00 equiv.) in CHCl (5 mL) was added dropwise at room temperature under a nitrogen atmosphere to HCl (gas) in 1,4-dioxane (5 mL, 4 M). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure to give ethyl (S)-3-amino-3-(4'-cyclopropyl-4-fluoro-2'-hydroxy-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate hydrochloride (400 mg, crude) as a white oil. LC-MS: (ES+H, m / z): [M+H] + =426.1 Intermediate 15 [ka]

[0199] Step 1: Preparation of (S)-ethyl 3-((tert-butoxycarbonyl)amino)-3-(4'-chloro-4-fluoro-2'-hydroxy-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate: A mixture of (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl]propanoate (700 mg, 1.39 mmol, 1.00 equiv.), 5-chloro-2-iodo-3-methylphenol (446 mg, 1.66 mmol, 1.20 equiv.), Pd(PPh3)4 (160 mg, 0.13 mmol, 0.10 equiv.), and K2HPO4 (723 mg, 4.15 mmol, 3.00 equiv.) in 1,4-dioxane / water = 10 / 1 (11 mL) was stirred overnight at 90 °C under a nitrogen atmosphere. The desired product could be detected by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (30 mL). The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were concentrated under reduced pressure, and the crude product was purified by reverse-phase flash chromatography (C18; mobile phase, MeCN / water (0.1% NH H O), 30% to 60% gradient in 30 min; detector: UV 220 nm) to give ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4′-chloro-4-fluoro-2′-hydroxy-6′-methyl-5-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)propanoate (270 mg, 46.4%) as a white solid. LC-MS: (ES+H, m / z): [M+H-tBu] + =464.1.

[0200] Step 2: Preparation of (S)-ethyl 3-amino-3-(4'-chloro-4-fluoro-2'-hydroxy-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate: A solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4'-chloro-4-fluoro-2'-hydroxy-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate (300 mg, 0.57 mmol, 1.00 equiv.) and HCl (gas) in 1,4-dioxane (5 mL, 4 M) in CHCl (2 mL) was stirred at room temperature under a nitrogen atmosphere for 1 hour. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure to give the HCl salt of ethyl (S)-3-amino-3-(4'-chloro-4-fluoro-2'-hydroxy-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate (300 mg, crude) as an off-white solid. LC-MS: (ES-H, m / z): [MH] - =418.1. Intermediate 16 [ka]

[0201] To a solution of 2,5-xylenol (11.00 g, 90.04 mmol, 1.00 equiv.) and bis(propan-2-yl)amine (0.91 g, 9.00 mmol, 0.10 equiv.) in CHCl (800 mL) was added NBS (16.03 g, 90.04 mmol, 1.00 equiv.) in CHCl (800 mL) dropwise over 3 h. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was monitored by TLC (PE:EtOAc = 8:1, Rf = 0.5). The mixture was acidified to pH 1 with concentrated HCl (1 M), and the resulting phases were separated. The organic phase was washed with HO (200 mL) and dried over NaSO. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (gradient of 5% to 20% in 20 min) to give 2-bromo-3,6-dimethylphenol (10.50 g, 58.0%) as a colorless liquid. 1H NMR (400MHz, CDCl3): δ6.94 (d, J = 7.6 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H), 5.66 (s, 1H), 2.35 (s, 3H), 2.26 (s, 3H).

[0202] Step 2: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-fluoro-2'-hydroxy-3',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate: To a stirred solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl]propanoate (610 mg, 1.20 mmol, 1.00 equiv.) and 2-bromo-3,6-dimethylphenol (242 mg, 1.20 mmol, 1.00 equiv.) in 1,4-dioxane (10 mL) and HO (0.5 mL), Pd(dppf)Cl.CHCl (98 mg, 0.12 mmol, 0.10 equiv.) and KCO (500 mg, 3.62 mmol, 3.00 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for an additional 2 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10% to 50% gradient in 10 min) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-fluoro-2'-hydroxy-3',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate (460 mg, 76.2%) as a yellow oil. LC-MS: (ES+H, m / z): [M+Na] + =522.2. 1H NMR (400MHz, CDCl3): δ7.52(dd,J=6.8,2.1Hz,1H),7.45(dd,J=6.7,2.1Hz,1H),7.06(d,J=7.6Hz,1H),6.77(d,J=7.6Hz,1H),5.79(s,1H),5.3 5(d,J=39.8Hz,1H),4.76-4.52(m,1H),4.10-4.00(m,2H),2.91(d,J=5. 6Hz, 2H), 2.25 (s, 3H), 1.99 (s, 3H), 1.41 (s, 9H), 1.19 (t, J = 7.1Hz, 3H). 19 F NMR (376MHz, CDCl3): δ-61.09,-61.12,-121.42.

[0203] Step 3: Preparation of ethyl (3S)-3-amino-3-[4-fluoro-2'-hydroxy-3',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate hydrochloride: To a stirred solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-fluoro-2'-hydroxy-3',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate (430 mg, 0.86 mmol, 1.00 equiv.) in CHCl (7 mL) was added dropwise under a nitrogen atmosphere at 0°C with HCl (gas) in 1,4-dioxane (5 mL, 4 M). The resulting mixture was stirred at room temperature for an additional 1.5 hours. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. This gave ethyl (3S)-3-amino-3-[4-fluoro-2'-hydroxy-3',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate hydrochloride (430 mg, crude) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =400.3 Intermediate 17 [ka]

[0204] Step 1: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-fluoro-2′-hydroxy-5,6′-bis(trifluoromethyl)-[1,1′-biphenyl]-3-yl]propanoate: To a stirred solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl]propanoate (1.00 g, 1.97 mmol, 1.00 equiv.) and 2-bromo-3-(trifluoromethyl)phenol (0.52 g, 2.17 mmol, 1.10 equiv.) in dioxane (10 mL), Pd(dppf)Cl.CHCl (109 mg, 0.19 mmol, 0.10 equiv.) and KHPO (1.03 g, 5.93 mmol, 3.00 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (200 mL). The residue was washed with water (2 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by silica gel column chromatography eluting with PE / EtOAc (0% to 30% gradient in 30 min) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-fluoro-2'-hydroxy-5,6'-bis(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate (510 mg, 47.7%) as a yellow oil. LC-MS: (ES+H, m / z): [M+H-tBu] + =484.0.

[0205] Step 2: Preparation of ethyl (3S)-3-amino-3-[4-fluoro-2'-hydroxy-5,6'-bis(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate: To a stirred solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-fluoro-2'-hydroxy-5,6'-bis(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate (510 mg, 0.94 mmol, 1.00 equiv.) in CHCl (6 mL) was added dropwise under a nitrogen atmosphere at 0°C. HCl (gas) in 1,4-dioxane (3 mL, 4 M) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This afforded ethyl (3S)-3-amino-3-[4-fluoro-2'-hydroxy-5,6'-bis(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate (350 mg, 84.3%) as a yellow oil. LC-MS: (ES+H, m / z): [M+H] + =440.0 Intermediate 18 [ka]

[0206] Step 1: Preparation of [3-bromo-5-(trifluoromethyl)phenyl](oxo)acetic acid: To a stirred mixture of 1-[3-bromo-5-(trifluoromethyl)phenyl]ethanone (4.00 g, 14.97 mmol, 1.00 equiv.) in pyridine (40 mL) was added SeO (2.49 g, 22.46 mmol, 1.50 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was acidified to pH 4 with concentrated HCl. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 150 mL). The resulting mixture was extracted with EtOAc (2 × 500 mL). The combined organic layers were washed with brine (1 × 500 mL), dried over anhydrous NaSO, filtered, and concentrated to give [3-bromo-5-(trifluoromethyl)phenyl](oxo)acetic acid (4.7 g, crude) as a red oil. LC-MS: (ES-H, m / z): [MH] - =294.8. 1H NMR (400MHz, DMSO-d6) δ8.39(q,J=1.9Hz,2H),8.24(s,1H).

[0207] Step 2: Preparation of tert-butyl 2-[3-bromo-5-(trifluoromethyl)phenyl]-2-oxoacetate: To a stirred mixture of [3-bromo-5-(trifluoromethyl)phenyl](oxo)acetic acid (4.00 g, 13.46 mmol, 1.00 equiv.) in CHCl (200 mL) was added (E)-N,N′-bis(propan-2-yl)(tert-butoxy)methanimidamide (5.40 g, 26.93 mmol, 2.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3×150 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (0% to 10% gradient in 30 min) to give tert-butyl 2-[3-bromo-5-(trifluoromethyl)phenyl]-2-oxoacetate (3.7 g, 77.8%) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ8.40-8.32 (m, 2H), 8.20 (td, J=1.6, 0.8Hz, 1H), 1.57 (s, 9H).

[0208] Step 3: Preparation of tert-butyl 2-[3-bromo-5-(trifluoromethyl)phenyl]-2-hydroxyacetate: To a stirred mixture of tert-butyl 2-[3-bromo-5-(trifluoromethyl)phenyl]-2-oxoacetate (3.5 g, 9.91 mmol, 1.00 equiv.) and NaBHCN (685 mg, 10.90 mmol, 1.10 equiv.) in CHCHOH (15 mL) was added CHCOOH (1.5 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The reaction was quenched with water (300 ml) at room temperature. The resulting mixture was extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (1×500 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by silica gel column chromatography eluting with PE / EtOAc (0% to 20% gradient in 30 min) to give tert-butyl 2-[3-bromo-5-(trifluoromethyl)phenyl]-2-hydroxyacetate (3 g, 85.2%) as a white solid. LC-MS: (ES-H, m / z): [MH] - =352.9. 1 H NMR (300MHz, DMSO-d6) δ7.92(d,J=4.2Hz,2H),7.80-7.60(m,1H),6.34(d,J=5.8Hz,1H),5.21(d,J=5.8Hz,1H),1.35(s,9H).

[0209] Step 4: Preparation of tert-butyl 2-[3-bromo-5-(trifluoromethyl)phenyl]-2-(methanesulfonyloxy)acetate: To a stirred mixture of tert-butyl 2-[3-bromo-5-(trifluoromethyl)phenyl]-2-hydroxyacetate (1.00 g, 2.81 mmol, 1.00 equiv.) and NEt (427 mg, 4.22 mmol, 1.50 equiv.) in CHCl (10 mL), MsCl (387 mg, 3.37 mmol, 1.20 equiv.) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was diluted with EtOAc (200 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous NaSO, filtered, and concentrated to give tert-butyl 2-[3-bromo-5-(trifluoromethyl)phenyl]-2-(methanesulfonyloxy)acetate (1.5 g, crude) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ 8.13 (s, 1H), 8.00 (s, 1H), 7.82 (s, 1H), 6.27 (s, 1H), 3.36 (s, 3H), 1.39 (s, 9H).

[0210] Step 5: Preparation of tert-butyl 2-[3-bromo-5-(trifluoromethyl)phenyl]-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate To a stirred mixture of tert-butyl 2-[3-bromo-5-(trifluoromethyl)phenyl]-2-(methanesulfonyloxy)acetate (1.49 g, 3.44 mmol, 1.30 equiv.) and 5-[2-(3-fluoroazetidin-1-yl)ethyl]-4-(trifluoromethyl)-1H-pyridin-2-one (700 mg, 2.64 mmol, 1.00 equiv.) in MeCN (20 mL) was added KCO (732 mg, 5.29 mmol, 2.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3×100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18; mobile phase, MeCN / water (0.1% NH3.HO), 10% to 50% gradient in 10 min; detector: UV 220 nm) to give tert-butyl 2-[3-bromo-5-(trifluoromethyl)phenyl]-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (300 mg, 18.8%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =601.0. 1 H NMR(300MHz,DMSO-d6)δ8.08(s,1H),8.04(d,J=2.1Hz,1H),7.93(s,1H),7.81(s,1H),6.88(s,1H),6.33(s,1H),5.06(dp,J =57.8,5.1Hz,1H),3.49(dq,J=14.6,7.2Hz,2H),3.12-2.93(m,2H),2.59-2.53(m,2H),2.44(t,J=6.8Hz,2H),1.40(s,9H).

[0211] Step 6: Preparation of [3-bromo-5-(trifluoromethyl)phenyl]({5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl})acetic acid: To a stirred mixture of tert-butyl 2-[3-bromo-5-(trifluoromethyl)phenyl]-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (300 mg, 0.49 mmol, 1.00 equiv.) in CHCl (6 mL) was added CFCOH (6 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18; mobile phase, MeCN / water (0.1% NH3.HO), 0-100% gradient in 20 min; detector: UV 220 nm) to give [3-bromo-5-(trifluoromethyl)phenyl]({5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl})acetic acid (250 mg, 91.9%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =545.0. Intermediate 19 [ka]

[0212] Step 1: Preparation of 2-{1-[(4-methoxyphenyl)methyl]-6-oxo-4-(trifluoromethyl)pyridin-3-yl}acetaldehyde: To a stirred mixture of 5-[(E)-2-ethoxyethenyl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one (10.00 g, 28.30 mmol, 1.00 equiv.) in CHCl (30 mL) was added CFCOOH (30 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with CHCl (200 mL). The resulting mixture was washed with 3×200 mL of saturated NaHCO (aq). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous NaSO, filtered, and concentrated to give 2-{1-[(4-methoxyphenyl)methyl]-6-oxo-4-(trifluoromethyl)pyridin-3-yl}acetaldehyde (9 g, crude) as a red oil. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =326.1.

[0213] Step 2: Preparation of 5-[2-(dimethylamino)ethyl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one: To a stirred mixture of 2-{1-[(4-methoxyphenyl)methyl]-6-oxo-4-(trifluoromethyl)pyridin-3-yl}acetaldehyde (9.00 g, 27.66 mmol, 1.00 equiv.) and dimethylamine (28 mL, 55.33 mmol, 2.00 equiv., 2 M in THF) in EtOH (30 mL) was added CHCOOH (166 mg, 2.76 mmol, 0.10 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. To the above mixture was added NaBHCN (3.48 g, 55.33 mmol, 2.00 equiv.) in portions over 10 minutes at room temperature. The resulting mixture was stirred at room temperature for an additional 4 hours. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The reaction was quenched by adding water (200 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (2 × 200 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by silica gel column chromatography eluting with CHCl / MeOH (0–10%, 20 min) to give 5-[2-(dimethylamino)ethyl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one (2 g, 20.4%) as a yellow oil. LC-MS: (ES+H, m / z): [M+H] + =355.1. 1 H NMR(400MHz,DMSO-d6)δ7.91(s,1H),7.25-7.18(m,2H),6.85-6.78(m,2H),6.69(s ,1H),4.94(s,2H),3.63(s,3H),2.60-2.55(m,2H),2.42-2.40(m,6H),2.35(s,2H). 19 F NMR (377MHz, DMSO-d6) δ-62.51.

[0214] Step 3: Preparation of 5-[2-(dimethylamino)ethyl]-4-(trifluoromethyl)-1H-pyridin-2-one: A stirred mixture of 5-[2-(dimethylamino)ethyl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one (2.00 g, 5.64 mmol, 1.00 equiv.) in CF3COOH (10 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 10% to 50% gradient in 25 min; detector: UV 254 nm / 220 nm) to give 5-[2-(dimethylamino)ethyl]-4-(trifluoromethyl)-1H-pyridin-2-one (750 mg, 56.7%) as a colorless oil. LC-MS: (ES+H, m / z): [M+H] + =235.0. 1 H NMR (400MHz, DMSO-d6) δ12.10(s,1H),7.54(s,1H),6.68(s,1H),2.56(t,J=7.5Hz,2H),2.37(t,J=8.3,6.7Hz,2H),2.16(s,6H). 19 F NMR (377MHz, DMSO-d6) δ-62.65.

[0215] Step 4: Preparation of tert-butyl 2-(3-bromophenyl)-2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate: To a stirred mixture of 5-[2-(dimethylamino)ethyl]-4-(trifluoromethyl)-1H-pyridin-2-one (750 mg, 3.20 mmol, 1.00 equiv.) and tert-butyl 2-(3-bromophenyl)-2-(methanesulfonyloxy)acetate (1.52 g, 4.16 mmol, 1.30 equiv.) in MeCN (10 mL) was added K2CO3 (885 mg, 6.40 mmol, 2.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse Combiflash chromatography (C18; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector: UV 254 nm / 220 nm) to give tert-butyl 2-(3-bromophenyl)-2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (710 mg, 44.0%) as an off-white solid. LC-MS: (ES+H, m / z): [M+H] + =503.0. 1 H NMR(400MHz,DMSO-d6)δ7.69-7.65(m,2H),7.57(s,1H),7.47-7.42(m,2H),6.85(s ,1H),6.27(s,1H),2.52-2.51(m,2H),2.34-2.23(m,2H),2.02(s,6H),1.41(s,9H). 19 F NMR (377MHz, DMSO-d6) δ-62.70.

[0216] Step 5: Preparation of (3-bromophenyl)({5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl})acetic acid: To a stirred mixture of tert-butyl 2-(3-bromophenyl)-2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (710 mg, 1.41 mmol, 1.00 equiv.) in CHCl (5 mL) was added CFCOOH (5 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse Combiflash chromatography (C18; mobile phase, MeCN / water (0.1% HCOOH), 10% to 50% gradient in 10 min; detector: UV 254 nm / 220 nm) to give (3-bromophenyl)({5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl})acetic acid (600 mg, 95.1%) as an off-white solid. LC-MS: (ES+H, m / z): [M+H] + =447.0. Intermediate 20 [ka]

[0217] Step 1: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2'-chloro-4-fluoro-6'-hydroxy-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate: A mixture of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl]propanoate (500 mg, 0.98 mmol, 1.00 equiv.), 2-bromo-3-chlorophenol (246 mg, 1.187 mmol, 1.20 equiv.), Pd(dppf)Cl.CHCl (80 mg, 0.10 mmol, 0.10 equiv.), and KHPO (517.03 mg, 2.96 mmol, 3.00 equiv.) in 1,4-dioxane (10 mL) and HO (1 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (0-30% gradient in 30 min) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2'-chloro-4-fluoro-6'-hydroxy-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate (400 mg, 79.9%) as a yellow oil. LC-MS: (ES+H, m / z): [M+Na] + =528.1.

[0218] Step 2: Preparation of (S)-ethyl 3-amino-3-(2'-chloro-4-fluoro-6'-hydroxy-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate hydrochloride: A solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2'-chloro-4-fluoro-6'-hydroxy-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate (350 mg, 0.69 mmol, 1.00 equiv.) and HCl (gas) in 1,4-dioxane (2.5 mL, 4 M) in CHCl (2.5 mL) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give ethyl (S)-3-amino-3-(2'-chloro-4-fluoro-6'-hydroxy-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate hydrochloride (350 mg, crude) as a light brown oil. LC-MS: (ES+H, m / z): [M+H] + =406.0. Intermediate 21 [ka]

[0219] Step 1: Preparation of 1-(2-methoxy-4,6-dimethylphenyl)-3-(trifluoromethyl)pyrazole-4-carbaldehyde: To a stirred solution of 2-methoxy-4,6-dimethylphenylboronic acid (10.97 g, 60.94 mmol, 2.00 equiv.) and 3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (5.00 g, 30.47 mmol, 1.00 equiv.) in DMF (30 mL), Cu(OAc) (6.09 g, 33.52 mmol, 1.10 equiv.) and pyridine (289 mg, 3.65 mmol, 2.00 equiv.) were added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere and then filtered. The filter cake was washed with EtOAc (2 x 300 mL), the combined organic layers were concentrated in vacuo, and the crude product was purified by silica gel column chromatography (PE / EtOAc (0% to 15% gradient in 30 min)) to give 1-(2-methoxy-4,6-dimethylphenyl)-3-(trifluoromethyl)pyrazole-4-carbaldehyde (1.5 g, 16.5%) as a yellow oil. LC-MS: (ES+H, m / z) [M+H]+ =299.0. 1 H NMR(300MHz,DMSO-d6)δ9.95(d,J=0.8Hz,1H),8.88(d,J=1.0Hz,1H),6.96(d,J= 1.7Hz, 1H), 6.84 (dd, J=1.8, 0.9Hz, 1H), 3.75 (s, 3H), 2.37 (s, 3H), 1.96 (s, 3H).

[0220] Step 2: Preparation of (R)-N-[(1Z)-[1-(2-methoxy-4,6-dimethylphenyl)-3-(trifluoromethyl)pyrazol-4-yl]methylidene]-2-methylpropane-2-sulfinamide: To a stirred solution of 1-(2-methoxy-4,6-dimethylphenyl)-3-(trifluoromethyl)pyrazole-4-carbaldehyde (1.50 g, 5.02 mmol, 1.00 equiv.) and (R)-2-methylpropane-2-sulfinamide (0.91 g, 7.54 mmol, 1.50 equiv.) in THF (30 mL) was added Ti(Oi-Pr) (2.86 g, 10.05 mmol, 2.00 equiv.) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 2 h. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), and quenched with water (50 mL). The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 50 mL). The aqueous layer was extracted with EtOAc (2 × 50 mL), and the combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0% to 50% gradient over 30 min)) to give (R)-N-[(1Z)-[1-(2-methoxy-4,6-dimethylphenyl)-3-(trifluoromethyl)pyrazol-4-yl]methylidene]-2-methylpropane-2-sulfinamide (1.5 g, 74.3%) as a yellow solid. LC-MS: (ES-H, m / z) [M+H] + =402.1. 1H NMR(400MHz,CDCl3)δ8.55(s,1H),7.93(d,J=1.0Hz,1H),6.68-6.64(m,1H) ,6.60(d,J=1.7Hz,1H),3.68(s,3H),2.31(s,3H),1.99(s,3H),1.19(s,9H).

[0221] Step 3: Preparation of ethyl (3S)-3-[1-(2-methoxy-4,6-dimethylphenyl)-3-(trifluoromethyl)pyrazol-4-yl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate: A mixture of Zn (1.22 g, 18.68 mmol, 5.00 equiv.) and TMSCl (0.20 g, 1.86 mmol, 0.50 equiv.) in THF (20 mL) was stirred at 60° C. for 1 hour under a nitrogen atmosphere. Ethyl bromoacetate (1.56 g, 9.34 mmol, 2.50 equiv.) was added dropwise to the mixture at room temperature over 10 minutes. The resulting mixture was stirred at 60° C. for an additional 1 hour. To the mixture was added (R)-N-[(1Z)-[1-(2-methoxy-4,6-dimethylphenyl)-3-(trifluoromethyl)pyrazol-4-yl]methylidene]-2-methylpropane-2-sulfinamide (1.50 g, 3.73 mmol, 1.00 equiv.) in THF (10 mL) over 5 minutes at −20° C. The resulting mixture was stirred at −20° C. to 0° C. for an additional 5 h and then quenched with saturated aqueous NH4Cl (100 mL) at 0° C. The resulting mixture was diluted with EtOAc (100 mL) and then stirred at room temperature for 10 min. The resulting mixture was extracted with EtOAc (2 × 50 mL), and the combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0% to 50% gradient over 30 min)) to afford ethyl (3S)-3-[1-(2-methoxy-4,6-dimethylphenyl)-3-(trifluoromethyl)pyrazol-4-yl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate (1.5 g, 82.0%) as a white solid. LC-MS: (ES+H, m / z) [M+H] + =490.2.1 H NMR(400MHz,DMSO-d6)δ7.95(d,J=1.2Hz,1H),6.90(d,J=1.8Hz,1H),6.81-6.75(m,1H),5.61(d,J=7.0Hz,1H),4.80(q,J=7.2Hz,1H),4.01(q,J=7 .1Hz,2H),3.71(s,3H),3.05(dd,J=15.4,6.6Hz,1H),2.87(dd,J=15.4,8 .2Hz,1H),2.35(s,3H),1.86(s,3H),1.12(t,J=7.1Hz,3H),1.07(s,9H).

[0222] Step 4: Preparation of ethyl (3S)-3-amino-3-[1-(2-methoxy-4,6-dimethylphenyl)-3-(trifluoromethyl)pyrazol-4-yl]propanoate: To a stirred solution of ethyl (3S)-3-[1-(2-methoxy-4,6-dimethylphenyl)-3-(trifluoromethyl)pyrazol-4-yl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate (1.50 g, 3.06 mmol, 1.00 equiv) in CHCl (5 mL) was added dropwise at room temperature under a nitrogen atmosphere with HCl in 1,4-dioxane (15 mL, 4 M). The resulting mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 gel; mobile phase, MeCN / water (0.1% NH3.HO), 0% to 70% gradient in 35 min; detector: UV 220 nm) to give ethyl (3S)-3-amino-3-[1-(2-methoxy-4,6-dimethylphenyl)-3-(trifluoromethyl)pyrazol-4-yl]propanoate (900 mg, 76.2%) as a colorless oil. LC-MS: (ES+H, m / z) [M+H] + =386.1. 1H NMR(400MHz,DMSO-d6)δ7.93(s,1H),6.90(d,J=1.8Hz,1H),6.78(d,J=1.7Hz,1H),4.34(t,J=7.0Hz,1H),4.0 3(q,J=7.1Hz,2H),3.71(s,3H),2.64(dd,J=7.0,2.1Hz,2H),2.35(s,3H),1.87(s,3H),1.14(t,J=7.1Hz,3H).

[0223] Step 5: Preparation of ethyl (3S)-3-amino-3-[1-(2-hydroxy-4,6-dimethylphenyl)-3-(trifluoromethyl)pyrazol-4-yl]propanoate: To a stirred solution of ethyl (3S)-3-amino-3-[1-(2-methoxy-4,6-dimethylphenyl)-3-(trifluoromethyl)pyrazol-4-yl]propanoate (750 mg, 1.94 mmol, 1.00 equiv.) in CHCl (20 mL) was added boron trichloride (7.80 mL, 7.78 mmol, 4.00 equiv., 1 M in hexanes) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 3 hours under a nitrogen atmosphere. The reaction was quenched by adding water (0.5 mL) at 0° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl / MeOH (gradient of 0% to 10% over 20 min)) to give ethyl (3S)-3-amino-3-[1-(2-hydroxy-4,6-dimethylphenyl)-3-(trifluoromethyl)pyrazol-4-yl]propanoate (450 mg, 62.2%) as a brown solid. LC-MS: (ES+H, m / z) [M+H] + =372.1. 1 H NMR(400MHz,DMSO-d6)δ10.10(s,1H),8.75(s,2H),8.29(s,1H),6.73(s,1H),6.62(s,1H),4.68(dd,J=8. 7,5.4Hz,1H),4.02(q,J=6.9Hz,2H),3.20-3.03(m,2H),2.25(s,3H),1.85(s,3H),1.11(t,J=6.8Hz,3H). Intermediates 22 and 23 [ka]

[0224] Step 1: Preparation of 5-[3-(dimethylamino)prop-1-yn-1-yl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one: A mixture of 5-bromo-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one (4.00 g, 11.05 mmol, 1.00 equiv.), dimethyl(prop-2-yn-1-yl)amine (3.67 g, 44.18 mmol, 4.00 equiv.), Pd(PPh)Cl (775 mg, 1.11 mmol, 0.10 equiv.), CuI (421 mg, 2.21 mmol, 0.20 equiv.), and TEA (22.35 g, 220.90 mmol, 20.00 equiv.) in DME (30 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. The mixture was then cooled to room temperature and concentrated. The residue was purified by reverse-phase flash chromatography (C18 gel; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 40% to 100% gradient in 30 min; detector: UV 220 nm) to give 5-[3-(dimethylamino)prop-1-yn-1-yl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one (3.00 g, 74.5%) as a yellow oil. LC-MS: (ES+H, m / z) [M+H] + =365.05. 1 H NMR(300MHz,CDCl3)δ7.56(s,1H),7.31-7.27(m,2H),6.93(d,J=2.1Hz,1H) ,6.90(d,J=1.3Hz,2H),5.06(s,2H),3.82(s,3H),3.43(s,2H),2.33(s,6H).

[0225] Step 2: Preparation of 5-[3-(dimethylamino)propyl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one: To a solution of 5-[3-(dimethylamino)prop-1-yn-1-yl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one (1.80 g, 4.94 mmol, 1.00 equiv) in EtOH (150 mL) was added Pd / C (5%, 900 mg) in a pressure tank. The mixture was hydrogenated at 30 psi hydrogen pressure at room temperature for 2 hours, filtered through a Celite pad, and concentrated under reduced pressure. The Celite pad was washed with CHCl (3 × 200 mL), and the combined filtrate was concentrated under reduced pressure to give 5-[3-(dimethylamino)propyl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one (1.80 g, crude) as a brown oil. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z) [M+H] + =369.1.

[0226] Step 3: Preparation of 5-[3-(dimethylamino)propyl]-4-(trifluoromethyl)-1H-pyridin-2-one: A solution of 5-[3-(dimethylamino)propyl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one (1.80 g, 3.91 mmol, 1.00 equiv) and CF₃COOH (30.00 mL) was stirred overnight at 80°C under a nitrogen atmosphere. The mixture was allowed to cool to room temperature, and the residue was purified by reverse-phase flash chromatography (C₁₈ gel; mobile phase, MeCN / water (0.1% NH₃.HO), 20% to 60% gradient over 30 min; detector: UV 220 nm) to give 5-[3-(dimethylamino)propyl]-4-(trifluoromethyl)-1H-pyridin-2-one (1 g, 82.4%) as a white solid. LC-MS: (ES+H, m / z) [M+H] + =249.05. 1 H NMR (300MHz, CDCl3) δ7.35(s,1H),6.89(s,1H),2.61-2.52(m,2H),2.34(dd,J=8.2,6.4Hz,2H),2.25(s,6H),1.72(p,J=7.5Hz,2H).

[0227] Step 4: Preparation of tert-butyl 2-(3-bromophenyl)-2-{5-[3-(dimethylamino)propyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate: A mixture of 5-[3-(dimethylamino)propyl]-4-(trifluoromethyl)-1H-pyridin-2-one (1.00 g, 4.03 mmol, 1.00 equiv.), tert-butyl 2-(3-bromophenyl)-2-(methanesulfonyloxy)acetate (1.54 g, 4.23 mmol, 1.05 equiv.), and KCO (1.11 g, 8.06 mmol, 2.00 equiv.) in CHCN (30 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by reverse-phase flash chromatography (C18 gel; mobile phase, MeCN / water (0.1% HCOOH), 35% to 65% gradient in 25 min; detector: UV 220 nm) to give tert-butyl 2-(3-bromophenyl)-2-{5-[3-(dimethylamino)propyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (1.10 g, 52.8%) as a colorless oil. LC-MS: (ES+H, m / z) [M+H] + =517.1. 1 H NMR(300MHz,CDCl3)δ7.61-7.51(m,2H),7.39-7.30(m,2H),7.21(s,1H),6.93(s,1H),6.7 3(s,1H),2.98-2.75(m,2H),2.67(s,6H),2.53(q,J=6.9Hz,2H),1.87(s,2H),1.50(s,9H).

[0228] Step 5: Preparation of (3-bromophenyl)({5-[3-(dimethylamino)propyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl})acetic acid: A solution of tert-butyl 2-(3-bromophenyl)-2-{5-[3-(dimethylamino)propyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (1.10 g, 2.13 mmol, 1.00 equiv.) and CF3COOH (15 mL) in CHCl2 (15 mL) was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 gel; mobile phase, MeCN / water (0.1% HCOOH), 0% to 40% gradient over 30 min; detector: UV 220 nm) to afford (3-bromophenyl)({5-[3-(dimethylamino)propyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl})acetic acid (900 mg, 91.8%) as a colorless oil. LC-MS: (ES+H, m / z) [M+H] + =461.0. Intermediate 24 [ka]

[0229] Step 1: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{2'-chloro-4-fluoro-6'-hydroxy-5-methyl-[1,1'-biphenyl]-3-yl}propanoate: To a stirred solution of 2-bromo-3-chlorophenol (505 mg, 2.43 mmol, 1.10 equiv.) and ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (1.00 g, 2.21 mmol, 1.00 equiv.) in 1,4-dioxane (15.00 mL) and HO (0.75 mL), KCO (918 mg, 6.64 mmol, 3.00 equiv.) and Pd(dppf)ClCHCl (180 mg, 0.22 mmol, 0.10 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 3 h. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (gradient: 0% to 50% over 30 min)) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{2'-chloro-4-fluoro-6'-hydroxy-5-methyl-[1,1'-biphenyl]-3-yl}propanoate (450 mg, 42.7%) as a yellow solid. LC-MS: (ES+H, m / z) [M+H] + =452.2. 1 H NMR(400MHz,CD3OD)δ7.14-7.05(m,2H),7.03(dd,J=7.2,2.2Hz,1H),6.94(dd,J=8.1,1.1Hz,1H),6.81(dd,J=8.2,1.1Hz,1 H),5.36(t,J=7.4Hz,1H),4.12-4.09(m,2H),2.78-2.75(m,2H),2.30(d,J=2.1Hz,3H),1.40(s,9H),1.20(t,J=7.1Hz,3H).

[0230] Step 2: Preparation of ethyl (3S)-3-amino-3-{2'-chloro-4-fluoro-6'-hydroxy-5-methyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride: To a stirred solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{2'-chloro-4-fluoro-6'-hydroxy-5-methyl-[1,1'-biphenyl]-3-yl}propanoate (440 mg, 0.97 mmol, 1.00 equiv.) in CHCl (2.50 mL) was added HCl in 1,4-dioxane (2.50 mL, 4 M) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 hours and then concentrated under reduced pressure. The crude product, ethyl (3S)-3-amino-3-{2'-chloro-4-fluoro-6'-hydroxy-5-methyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride (450 mg, crude), was used directly in the next step without further purification. LC-MS: (ES+H, m / z) [M+H] + =352.2. Intermediate 25 [ka]

[0231] Step 1: Preparation of tert-butyl 2-(5-bromo-2-fluorophenyl)-2-{5-[3-(dimethylamino)propyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate: To a stirred solution of 5-[3-(dimethylamino)propyl]-4-(trifluoromethyl)-1H-pyridin-2-one (350 mg, 1.41 mmol, 1.00 equiv.) and tert-butyl 2-(5-bromo-2-fluorophenyl)-2-(methanesulfonyloxy)acetate (540 mg, 1.41 mmol, 1.00 equiv.) in MeCN (10 mL) was added KCO (389 mg, 2.82 mmol, 2.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was heated at 80° C. for 2 hours, then cooled to room temperature and diluted with water. The resulting mixture was extracted with EtOAc (4×50 mL). The combined organic layers were washed with brine (1×10 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by reverse-phase flash chromatography (C18 gel; mobile phase, MeCN / water (0.1% NH3.HO), 40% to 80% gradient in 20 min; detector: UV 254 nm) to give tert-butyl 2-(5-bromo-2-fluorophenyl)-2-{5-[3-(dimethylamino)propyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (500 mg, 66.2%) as a pale yellow oil. LC-MS: (ES+H, m / z) [M+H] + =537.05. 1 H NMR(300MHz,CDCl3)δ7.60-7.50(m,2H),7.13(s,1H),7.05(dd,J=9.6,8.7Hz,1H),6.91(s,1H),6.77 (s,1H),2.48(dd,J=8.9,6.4Hz,2H),2.35-2.20(m,2H),2.17(s,6H),1.69-1.56(m,2H),1.49(s,9H). 19 F NMR (282MHz, CDCl3) δ-63.96,-116.36.

[0232] Step 2: Preparation of (5-bromo-2-fluorophenyl)({5-[3-(dimethylamino)propyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl})acetic acid: To a stirred solution of tert-butyl 2-(5-bromo-2-fluorophenyl)-2-{5-[3-(dimethylamino)propyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (430 mg, 0.80 mmol, 1.00 equiv.) in CHCl (2.5 mL) was added CFCOOH (5 mL) dropwise under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to afford (5-bromo-2-fluorophenyl)({5-[3-(dimethylamino)propyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetic acid (680 mg, crude) as a light brown oil. The crude product mixture was used directly in the next step without further purification. LC-MS: (ES+H, m / z) [M+H] + =479.10. Intermediates 26 and 27 [ka]

[0233] Step 1: Preparation of 5-(3-(azetidin-1-yl)prop-1-yn-1-yl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)pyridin-2(1H)-one: To a stirred mixture of propargyl bromide (4.93 g, 41.42 mmol, 3.00 equiv.) and azetidine (4.73 g, 82.84 mmol, 6.00 equiv.) in DMF (30 mL) was added K2CO3 (11.45 g, 82.84 mmol, 6.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 4 h. To the above mixture was added CuI (0.53 g, 2.76 mmol, 0.20 equiv.), Pd(PPh3)2Cl2 (0.97 g, 1.38 mmol, 0.10 equiv.), triethylamine (38 mL, 276.14 mmol, 20.00 equiv.), and DME (100 mL) at room temperature. The resulting mixture was stirred at 100 °C overnight, cooled to room temperature, and filtered. The filter cake was washed with CHCl (3×20 mL), and the combined filtrates were concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18; mobile phase, MeCN / water (10 mmol / L NHHCO), 10% to 50% gradient in 20 min; detector: UV 220 nm) to give 5-[3-(azetidin-1-yl)prop-1-yn-1-yl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one (2.00 g, 38.4%) as a yellow oil. LC-MS: (ES+H, m / z) [M+H] + =377.10. 1 H NMR (400MHz, CDCl3) δ7.68(s,1H),7.31-7.28(m,2H),6.93-6.90(m,3H),5.07(s,2H),3.95(t,J=8.0Hz,4H),3.81(s,5H),2.44-2.34(m,2H). 19 F NMR (400MHz, CDCl3) δ-65.83.

[0234] Step 2: Preparation of 5-(3-(azetidin-1-yl)propyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)pyridin-2(1H)-one: A mixture of 5-[3-(azetidin-1-yl)prop-1-yn-1-yl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one (2.00 g, 5.31 mmol, 1.00 equiv.) and Pd / C (1.00 g, 10% by weight) in EtOAc (50 mL) was stirred under a hydrogen atmosphere at room temperature for 3 h. The reaction mixture was then filtered, and the filter cake was washed with CHCl (3 × 100 mL). The combined filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (CHCl / MeOH (0–15% gradient over 30 min)) to give 5-[3-(azetidin-1-yl)propyl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one (750 mg, 37.1%) as a yellow oil. LC-MS: (ES+H, m / z) [M+H] + =381.15.

[0235] Step 3: Preparation of 5-(3-(azetidin-1-yl)propyl)-4-(trifluoromethyl)pyridin-2(1H)-one: A solution of 5-[3-(azetidin-1-yl)propyl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one (1.10 g, 2.89 mmol, 1.00 equiv.) in TFA (10 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. The resulting mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 10% to 50% gradient in 20 min; detector: UV 220 nm) to give 5-[3-(azetidin-1-yl)propyl]-4-(trifluoromethyl)-1H-pyridin-2-one (600 mg, 79.7%) as a yellow solid. LC-MS: (ES+H, m / z) [M+H-tBu] + =261.20. 1H NMR(400MHz,DMSO-d6)δ7.46(s,1H),6.67(s,1H),3.09(t,J=7.0Hz,4H),2.47 -2.39(m,2H),2.36(t,J=6.9Hz,2H),2.00-1.90(m,2H),1.45(p,J=7.1Hz,2H). 19 F NMR (377MHz, DMSO-d6) δ-62.71.

[0236] Step 4: Preparation of tert-butyl 2-{5-[3-(azetidin-1-yl)propyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}-2-(5-bromo-2-fluorophenyl)acetate: To a stirred solution of 5-[3-(azetidin-1-yl)propyl]-4-(trifluoromethyl)-1H-pyridin-2-one (400 mg, 1.53 mmol, 1.00 equiv.) and tert-butyl 2-(5-bromo-2-fluorophenyl)-2-(methanesulfonyloxy)acetate (589 mg, 1.53 mmol, 1.00 equiv.) in MeCN (15 mL) was added KCO (424 mg, 3.07 mmol, 2.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18; mobile phase, MeOH / water (10 mmol / L NH4HCO3), 10% to 50% gradient in 20 min; detector: UV 220 nm) to give tert-butyl 2-{5-[3-(azetidin-1-yl)propyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}-2-(5-bromo-2-fluorophenyl)acetate (450 mg, 53.4%) as a colorless oil. LC-MS: (ES+H, m / z) [M+H] + =547.15. 1 H NMR(400MHz,CDCl3)δ7.60-7.50(m,2H),7.13-7.01(m,2H),6.90(s,1H),6.77(s,1H ),3.11(t,J=7.0Hz,4H),2.49-2.26(m,4H),2.07-2.01(m,2H),1.57-1.44(m,11H). 19F NMR(377MHz, CDCl3)δ-64.00,-116.34.

[0237] Step 5: Preparation of 2-(5-(3-(azetidin-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2-(5-bromo-2-fluorophenyl)acetic acid: To a stirred solution of tert-butyl 2-{5-[3-(azetidin-1-yl)propyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}-2-(5-bromo-2-fluorophenyl)acetate (400 mg, 0.73 mmol, 1.00 equiv.) in CHCl (2 mL) was added CFCOOH (4 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere and then concentrated under reduced pressure. The residue was purified by trituration with EtO (20 mL) to give {5-[3-(azetidin-1-yl)propyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}(5-bromo-2-fluorophenyl)acetic acid (650 mg, crude) as an off-white solid. LC-MS: (ES+H, m / z) [M+H] + =491.0. Intermediates 28 and 29 [ka]

[0238] Step 1: Preparation of (R)-N-[(1E)-(5-bromo-3-chloro-2-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide: A solution of 5-bromo-3-chloro-2-fluorobenzaldehyde (3.00 g, 12.63 mmol, 1.00 equiv.), (R)-2-methylpropane-2-sulfinamide (1.68 g, 13.90 mmol, 1.10 equiv.), and Ti(Oi-Pr) (7.18 g, 25.27 mmol, 2.00 equiv.) in THF (50 mL) was stirred at room temperature under a nitrogen atmosphere for 4 hours. The resulting mixture was diluted with water (100 mL) and EtOAc (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA (0-40% in 20 min) to give (R)-N-[(1E)-(5-bromo-3-chloro-2-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide (4.00 g, 92.9%) as a white solid. LC-MS: (ES+H, m / z) [M+H] + =339.9. 1 H NMR (300MHz, DMSO-d6) δ8.60(s, 1H), 8.15(dd, J=6.5, 2.5Hz, 1H), 8.07(dd, J=5.6, 2.5Hz, 1H), 1.20(s, 9H). 19 F NMR(282MHz,DMSO-d6)δ-121.85.

[0239] Step 2: Preparation of ethyl (3S)-3-(5-bromo-3-chloro-2-fluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate: A mixture of Zn (1.34 g, 20.50 mmol, 4.99 equiv) and TMSCl (111 mg, 1.02 mmol, 0.25 equiv) in THF (10 mL) was stirred at 60° C. for 1 hour under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. To the mixture was added ethyl 2-bromoacetate (1.72 g, 10.29 mmol, 2.51 equiv) dropwise over 10 minutes at room temperature. The resulting mixture was stirred at 60° C. for an additional hour. The mixture was allowed to cool to 0° C. To the mixture was added a solution of (R)-N-[(1E)-(5-bromo-3-chloro-2-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide (1.40 g, 4.11 mmol, 1.00 equiv) in THF (5 mL) dropwise over 15 minutes at 0° C. The resulting mixture was stirred at 0°C for an additional 1 hour and then filtered. The filter cake was washed with EtOAc, and the combined filtrates were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether (20% to 50% in 25 minutes) to give ethyl (3S)-3-(5-bromo-3-chloro-2-fluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate (1.05 g, 59.5%) as a yellow oil. LC-MS: (ES+H, m / z) [M+H] + =427.9.

[0240] Step 3: Preparation of ethyl (3S)-3-amino-3-(5-bromo-3-chloro-2-fluorophenyl)propanoate: A solution of ethyl (3S)-3-(5-bromo-3-chloro-2-fluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate (1.00 g, 2.33 mmol, 1.00 equiv.) in CHCl (5 mL) was treated with HCl (gas) in 1,4-dioxane (5 mL, 4 M) for 5 minutes at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour and then concentrated. The residue was purified by reverse-phase flash chromatography (C18; mobile phase, MeCN / water (10 mmol / L NHHCO), 20% to 50% gradient over 25 minutes; detector: UV 220 nm) to give ethyl (3S)-3-amino-3-(5-bromo-3-chloro-2-fluorophenyl)propanoate (690 mg, 91.2%) as a yellow oil. LC-MS: (ES+H, m / z) [M+H] + =323.9. 1 H NMR(400MHz,DMSO-d6)δ7.80-7.70(m,2H),4.45(t,J=7.6,6.4Hz,1H),4.02(q, J=7.1Hz,2H),2.61(dd,J=7.0,2.9Hz,2H),2.24(s,2H),1.12(t,J=7.1Hz,3H). 19 F NMR (400MHz, DMSO-d6) 123.14.

[0241] Step 4: Preparation of ethyl (3S)-3-(5-bromo-3-chloro-2-fluorophenyl)-3-[(tert-butoxycarbonyl)amino]propanoate: To a stirred mixture of ethyl (3S)-3-amino-3-(5-bromo-3-chloro-2-fluorophenyl)propanoate (528 mg, 1.62 mmol, 1.00 equiv.) and BocO (532 mg, 2.44 mmol, 1.50 equiv.) in CHCl (8 mL), DIEA (630 mg, 4.88 mmol, 3.00 equiv.) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h and then concentrated. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether (20–50% in 25 min) to give ethyl (3S)-3-(5-bromo-3-chloro-2-fluorophenyl)-3-[(tert-butoxycarbonyl)amino]propanoate (580 mg, 83.9%) as a yellow oil. LC-MS: (ES-H, m / z) [MH] - =422.1.

[0242] Step 5: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[3-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate: To a stirred mixture of ethyl (3S)-3-(5-bromo-3-chloro-2-fluorophenyl)-3-[(tert-butoxycarbonyl)amino]propanoate (580 mg, 1.36 mmol, 1.00 equiv.) and bis(pinacolato)diboron (416 mg, 1.63 mmol, 1.20 equiv.) in 1,4-dioxane (8 mL), Pd(dppf)Cl.CHCl (55 mg, 0.06 mmol, 0.05 equiv.) and KOAc (268 mg, 2.73 mmol, 2.00 equiv.) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 3 hours and then cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether (30-60% in 25 min) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[3-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (415 mg, 64.4%) as a yellow oil. LC-MS: (ES+H, m / z) [M+H] + =472.2.

[0243] Step 6: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{5-chloro-4-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl}propanoate: To a stirred mixture of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[3-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (415 mg, 0.88 mmol, 1.00 equiv.) and 2-bromo-3-methylphenol (197 mg, 1.05 mmol, 1.20 equiv.) in 1,4-dioxane (5 mL), Pd(dppf)Cl.CHCl (35 mg, 0.04 mmol, 0.05 equiv.) and KCO (243 mg, 1.76 mmol, 2.00 equiv.) were added portionwise under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 3 h and then cooled to room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc, and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA (20% to 50% in 25 min) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{5-chloro-4-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl}propanoate (360 mg, 90.5%) as a yellow oil. LC-MS: (ES-H, m / z) [MH] - =450.1. 1 H NMR(400MHz,DMSO-d6)δ9.28(s,1H),7.60(d,J=8.7Hz,1H),7.30-7.17(m,2H),7.07(t,J=7.8Hz,1H),6.75(dd,J=12.5,7. 8Hz,2H), 5.27(q,J=8.0Hz,1H),4.07-4.01(m,2H),2.72(d,J=7.4Hz,2H),1.97(s,3H),1.34(s,9H),1.13(t,J=7.1Hz,3H). 19 F NMR (400MHz, DMSO-d6) 125.31.

[0244] Step 7: Preparation of ethyl (3S)-3-amino-3-{5-chloro-4-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride: A solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{5-chloro-4-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl}propanoate (360 mg, 0.79 mmol, 1.00 equiv.) in CHCl (2 mL) was treated with HCl (gas) in 1,4-dioxane (2 mL, 4 M) at room temperature under a nitrogen atmosphere for 3 minutes. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours and then concentrated in vacuo to give ethyl (3S)-3-amino-3-{5-chloro-4-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride (300 mg, crude) as a crude yellow oil. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z) [M+H] + =352.05. Intermediate 30 [ka]

[0245] Step 1: Preparation of 5-fluoro-2-iodo-3-methylphenol: To a stirred mixture of 3-fluoro-5-methylphenol (5.00 g, 39.64 mmol, 1.00 equiv) in PhCH (50 mL) was added NaH (3.17 g, 79.28 mmol, 2.00 equiv, 60% in mineral oil) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at room temperature for 30 min, and then I (10.06 g, 39.64 mmol, 1.00 equiv) was added dropwise. The resulting mixture was stirred at room temperature for an additional 3 h and then diluted with water (150 mL). The mixture was acidified to pH 3 with 3 M HCl (aq) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (1 × 300 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (gradient from 0% to 20% in 30 min)) to give 5-fluoro-2-iodo-3-methylphenol (900 mg, 9%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ10.73(s, 1H), 6.71(ddd, J=9.6, 2.9, 0.8Hz, 1H), 6.53(dd, J=10.5, 2.9Hz, 1H), 2.36(s, 3H).

[0246] Step 2: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4,4'-difluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate: To a stirred mixture of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (500 mg, 1.10 mmol, 1.00 equiv.) and 5-fluoro-2-iodo-3-methylphenol (307 mg, 1.21 mmol, 1.10 equiv.) in dioxane (10 mL) and HO (2 mL), Pd(dppf)Cl (81 mg, 0.11 mmol, 0.10 equiv.) and KCO (459 mg, 3.32 mmol, 3.00 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (gradient: 0% to 30% over 30 min)) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4,4'-difluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate (450 mg, 90.3%) as a white solid. LC-MS: (ES+H, m / z) [M+H] + =450.2. 1H NMR(300MHz,DMSO-d6)δ9.64(s,1H),7.51(d,J=8.9Hz,1H),7.02(d,J=6.5Hz,1H),6.95(dd,J=7.2,2.2Hz,1H),6.61-6.50(m,2H),5.27(d,J= 8.4Hz,1H), 4.04(ttd,J=7.1,4.5,2.3Hz,2H),2.65(d,J=7.4Hz,2H),2.24(d,J=2.0Hz,3H),1.95(s,3H),1.34(s,9H),1.14(t,J=7.1Hz,3H).

[0247] Step 3: Preparation of ethyl (3S)-3-amino-3-{4,4'-difluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride: To a stirred mixture of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4,4'-difluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate (350 mg, 0.77 mmol, 1.00 equiv.) in CHCl (2 mL) was added HCl (gas) in 1,4-dioxane (4 mL, 4 M) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour and then concentrated to give ethyl (3S)-3-amino-3-{4,4'-difluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride (350 mg, crude) as a white solid. LC-MS: (ES+H, m / z) [M+H] + =350.1. Intermediate 31 [ka]

[0248] Step 1: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4-fluoro-2'-hydroxy-4',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propanoate: To a stirred mixture of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (500 mg, 1.11 mmol, 1.00 equiv.) and 2-bromo-3,5-dimethylphenol (245 mg, 1.22 mmol, 1.10 equiv.) in dioxane (10 mL) and HO (0.5 mL), Pd(dppf)Cl (81 mg, 0.11 mmol, 0.10 equiv.) and KCO (459 mg, 3.32 mmol, 3.00 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours and then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (0-20% gradient over 30 min)) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4-fluoro-2'-hydroxy-4',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propanoate (300 mg, 60.8%) as a pale yellow solid. LC-MS: (ES+H, m / z) [M+H-tBu] + =390.1. 1 H NMR(300MHz,DMSO-d6)δ8.96(s,1H),7.51(d,J=8.9Hz,1H),7.01(d,J=6.7Hz,1H),6.93(d,J=7.2Hz,1H),6.55(d,J=5.3Hz,2H),5. 27(d,J=8.0Hz,1H),4.08-4.00(m,2H),2.65(d,J=7.3Hz,2H),2.26-2.19(m,6H),1.91(s,3H),1.34(s,9H),1.14(t,J=7.1Hz,3H). 19 F NMR(282MHz,DMSO-d6)δ-127.73.

[0249] Step 2: Preparation of ethyl (3S)-3-amino-3-{4-fluoro-2'-hydroxy-4',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride: To a stirred mixture of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4-fluoro-2'-hydroxy-4',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propanoate (280 mg, 0.63 mmol, 1.00 equiv.) in CHCl (5 mL) was added dropwise at room temperature under a nitrogen atmosphere with HCl (gas) in 1,4-dioxane (5 mL, 4 M). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours and then concentrated to give ethyl (3S)-3-amino-3-{4-fluoro-2'-hydroxy-4',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride (260 mg, crude) as a pale yellow oil. LC-MS: (ES+H, m / z) [M+H] + =346.1. Intermediate 32 [ka]

[0250] Step 1: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-fluoro-2'-hydroxy-5-methyl-6'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate: To a stirred solution of 2-bromo-3-(trifluoromethyl)phenol (0.53 g, 2.22 mmol, 1.00 equiv.) and ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (1.00 g, 2.21 mmol, 1.00 equiv.) in dioxane (10 mL) and water (1 mL), Pd(dppf)ClCHCl (0.09 g, 0.11 mmol, 0.05 equiv.) and KHPO (0.9 g, 6.65 mmol, 3.00 equiv.) were added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere and then cooled to room temperature. The resulting mixture was diluted with EtOAc (200 mL). The residue was washed with water (2 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (gradient from 0% to 30% in 30 min)) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-fluoro-2'-hydroxy-5-methyl-6'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate (350 mg, 32.5%) as a yellow oil. LC-MS: (ES+H, m / z) [M+H] + =486.2.

[0251] Step 2: Preparation of ethyl (3S)-3-amino-3-[4-fluoro-2'-hydroxy-5-methyl-6'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate hydrochloride: To a stirred solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-fluoro-2'-hydroxy-5-methyl-6'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate (500 mg, 1.03 mmol, 1.00 equiv.) in CHCl (6 mL) was added dropwise under a nitrogen atmosphere at 0°C with HCl (gas) in 1,4-dioxane (3 mL, 4 M). The resulting mixture was stirred at room temperature for 3 hours and then concentrated to give ethyl (3S)-3-amino-3-[4-fluoro-2'-hydroxy-5-methyl-6'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate hydrochloride (470 mg, crude) as a yellow oil. LC-MS: (ES+H, m / z) [M+H] + =386.1 Intermediate 33 [ka]

[0252] Step 1: Preparation of tert-butyl 2-(5-bromo-2-fluorophenyl)-2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate: To a stirred solution of tert-butyl 2-(5-bromo-2-fluorophenyl)-2-(methanesulfonyloxy)acetate (654 mg, 1.70 mmol, 1.00 equiv.) and 5-[2-(dimethylamino)ethyl]-4-(trifluoromethyl)-1H-pyridin-2-one (400 mg, 1.70 mmol, 1.00 equiv.) in CHCN (12 mL) was added KCO (472 mg, 3.41 mmol, 2.00 equiv.) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60° C. under a nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature and then diluted with water (50 mL). The resulting mixture was extracted with CHCl (4×100 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by reverse-phase flash chromatography (C18; mobile phase, MeCN / water (0.1% NH3.HO), 50% to 70% gradient in 15 min; detector: UV 220 nm) to give tert-butyl 2-(5-bromo-2-fluorophenyl)-2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (463 mg, 52.0%) as a pale yellow liquid. LC-MS: (ES+H, m / z) [M+H] + =521.05. 1 H NMR(400MHz,DMSO-d6)δ7.77-7.69(m,2H),7.62(dd,J=6.5,2.5Hz,1H),7.36(dd,J=10.0,8.8Hz ,1H),6.88(s,1H),6.53(s,1H),2.56-2.52(m,2H),2.40-2.25(m,2H),2.05(s,6H),1.42(s,9H). 19 F NMR (400MHz, DMSO-d6) 62.69, -116.59.

[0253] Step 2: Preparation of (5-bromo-2-fluorophenyl)({5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl})acetic acid: To a stirred solution of tert-butyl 2-(5-bromo-2-fluorophenyl)-2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (400 mg, 0.76 mmol, 1.00 equiv) in CHCl (4 mL) was added dropwise under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred overnight under a nitrogen atmosphere at 30 °C, then cooled to room temperature and concentrated. The residue was purified by trituration with EtO (20 mL) to give (5-bromo-2-fluorophenyl)({5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetic acid (485 mg, crude) as a white solid. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z) [M+H] + =465.0. 1 H NMR(400MHz,DMSO-d6)δ9.82(s,1H),7.83(s,1H),7.74-7.65(m,2H),7.36-7. 27(m,1H),6.95(s,1H),6.54(s,1H),3.15(t,J=8.5Hz,2H),2.89-2.77(m,8H). 19 F NMR(400MHz,DMSO-d6)62.63,-116.49. Intermediate 34 [ka]

[0254] Step 1: Preparation of 2-bromo-4-fluoro-3-methylphenol: To a stirred mixture of 4-fluoro-3-methylphenol (5.00 g, 39.64 mmol, 1.00 equiv.) in CH3COOH (150 mL) was added Br2 (2 mL, 39.64 mmol, 1.00 equiv.) in HO (20 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for 2 h and then diluted with diethyl ether (500 mL). The residue was washed with Na2SO3 (1 × 400 mL), NaHCO3 (1 × 400 mL), and then concentrated. The residue was purified by silica gel column chromatography (CHCl2 / PE (0% to 10% gradient over 30 min)) to give 2-bromo-4-fluoro-3-methylphenol (5 g, crude) as a yellow solid. The crude product (2.5 g) was further purified by preparative SFC (column: NB_CHIRALPAK AD, 3 × 25 cm, 5 μm; mobile phase A: CO, mobile phase B: CHOH:EtOH:Hexane = 1:1:2 (20 mM NNH); flow rate: 100 mL / min; gradient: isocratic 10% B; column temperature (°C): 35; back pressure (bar): 120; wavelength: 285 / 260 nm; sample solvent: CHOH-HPLC; injection volume: 0.2 mL) to give 2-bromo-4-fluoro-3-methylphenol (1.2 g, 14.7%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ6.93(t,J=8.8Hz,1H),6.85(dd,J=9.0,4.9Hz,1H),2.33(d,J=2.4Hz,3H).

[0255] Step 2: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{3',4-difluoro-6'-hydroxy-2',5-dimethyl-[1,1'-biphenyl]-3-yl}propanoate: To a stirred mixture of 2-bromo-4-fluoro-3-methylphenol (190 mg, 0.93 mmol, 1.05 equiv.) and ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (400 mg, 0.88 mmol, 1.00 equiv.) in dioxane (10 mL) and HO (1 mL), KCO (367 mg, 2.65 mmol, 3.00 equiv.) and Pd(dppf)Cl (64 mg, 0.08 mmol, 0.10 equiv.) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 2 hours and then cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 100 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (gradient: 0% to 30% in 30 min)) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{3',4-difluoro-6'-hydroxy-2',5-dimethyl-[1,1'-biphenyl]-3-yl}propanoate (250 mg, 62.7%) as a white solid. LC-MS: (ES+H, m / z) [M+H] + =450.2.

[0256] Step 3: Preparation of ethyl (3S)-3-amino-3-{3',4-difluoro-6'-hydroxy-2',5-dimethyl-[1,1'-biphenyl]-3-yl}propanoate: To a stirred mixture of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{3',4-difluoro-6'-hydroxy-2',5-dimethyl-[1,1'-biphenyl]-3-yl}propanoate (250 mg, 0.55 mmol, 1.00 equiv.) in CHCl (2 mL) was added HCl (gas) in 1,4-dioxane (4 mL, 4 M) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at room temperature for 1 h and then concentrated. The residue was purified by reverse-phase flash chromatography (C18 gel; mobile phase, MeCN / water (0.1% NH3.HO), 10% to 60% gradient in 30 min; detector: UV 220 nm) to give ethyl (3S)-3-amino-3-{3',4-difluoro-6'-hydroxy-2',5-dimethyl-[1,1'-biphenyl]-3-yl}propanoate (180 mg, 92.6%) as a white solid. LC-MS: (ES+H, m / z) [M+H] + =350.1. Intermediates 35 and 36 [ka]

[0257] Step 1: Preparation of (R)-N-[(1Z)-(5-bromo-2,3-difluorophenyl)methylidene]-2-methylpropane-2-sulfinamide: To a stirred solution of 5-bromo-2,3-difluorobenzaldehyde (9.00 g, 40.72 mmol, 1.00 equiv.) and (R)-2-methylpropane-2-sulfinamide (5.43 g, 44.79 mmol, 1.10 equiv.) in THF (90 mL) was added Ti(Oi-Pr) (23.15 g, 81.44 mmol, 2.00 equiv.) dropwise at 20 °C under a nitrogen atmosphere. The resulting mixture was stirred at 35 °C under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to 0 °C and quenched with water at 0 °C. The resulting mixture was diluted and extracted with ethyl acetate (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL), and the combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA (50:1 to 7:1)) to give (R)-N-[(1Z)-(5-bromo-2,3-difluorophenyl)methylidene]-2-methylpropane-2-sulfinamide (13.00 g, 98.4%) as an off-white solid. LC-MS: (ES+H, m / z) [M+H] + =323.8. 1 H NMR (400MHz, CDCl3) δ8.74 (s, 1H), 7.82-7.78 (m, 1H), 7.42-7.38 (m, 1H), 1.21 (s, 9H).

[0258] Step 2: Preparation of ethyl (3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate: To a stirred mixture of Zn (7.26 g, 111.04 mmol, 4.00 equiv.) and THF (75 mL), TMSCl (0.60 g, 5.55 mmol, 0.20 equiv.) was added dropwise at 20° C. under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to 20° C., and ethyl bromoacetate (11.59 g, 69.40 mmol, 2.50 equiv.) was added dropwise at 20° C. under a nitrogen atmosphere. The resulting mixture was stirred at 60° C. for an additional 1 h. The mixture was then cooled to 0° C. and treated dropwise with a solution of (R)—N-[(1Z)-(5-bromo-2,3-difluorophenyl)methylidene]-2-methylpropane-2-sulfinamide (9.00 g, 27.76 mmol, 1.00 equiv) in THF (15 mL). The resulting mixture was stirred at room temperature for an additional 1 h, cooled to 0° C., and quenched with water at 0° C. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (2×200 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA (60:1 to 5:1)) to give ethyl (3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate (7.00 g, 61.1%) as an off-white oil. LC-MS: (ES+H, m / z) [M+H] + =411.85. 1 H NMR(300MHz,DMSO-d6)δ7.73(ddd,J=9.7,6.9,2.4Hz,1H),7.57(dt,J=5.1,2.1Hz,1H),5.84(d,J=7.0H z,1H),4.95-4.92(m,1H),4.03(q,J=7.1Hz,2H),3.07-2.84(m,2H),1.12(t,J=7.1Hz,3H),1.05(s,9H).

[0259] Step 3: Preparation of (S)-ethyl 3-amino-3-(5-bromo-2,3-difluorophenyl)propanoate: To a stirred mixture of (S)-ethyl 3-(5-bromo-2,3-difluorophenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate (2.00 g, 5.07 mmol, 1.00 equiv.) in DCM (5 mL) was added dropwise HCl (gas) in 1,4-dioxane (10 mL, 4 M) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours and then concentrated in vacuo to give ethyl (S)-3-amino-3-(5-bromo-2,3-difluorophenyl)propanoate (1.3 g, 88.3%) as a yellow oil. LC-MS: (ES+H, m / z) [M+H] + =308.0.

[0260] Step 4: Preparation of ethyl (3S)-3-(5-bromo-2,3-difluorophenyl)-3-[(tert-butoxycarbonyl)amino]propanoate: To a stirred mixture of ethyl (3S)-3-amino-3-(5-bromo-2,3-difluorophenyl)propanoate (1.47 g, 4.77 mmol, 1.00 equiv.) in CHCl (20 mL) was added BocO (2.08 g, 9.54 mmol, 2.00 equiv.) and DIEA (1.85 g, 14.31 mmol, 3.00 equiv.) at room temperature. After 2 h at room temperature, the resulting mixture was diluted with water (50 mL) and extracted with CHCl (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0% to 20% gradient in 25 min)) to give ethyl (3S)-3-(5-bromo-2,3-difluorophenyl)-3-[(tert-butoxycarbonyl)amino]propanoate (1.53 g, 78.5%) as a white solid. LC-MS: (ES-H, m / z) [MH] - =406.0.

[0261] Step 5: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate: To a stirred mixture of (3S)-ethyl 3-(5-bromo-2,3-difluorophenyl)-3-[(tert-butoxycarbonyl)amino]propanoate (1 g, 2.45 mmol, 1.00 equiv.) in dioxane (10 mL), Pd(dppf)Cl.CHCl (0.14 g, 0.24 mmol, 0.10 equiv.), KOAc (0.72 g, 7.35 mmol, 3.00 equiv.), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (0.62 g, 2.45 mmol, 1.00 equiv.) were added in portions at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h, cooled to room temperature, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0% to 20% gradient in 25 min)) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (610 mg, 54.7%) as a yellow oil. LC-MS: (ES+H, m / z) [M+H-Boc] + =356.1.

[0262] Step 6: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4,5-difluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl}propanoate: To a stirred mixture of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (500 mg, 1.09 mmol, 1.00 equiv.) and 2-bromo-3-methylphenol (246 mg, 1.32 mmol, 1.20 equiv.) in dioxane (10 mL) and HO (1 mL), KCO (455 mg, 3.29 mmol, 3.00 equiv.) and Pd(dppf)Cl.CHCl (89 mg, 0.11 mmol, 0.10 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h, then cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0% to 20% gradient in 25 min)) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4,5-difluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl}propanoate (410 mg, 85.7%) as a pale yellow oil. LC-MS: (ES+H, m / z) [M+H-Boc] + =336.1.

[0263] Step 7: Preparation of ethyl (3S)-3-amino-3-{4,5-difluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride: To a stirred mixture of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4,5-difluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl}propanoate (410 mg, 0.94 mmol, 1.00 equiv.) in CHCl (3 mL) was added HCl (gas) in 1,4-dioxane (3 mL, 4 M) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour and then concentrated to give ethyl (3S)-3-amino-3-{4,5-difluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride (370 mg, crude) as a colorless oil. LC-MS: (ES+H, m / z) [M+H] + =336.1. Intermediates 37 and 38 [ka]

[0264] Step 1: Preparation of (R)-N-[(1E)-(5-bromo-2-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide: To a stirred solution of 5-bromo-2-fluorobenzaldehyde (10.50 g, 51.72 mmol, 1.00 equiv.) and (R)-2-methylpropane-2-sulfinamide (7.52 g, 62.06 mmol, 1.20 equiv.) in THF (150 mL) was added tetrakis(propan-2-yloxy)titanium (22.05 g, 77.58 mmol, 1.50 equiv.) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 2 hours under a nitrogen atmosphere and then cooled to room temperature. To the above mixture was added water (500 mL) and EtOAc (200 mL). The resulting mixture was stirred at room temperature for an additional 10 minutes. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3×100 mL). The aqueous layer was extracted with EtOAc (2×500 mL) and the combined organic layers were washed with brine (3×500 mL), dried over anhydrous NaSO, filtered, and concentrated to give (R)—N-[(1E)-(5-bromo-2-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide (15.40 g, 97.2%) as a pale yellow oil. LC-MS: (ES+H, m / z) [M+H] + =305.9.

[0265] Step 2: Preparation of ethyl (3S)-3-(5-bromo-2-fluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate: A solution of Zn (12.81 g, 195.95 mmol, 4.00 equiv) in THF (200 mL) was treated with TMSCl (1.06 g, 9.79 mmol, 0.20 equiv) under a nitrogen atmosphere at 60° C. for 1 hour, followed by the dropwise addition of ethyl 2-bromoacetate (20.45 g, 122.47 mmol, 2.50 equiv) at 0° C. The resulting mixture was stirred at 60° C. for 1 hour under a nitrogen atmosphere. To the above mixture was added dropwise (R)—N-[(1E)-(5-bromo-2-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide (15.00 g, 48.98 mmol, 1.00 equiv) at 0° C. The resulting mixture was stirred at room temperature for 2 hours and then quenched with water at 0° C. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 200 mL). The combined filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc (0% to 30% in 20 min) to give ethyl (3S)-3-(5-bromo-2-fluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate (10.75 g, 55.6%) as a colorless oil. LC-MS: (ES+H, m / z) [M+H] + =393.90. 1 H NMR(300MHz,CDCl3)δ7.55-7.36(m,2H),7.01-6.91(m,1H),5.03(q,J=6.1Hz,1H),4. 75(d,J=5.9Hz,1H),4.14(q,J=7.2Hz,2H),3.02-2.86(m,2H),1.25(d,J=6.5Hz,12H). 19 F NMR(282MHz, CDCl3)δ-119.47.

[0266] Step 3: Preparation of ethyl (3S)-3-amino-3-(5-bromo-2-fluorophenyl)propanoate: A solution of ethyl (3S)-3-(5-bromo-2-fluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate (6.30 g, 15.98 mmol, 100 equiv.) and HCl (gas) in 1,4-dioxane (4 M, 100 mL) in CHCl (50 mL) was stirred overnight at room temperature under a nitrogen atmosphere and then concentrated under reduced pressure. The residue was dissolved in water (150 mL) and washed with EtOAc (2 × 50 mL). The aqueous layer was then basified to pH 10 with NH HO and extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous NaSO, filtered, and concentrated to give ethyl (3S)-3-amino-3-(5-bromo-2-fluorophenyl)propanoate (4.30 g, crude, ee% = 98.5%) as a pale yellow oil. The crude product was used directly in the next step without further purification. LC-MS: (ES + H, m / z) [M + H] + =290.05. 1 H NMR(300MHz,CDCl3)δ7.62(dd,J=6.5,2.5Hz,1H),7.39-7.32(m,1H),6.94(dd,J=10.1,8.7Hz,1H),4.6 5(dd,J=8.6,4.7Hz,1H),4.17(q,J=7.1Hz,2H),2.79-2.59(m,2H),1.85(s,2H),1.26(t,J=7.1Hz,3H). 19 F NMR(282MHz, CDCl3)δ-120.93.

[0267] Step 4: Preparation of ethyl (3S)-3-(5-bromo-2-fluorophenyl)-3-[(tert-butoxycarbonyl)amino]propanoate: A solution of ethyl (3S)-3-amino-3-(5-bromo-2-fluorophenyl)propanoate (4.20 g, 14.48 mmol, 1.00 equiv.), (Boc)O (6.32 g, 28.95 mmol, 2.00 equiv.), and DIEA (5.61 g, 43.43 mmol, 3.00 equiv.) in DCM (150 mL) was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was diluted with water (150 mL) and extracted with CHCl (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0% to 50% in 20 min) to give ethyl (3S)-3-(5-bromo-2-fluorophenyl)-3-[(tert-butoxycarbonyl)amino]propanoate (5.50 g, 97.4%) as a white solid. LC-MS: (ES+H, m / z) [M+H-tBu] + =333.95. 1 H NMR(300MHz,CDCl3)δ7.45(dd,J=6.7,2.5Hz,1H),7.39-7.32(m,1H),6.93(dd,J=10.1,8.7Hz,1H ),5.66(s,1H),4.08(q,J=7.1Hz,2H),2.82(d,J=6.0Hz,2H),1.43(s,9H),1.18(t,J=7.1Hz,3H). 19 F NMR (282MHz, CDCl3)δ-120.24.

[0268] Step 5: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate: A mixture of ethyl (3S)-3-(5-bromo-2-fluorophenyl)-3-[(tert-butoxycarbonyl)amino]propanoate (5.40 g, 13.84 mmol, 1.00 equiv.), bis(pinacolato)diboron (7.03 g, 27.67 mmol, 2.00 equiv.), Pd(dppf)Cl (1.01 g, 1.38 mmol, 0.10 equiv.), and KOAc (2.72 g, 27.67 mmol, 2.00 equiv.) in 1,4-dioxane (100 mL) was stirred at 100 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (3 × 150 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc (0% to 60% in 20 min) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (5.10 g, 84.3%) as a light brown oil. LC-MS: (ES+H, m / z) [M+H-tBu] + =382.10. 1 H NMR(300MHz,CDCl3)δ7.80-7.67(m,2H),7.04(dd,J=11.0,8.2Hz,1H),5.48(s,1H),5.35(s,1H) ),4.10(p,J=7.1Hz,2H),2.94-2.72(m,2H),1.43(s,9H),1.34(s,12H),1.19(t,J=7.1Hz,3H). 19 F NMR(282MHz, CDCl3)δ-113.67.

[0269] Step 6: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl}propanoate: A solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (5.00 g, 11.43 mmol, 1.00 equiv.), 2-bromo-3-methylphenol (2.25 g, 12.00 mmol, 1.05 equiv.), KCO (3.16 g, 22.87 mmol, 2.00 equiv.), and Pd(dppf)Cl (418 mg, 0.57 mmol, 0.05 equiv.) in 1,4-dioxane (100 mL) and HO (5 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature, diluted with water (100 mL), and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (3 × 150 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc (0% to 60% in 20 min) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl}propanoate (3.20 g, 67.0%) as a pale yellow oil. LC-MS: (ES+H, m / z) [M+Na + ] + =440.2. 1 H NMR(300MHz,CDCl3)δ7.31(d,J=7.1Hz,1H),7.23-7.15(m,3H),6.86(d,J=7.8Hz,2H),5.77(d,J=8.7Hz,1H),5.38(s,1H) ,4.80(s,1H),4.11(ddd,J=11.7,8.4,6.0Hz,2H),2.91(d,J=5.7Hz,2H),2.06(s,3H),1.43(s,9H),1.20(t,J=7.1Hz,3H). 19 F NMR(282MHz, CDCl3)δ-119.04.

[0270] Step 7: Preparation of ethyl (3S)-3-amino-3-{4-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl}propanoate: A solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl}propanoate (3.00 g, 7.19 mmol, 1.00 equiv) and HCl gas in 1,4-dioxane (4 M, 50 mL) in CHCl (50 mL) was stirred at room temperature under a nitrogen atmosphere for 4 hours and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18; mobile phase, MeCN / water (0.1% NH3.HO), 40% to 70% gradient in 15 min; detector: UV 220 nm) to give ethyl (3S)-3-amino-3-{4-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl}propanoate (2.00 g, 87.7%) as a brown solid. LC-MS: (ES+H, m / z) [M+H] + =318.05. Intermediate 39 [ka]

[0271] Step 1: Preparation of 2-bromo-3,4-dimethylphenol: To a stirred mixture of 3,4-dimethylphenol (5.00 g, 40.93 mmol, 1.00 equiv) in CHCOOH (120 mL) was added Br (2.1 mL, 40.93 mmol, 1.00 equiv) in HO (17 mL) and CHCOOH (10 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The resulting mixture was diluted with diethyl ether (600 mL) and washed with NaSO (aq., 0.63 M) (1 × 500 mL) and saturated NaHCO (aq.) (1 × 500 mL). The organic layer was then dried over anhydrous NaSO, filtered, and concentrated. The residue was first purified by silica gel column chromatography (PE / CH2Cl2 (0% to 30% in 50 min) to give 2-bromo-3,4-dimethylphenol (700 mg, crude) as a white solid, which was then further purified by preparative SFC (column: CHIRALPAK IG-3, 4.6 × 50 Purification by HPLC (MS): 284 / 220 nm; RT1 (min): 7.65; RT2 (min): 8.57; sample solvent: CHOH:CHCl = 16:1; injection volume: 0.2 mL) afforded 2-bromo-3,4-dimethylphenol (290 mg, 3.5%) as a pale yellow solid. LC-MS: (ES-H, m / z) [MH] - =199.98. 1 H NMR (300MHz, DMSO-d6) δ9.79 (s, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 2.27 (s, 3H), 2.19 (s, 3H).

[0272] Step 2: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4-fluoro-6'-hydroxy-2',3',5-trimethyl-[1,1'-biphenyl]-3-yl}propanoate: To a stirred mixture of 2-bromo-3,4-dimethylphenol (220 mg, 1.09 mmol, 1.00 equiv.) and ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (494 mg, 1.09 mmol, 1.00 equiv.) in 1,4-dioxane (5 mL):HO (0.5 mL) was added KCO (454 mg, 3.28 mmol, 3.00 equiv.) and Pd(dppf)Cl.CHCl (178 mg, 0.22 mmol, 0.20 equiv.) at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h, then cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (20% to 100% in 40 min) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4-fluoro-6'-hydroxy-2',3',5-trimethyl-[1,1'-biphenyl]-3-yl}propanoate (300 mg, 61.5%) as a pale yellow solid. LC-MS: (ES+H, m / z) [M+H] + =446.2. 1 H NMR(300MHz,DMSO-d6)δ8.82(s,1H),7.48(d,J=8.4Hz,1H),7.03(d,J=6.8Hz,1H),6.93(dd,J=8.2,3.5Hz,2H),6.65(d,J=8.1Hz,1H),5.39-5. 17(m,1H),4.08-4.00(m,2H),2.66(d,J=7.5Hz,2H),2.24(d,J=1.9Hz,3 H),2.15(s,3H),1.83(d,J=6.8Hz,3H),1.34(s,9H),1.19-1.11(m,3H).

[0273] Step 3: Preparation of ethyl (3S)-3-amino-3-{4-fluoro-6'-hydroxy-2',3',5-trimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride: To a stirred solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4-fluoro-6'-hydroxy-2',3',5-trimethyl-[1,1'-biphenyl]-3-yl}propanoate (250 mg, 0.56 mmol, 1.00 equiv.) in CHCl (2 mL) was added dropwise at room temperature under a nitrogen atmosphere with HCl (gas) in 1,4-dioxane (2 mL, 8.00 mmol, 14.26 equiv., 4 M). The resulting mixture was stirred at room temperature for 1 hour and then concentrated. The resulting solid was treated with THF (10 mL) and concentrated to give ethyl (3S)-3-amino-3-{4-fluoro-6'-hydroxy-2',3',5-trimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride (240 mg, crude) as a pale yellow solid. LC-MS: (ES+H, m / z) [M+H] + =346.2. Intermediates 40 and 41 [ka]

[0274] Step 1: Preparation of 4-bromo-2-(difluoromethyl)-1-fluorobenzene: To a stirred mixture of 5-bromo-2-fluorobenzaldehyde (50.00 g, 246.29 mmol, 1.00 equiv) in CHCl (500 mL) was added BAST (108.98 g, 492.59 mmol, 2.00 equiv) dropwise under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at room temperature overnight and then quenched with water at 0 °C. The resulting mixture was diluted with water (500 mL) and then extracted with CHCl (3 × 500 mL). The combined organic layers were washed with brine (3 × 500 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / CHCl (0–5% gradient over 30 min)) to give 4-bromo-2-(difluoromethyl)-1-fluorobenzene (45.00 g, 81.2%) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ7.87-7.79 (m, 2H), 7.43-7.35 (m, 1H), 7.20 (t, J = 53.9Hz, 1H). 19 F NMR (377MHz, DMSO-d6) δ -113.77, -119.77.

[0275] Step 2: Preparation of 5-bromo-3-(difluoromethyl)-2-fluorobenzaldehyde: To a stirred solution of 4-bromo-2-(difluoromethyl)-1-fluorobenzene (45.00 g, 199.99 mmol, 1.00 equiv) in THF (400 mL) was added LDA (150 mL, 299.99 mmol, 1.50 equiv, 2 M in THF) dropwise at −78° C. under a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 1 hour under a nitrogen atmosphere. To the above mixture was added DMF (77 mL, 999.97 mmol, 5.00 equiv) dropwise at −78° C. The resulting mixture was stirred at −78° C. for 1 hour and then quenched with saturated NH4Cl (aq) at 0° C. The resulting mixture was diluted with EtOAc (1000 mL), washed with water (3×500 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0 to 10% gradient in 40 min)) to give 5-bromo-3-(difluoromethyl)-2-fluorobenzaldehyde (38.00 g, 75.1%) as a yellow solid. 1 H NMR (300MHz, DMSO-d6) δ10.15 (s, 1H), 8.19-8.10 (m, 2H), 7.28 (t, J = 53.6Hz, 1H). 19 F NMR(282MHz,DMSO-d6)δ-114.11,-126.83.

[0276] Step 3: Preparation of (R,E)-N-(5-bromo-3-(difluoromethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide: To a stirred mixture of 5-bromo-3-(difluoromethyl)-2-fluorobenzaldehyde (38.00 g, 150.19 mmol, 1.00 equiv.) and (R)-2-methylpropane-2-sulfinamide (20.02 g, 165.21 mmol, 1.10 equiv.) in THF (360 mL) was added tetrakis(propan-2-yloxy)titanium (85.37 g, 300.37 mmol, 2.00 equiv.) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours, then diluted with EtOAc (300 mL) and water (300 mL) and filtered. The filter cake was washed with EtOAc (3 × 100 mL), and the combined filtrate was concentrated under reduced pressure. The combined organic layers were washed with brine (3 × 300 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0-20% gradient in 40 min)) to give (R,E)-N-(5-bromo-3-(difluoromethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (44.00 g, 82.2%) as a white solid. LC-MS: (ES-H, m / z) [M+H] + =356.0. 1 H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.28(dd,J=6.0,2.6Hz,1H),8.05(dd,J=6.0,2.7Hz,1H),7.27(t,J=53.7Hz,1H),1.21(s,9H). 19 F NMR(376MHz,DMSO-d6)δ-114.18,-124.78.

[0277] Step 4: Preparation of ethyl (S)-3-(5-bromo-3-(difluoromethyl)-2-fluorophenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate: To a stirred solution of Zn (14.68 g, 224.59 mmol, 4.00 equiv.) in THF (20 mL) was added TMSCl (2.44 g, 22.46 mmol, 0.40 equiv.) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60° C. for 1 hour under a nitrogen atmosphere. To the above mixture was added 2-bromoethyl acetate (23.44 g, 140.37 mmol, 2.50 equiv.) dropwise at room temperature. The resulting mixture was stirred at 50° C. for an additional 1 hour, and then (R,E)-N-(5-bromo-3-(difluoromethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (20.00 g, 56.15 mmol, 1.00 equiv.) in THF (10 mL) was added dropwise at −20° C. The resulting mixture was stirred at room temperature for 1 hour, then diluted with water (200 mL) and EtOAc (200 mL), and filtered. The filter cake was washed with EtOAc (3 × 50 mL), and the aqueous layer was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (30% to 60% gradient over 40 min)) to afford ethyl (3S)-3-[5-bromo-3-(difluoromethyl)-2-fluorophenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate (19.50 g, 78.1%) as a yellow oil. LC-MS: (ES+H, m / z) [M+H] + =444.0. 1 H NMR(400MHz,CDCl3)δ7.68-7.61(m,2H),6.84(t,J=54.7Hz,1H),5.05(dt,J=7.0,5.5Hz,1H),4.80(d ,J=5.8Hz,1H),4.16-4.08(m,2H),2.93(qd,J=16.2,6.1Hz,2H),1.24(s,9H),1.21(t,J=7.1Hz,3H).

[0278] Step 5: Preparation of (S)-ethyl 3-amino-3-(5-bromo-3-(difluoromethyl)-2-fluorophenyl)propanoate: To a stirred solution of ethyl (3S)-3-[5-bromo-3-(difluoromethyl)-2-fluorophenyl]-3-{[(S)-2-methylpropane-2-sulfinyl]amino}propanoate (19.30 g, 43.44 mmol, 1.00 equiv.) in CHCl (50 mL) was added dropwise at room temperature under a nitrogen atmosphere with HCl (gas) in 1,4-dioxane (150 mL, 600.00 mmol, 13.81 equiv., 4 M). The resulting mixture was stirred at room temperature for 2 h and concentrated. The residue was diluted with water (residue 100 mL) and basified to pH 10 with NH H0. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous NaSO, filtered, and concentrated to give ethyl (S)-3-amino-3-(5-bromo-3-(difluoromethyl)-2-fluorophenyl)propanoate (14.00 g, 93.7%) as a yellow oil. LC-MS: (ES+H, m / z) [M+H] + =340.0.

[0279] Step 6: Preparation of (S)-ethyl 3-(5-bromo-3-(difluoromethyl)-2-fluorophenyl)-3-((tert-butoxycarbonyl)amino)propanoate: To a stirred solution of (S)-ethyl 3-amino-3-(5-bromo-3-(difluoromethyl)-2-fluorophenyl)propanoate (13.70 g, 40.28 mmol, 1.00 equiv.) in CHCl (140 mL) was added DIEA (15.62 g, 120.83 mmol, 3.00 equiv.) and BocO (17.58 g, 80.56 mmol, 2.00 equiv.) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h, then diluted with CHCl (400 mL) and washed with water (3 × 200 mL). The organic layer was washed with brine (3 × 200 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0-20% gradient in 40 min)) to give (S)-ethyl 3-(5-bromo-3-(difluoromethyl)-2-fluorophenyl)-3-((tert-butoxycarbonyl)amino)propanoate (14.80 g, 83.4%) as a white solid. LC-MS: (ES-H, m / z) [MH] - =438.0. 1 1H NMR(400MHz,DMSO-d6)δ7.81(dd,J=6.3,2.5Hz,1H),7.73(dd,J=5.8,2.5Hz,1H),7.66(d,J=8.5Hz,1H),7.19(t,J=53.9Hz ,1H),5.22(q,J=8.0Hz,1H),4.03(tq,J=7.1,3.3Hz,2H),2.71(dt,J=15.4,8.1Hz,2H),1.35(s,9H),1.12(t,J=7.1Hz,3H).

[0280] Step 7: Preparation of (S)-ethyl 3-((tert-butoxycarbonyl)amino)-3-(3-(difluoromethyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate: To a stirred mixture of (S)-ethyl 3-(5-bromo-3-(difluoromethyl)-2-fluorophenyl)-3-((tert-butoxycarbonyl)amino)propanoate (4.00 g, 9.09 mmol, 1.00 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.31 g, 9.09 mmol, 1.00 equiv) in 1,4-dioxane (50 mL) was added Pd(dppf)Cl.CHCl (0.74 g, 0.91 mmol, 0.10 equiv) and KOAc (2.68 g, 27.26 mmol, 3.00 equiv). The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 2 hours, then cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0-20% gradient over 30 minutes)) to give ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(3-(difluoromethyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (2.90 g, 65.5%) as a yellow oil. LC-MS: (ES+H, m / z) [M+H-tBu] + =430.1. 1 H NMR(300MHz,DMSO-d6)δ7.95(d,J=7.3Hz,1H),7.76(dd,J=14.3,7.6Hz,2H),7.23(t,J=54.2Hz,1H),5.25(q ,J=7.9Hz,1H),4.06-3.99(m,2H),2.72(qd,J=15.6,7.5Hz,2H),1.41-1.28(m,21H),1.11(t,J=7.1Hz,3H).

[0281] Step 8: Preparation of (S)-ethyl 3-((tert-butoxycarbonyl)amino)-3-(5-(difluoromethyl)-4-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate: To a stirred mixture of (S)-ethyl 3-((tert-butoxycarbonyl)amino)-3-(3-(difluoromethyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (1.00 g, 2.05 mmol, 1.00 equiv.) and 2-bromo-3-methylphenol (0.58 g, 3.08 mmol, 1.50 equiv.) in 1,4-dioxane (20 mL) and HO (1 mL) was added Pd(dppf)Cl.CHCl (0.17 g, 0.21 mmol, 0.10 equiv.) and KCO (0.85 g, 6.16 mmol, 3.00 equiv.). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours and then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (0% to 20% gradient over 30 min)) to give (S)-ethyl 3-((tert-butoxycarbonyl)amino)-3-(5-(difluoromethyl)-4-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate (660 mg, 68.8%) as a yellow solid. LC-MS: (ES+H, m / z) [M+H-tBu] + =412.1. 1 H NMR(400MHz,DMSO-d6)δ9.28(s,1H),7.60(d,J=8.8Hz,1H),7.45(d,J=6.6Hz,1H),7.36-7.20(m,2H),7.08(t,J=7.8Hz,1H),6.76(dd,J=11.0,7.8 Hz,2H),5.31(d,J=8.4Hz,1H),4.02(qt,J=6.9,4.7Hz,2H),2.83-2.64(m ,2H),1.98(d,J=10.4Hz,3H),1.34(s,9H),1.15(dt,J=21.0,7.1Hz,3H).

[0282] Step 9: Preparation of (S)-3-amino-3-(5-(difluoromethyl)-4-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate ethyl hydrochloride: To a stirred solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[5-(difluoromethyl)-4-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl]propanoate (600 mg, 1.28 mmol, 1.00 equiv.) in CHCl (5 mL) was added dropwise under a nitrogen atmosphere at room temperature with HCl (gas) in 1,4-dioxane (5 mL, 20.00 mmol, 15.58 equiv., 4 M). The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour and then concentrated to give ethyl (S)-3-amino-3-(5-(difluoromethyl)-4-fluoro-2'-hydroxy-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride (510 mg, crude) as a yellow solid. LC-MS: (ES+H, m / z) [M+H] + =368.2. Intermediates 42 and 43 [ka]

[0283] Step 1: Preparation of 5-bromo-3-chloro-2-fluorobenzoic acid: A stirred solution of 3-chloro-2-fluorobenzoic acid (10.0 g, 57.28 mmol, 1.00 equiv) in H2SO4 (50 mL) was treated portionwise with NBS (10.7 g, 60.15 mmol, 1.05 equiv) at 0 °C. The resulting solution was stirred at 0 °C for 3 h, then warmed to room temperature and stirred overnight. The mixture was poured into ice water (200 mL), and the precipitated solid was collected by filtration and washed with water (100 mL). The resulting solid was dried in an oven under reduced pressure to give 5-bromo-3-chloro-2-fluorobenzoic acid (12.0 g, 82.6%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ8.25-8.12 (m, 1H), 7.94-7.80 (m, 1H).

[0284] Step 2: Preparation of 5-bromo-3-chloro-2-fluoro-N-methoxy-N-methylbenzamide: To a stirred solution of 5-bromo-3-chloro-2-fluorobenzoic acid (8.00 g, 31.56 mmol, 1.00 equiv.) and HATU (14.40 g, 37.87 mmol, 1.20 equiv.) in CHCl (100 mL) was added DIEA (12.20 g, 94.69 mmol, 3.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 30° C. for 30 minutes under a nitrogen atmosphere. N,O-dimethylhydroxylamine hydrochloride (3.39 g, 34.72 mmol, 1.10 equiv.) was added to the above mixture at room temperature and then stirred at 30° C. for an additional 2 hours. The mixture was cooled to room temperature and diluted with CHCl (150 mL). The resulting mixture was washed with water (3×150 mL), brine (3×150 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc / PE (0-25% gradient in 30 min)) to give 5-bromo-3-chloro-2-fluoro-N-methoxy-N-methylbenzamide (7.6 g, 81.2%) as a yellow solid. LC-MS: (ES+H, m / z) [M+H] + =295.9. 1 H NMR (300MHz, DMSO-d6) δ8.04 (dd, J = 6.5, 2.4 Hz, 1H), 7.77 (dd, J = 5.2, 2.5 Hz, 1H), 3.60 (s, 3H), 3.29 (s, 3H).

[0285] Step 3: Preparation of 1-(5-bromo-3-chloro-2-fluorophenyl)ethanone: To a stirred solution of 5-bromo-3-chloro-2-fluoro-N-methoxy-N-methylbenzamide (7.60 g, 25.63 mmol, 1.00 equiv) in THF (100 mL) was added bromo(methyl)magnesium (77 mL, 276.89 mmol, 3.00 equiv, 1 M in THF) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h and then quenched with saturated aqueous NH4Cl (80 mL) at room temperature. The resulting mixture was extracted with EtOAc (150 mL). The organic layer was washed with water (3 × 120 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 1-(5-bromo-3-chloro-2-fluorophenyl)ethanone (6.2 g, 96.2%) as a yellow solid. 1 H NMR (300MHz, DMSO-d6) δ8.17 (dd, J = 6.2, 2.5 Hz, 1H), 7.88 (dd, J = 6.2, 2.5 Hz, 1H), 2.61 (d, J = 3.9 Hz, 3H).

[0286] Step 4: Preparation of (5-bromo-3-chloro-2-fluorophenyl)(oxo)acetic acid: A stirred solution of 1-(5-bromo-3-chloro-2-fluorophenyl)ethanone (3.00 g, 11.93 mmol, 1.00 equiv) in pyridine (25 mL) was treated with SeO (2.00 g, 17.89 mmol, 1.50 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h and then cooled to room temperature. The mixture was acidified to pH 1 with 3 M HCl (aq) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with water (3 × 150 mL), dried over anhydrous NaSO, filtered, and concentrated to give (5-bromo-3-chloro-2-fluorophenyl)(oxo)acetic acid (2.8 g, 83.4%) as a yellow solid. LC-MS: (ES-H, m / z) [MH] - =278.8.

[0287] Step 5: Preparation of tert-butyl 2-(5-bromo-3-chloro-2-fluorophenyl)-2-oxoacetate: To a stirred solution of (5-bromo-3-chloro-2-fluorophenyl)(oxo)acetic acid (2.70 g, 9.59 mmol, 1.00 equiv.) in CHCl (30 mL) was added N,N'-diisopropyl tert-butoxymethaneimidamide (3.80 g, 19.19 mmol, 2.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 h and then filtered. The filter cake was washed with CHCl (3 × 20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE (0–15% gradient over 20 min)) to afford tert-butyl 2-(5-bromo-3-chloro-2-fluorophenyl)-2-oxoacetate (2.4 g, 74.1%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.33 (dd, J=6.4, 2.5Hz, 1H), 7.95 (dd, J=5.5, 2.5Hz, 1H), 1.54 (s, 9H).

[0288] Step 6: Preparation of tert-butyl 2-(5-bromo-3-chloro-2-fluorophenyl)-2-hydroxyacetate: To a stirred solution of tert-butyl 2-(5-bromo-3-chloro-2-fluorophenyl)-2-oxoacetate (2.40 g, 7.11 mmol, 1.00 equiv.) in CH3CH2OH (30 mL) and CH3COOH (3 mL) was added NaBH3CN (491 mg, 7.82 mmol, 1.10 equiv.) at room temperature under a nitrogen atmosphere. After 2 h, the reaction was quenched by adding water (4 mL) at room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (2 × 80 mL). The combined organic layers were washed with water (2 × 120 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc / PE (0-15% gradient in 20 min)) to give tert-butyl 2-(5-bromo-3-chloro-2-fluorophenyl)-2-hydroxyacetate (2.0 g, 82.8%) as a yellow oil. LC-MS: (ES-H, m / z) [MH] - =337.0.

[0289] Step 7: Preparation of tert-butyl 2-(5-bromo-3-chloro-2-fluorophenyl)-2-(methanesulfonyloxy)acetate (Intermediate 42): To a stirred solution of tert-butyl 2-(5-bromo-3-chloro-2-fluorophenyl)-2-hydroxyacetate (2.10 g, 6.18 mmol, 1.00 equiv.) and EtN (1.90 g, 18.55 mmol, 3.00 equiv.) in CHCl (30 mL), MsCl (1.70 g, 7.42 mmol, 1.20 equiv., 50% in CHCl) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h and then concentrated. The residue was purified by silica gel column chromatography (EtOAc / PE (0–20% gradient over 20 min)) to give tert-butyl 2-(5-bromo-3-chloro-2-fluorophenyl)-2-(methanesulfonyloxy)acetate (2.1 g, 81.3%) as a colorless solid. 1 H NMR (400MHz, CDCl3) δ7.61(dd,J=6.3,2.4Hz,1H),7.46(dd,J=5.5,2.4Hz,1H),6.04(s,1H),3.21(s,3H),1.46(s,9H).

[0290] Step 8: Preparation of tert-butyl 2-(5-bromo-3-chloro-2-fluorophenyl)-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate To a stirred solution of tert-butyl 2-(5-bromo-3-chloro-2-fluorophenyl)-2-(methanesulfonyloxy)acetate (400 mg, 0.95 mmol, 1.10 equiv.) and 5-[2-(3-fluoroazetidin-1-yl)ethyl]-4-(trifluoromethyl)-1H-pyridin-2-one (230 mg, 0.87 mmol, 1.00 equiv.) in CHCN (5 mL) was added KCO (360 mg, 2.61 mmol, 3.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours and then cooled to room temperature. The reaction was filtered, and the filter cake was washed with CHCl (3 × 6 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 gel; mobile phase, CH3CN / water (0.1% NH3.HO), 50% to 80% gradient in 30 min; detector: UV 254 nm) to give tert-butyl 2-(5-bromo-3-chloro-2-fluorophenyl)-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (300 mg, 58.8%) as a colorless oil. LC-MS: (ES+H, m / z) [M+H] + =585.0. 1 H NMR(300MHz,DMSO-d6)δ8.05(dd,J=6.4,2.4Hz,1H),7.73(s,1H),7.58(dd,J=5.8,2.4Hz,1H),6.89(s,1H),6.53(s, 1H),5.25-4.85(m,1H),3.57-3.40(m,2H),3.09-2.95(m,2H),2.59-2.54(m,2H),2.44(t,J=7.2Hz,2H),1.41(s,9H).

[0291] Step 9: Preparation of (5-bromo-3-chloro-2-fluorophenyl)({5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl})acetic acid (Intermediate 43): To a stirred solution of tert-butyl 2-(5-bromo-3-chloro-2-fluorophenyl)-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (300 mg, 0.51 mmol, 1.00 equiv) in CHCl (6 mL) was added CFCOOH (3.00 mL, 40.38 mmol, 78.87 equiv) at room temperature under a nitrogen atmosphere. After 5 h, the reaction was concentrated and the residue was purified by reverse-phase flash chromatography (C18 gel; mobile phase, CH3CN / water (0.1% NH3.HO), 10% to 70% gradient in 50 min; detector: UV 254 nm) to give (5-bromo-3-chloro-2-fluorophenyl)({5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl})acetic acid (200 mg, 73.7%) as a white solid. LC-MS: (ES+H, m / z) [M+H] + =528.9. Intermediates 44 and 45 [ka]

[0292] Step 1: Preparation of 5-chloro-4-(trifluoromethyl)-1H-pyridin-2-one (Intermediate 44): A solution of 4-(trifluoromethyl)-1H-pyridin-2-one (5.00 g, 30.66 mmol, 1.00 equiv.) and NCS (4.09 g, 30.66 mmol, 1.00 equiv.) in CHCl3 (20 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h and then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL). The organic layer was washed with water (3 × 40 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was recrystallized from petroleum ether / acetone (2:1 120 mL) to give 5-chloro-4-(trifluoromethyl)-1H-pyridin-2-one (3.50 g, 57.8%) as an off-white solid. LC-MS: (ES+H, m / z) [M+H] + =197.95. 1H NMR (400MHz, DMSO-d6) δ12.53-12.24 (m, 1H), 8.01 (s, 1H), 6.91 (s, 1H). 19 F NMR (377MHz, DMSO-d6) δ-64.36.

[0293] Step 2: Preparation of tert-butyl 2-(3-bromophenyl)-2-[5-chloro-2-oxo-4-(trifluoromethyl)pyridin-1-yl]acetate: A solution of 5-chloro-4-(trifluoromethyl)-1H-pyridin-2-one (300 mg, 1.52 mmol, 1.00 equiv.), tert-butyl 2-(3-bromophenyl)-2-(methanesulfonyloxy)acetate (555 mg, 1.52 mmol, 1.00 equiv.), and KCO (420 mg, 3.04 mmol, 2.00 equiv.) in MeCN (10 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h and then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc (0% to 60% in 20 min) to give tert-butyl 2-(3-bromophenyl)-2-[5-chloro-2-oxo-4-(trifluoromethyl)pyridin-1-yl]acetate (380 mg, 53.6%) as a white solid. LC-MS: (ES-H, m / z) [MH] - =463.70. 1 H NMR(400MHz,DMSO-d6)δ7.94(s,1H),7.75(t,J=1.9Hz,1H),7.65(ddd,J=7.9,2.0,1.1Hz,1H ),7.49(dt,J=7.8,1.5Hz,1H),7.42(t,J=7.8Hz,1H),7.10(s,1H),6.27(s,1H),1.42(s,9H). 19 F NMR(377MHz,DMSO-d6)δ-64.42.

[0294] Step 3: Preparation of (3-bromophenyl)[5-chloro-2-oxo-4-(trifluoromethyl)pyridin-1-yl]acetic acid (Intermediate 45): A solution of tert-butyl 2-(3-bromophenyl)-2-[5-chloro-2-oxo-4-(trifluoromethyl)pyridin-1-yl]acetate (350 mg, 0.75 mmol, 1.00 equiv.) and trifluoroacetic acid (5 mL) in CHCl (5 mL) was stirred overnight at room temperature under a nitrogen atmosphere and then concentrated. The residue was purified by reverse-phase flash chromatography (C gel; mobile phase, MeCN / water (10 mmol / L NHHCO), 30% to 100% gradient in 15 min; detector: UV 220 nm) to give (3-bromophenyl)[5-chloro-2-oxo-4-(trifluoromethyl)pyridin-1-yl]acetic acid (300 mg, 97.4%) as a white solid. LC-MS: (ES+H, m / z) [M+H] + =409.85. Intermediates 46 and 47 [ka]

[0295] Step 1: Preparation of 1-{5-[(1,5-dimethylpyrazol-3-yl)oxy]-2-fluorophenyl}ethanone: To a stirred solution of 1-(2-fluoro-5-hydroxyphenyl)ethanone (3.00 g, 19.46 mmol, 1.00 equiv.) and 3-bromo-1,5-dimethylpyrazole (4.50 g, 25.69 mmol, 1.32 equiv.) in dioxane (120 mL), CuI (1.85 g, 9.73 mmol, 0.50 equiv.), 2-(dimethylamino)acetic acid (2.01 g, 19.46 mmol, 1.00 equiv.), and CsCO (12.68 g, 38.92 mmol, 2.00 equiv.) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 120 °C under a nitrogen atmosphere overnight and then cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (0% to 40% gradient in 40 min)) to give 1-{5-[(1,5-dimethylpyrazol-3-yl)oxy]-2-fluorophenyl}ethanone (1.80 g, 29.8%) as a yellow oil. LC-MS: (ES-H, m / z) [M+H] + =249.3. 1 H NMR(400MHz,CDCl3)δ7.57(dd,J=5.9,3.2Hz,1H),7.31-7.26(m,1H),7.08(dd,J =10.3,8.9Hz,1H),5.57(s,1H),3.67(s,3H),2.62(d,J=5.1Hz,3H),2.24(s,3H).

[0296] Step 2: Preparation of {5-[(1,5-dimethylpyrazol-3-yl)oxy]-2-fluorophenyl}(oxo)acetic acid: To a stirred solution of 1-{5-[(1,5-dimethylpyrazol-3-yl)oxy]-2-fluorophenyl}ethanone (1.40 g, crude) in pyridine (10 mL) was added SeO (938 mg, 8.46 mmol, 1.50 equiv) portionwise at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h and then cooled to room temperature. The resulting mixture was diluted with EtOAc (150 mL), washed with 1 M HCl (aq) (3 × 150 mL), brine (1 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated to give {5-[(1,5-dimethylpyrazol-3-yl)oxy]-2-fluorophenyl}(oxo)acetic acid (1.3 g, crude) as a yellow oil. LC-MS: (ES-H, m / z) [M+H] + =279.0. 1 H NMR (400MHz, DMSO-d6) δ7.41-7.36(m,2H),7.29-7.26(m,1H),5.73(d,J=0.8Hz,1H),2.23(d,J=1.8Hz,3H),1.99(s,3H). 19 F NMR (377MHz, DMSO-d6) δ-119.20.

[0297] Step 3: Preparation of tert-butyl 2-{5-[(1,5-dimethylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-oxoacetate: To a stirred solution of {5-[(1,5-dimethylpyrazol-3-yl)oxy]-2-fluorophenyl}(oxo)acetic acid (1.50 g, 5.39 mmol, 1.00 equiv.) in CHCl (15 mL) was added N,N'-diisopropyl tert-butoxymethaneimidamide (2.16 g, 10.78 mmol, 2.00 equiv.) in portions at room temperature. The resulting mixture was stirred overnight at room temperature and then diluted with water (150 mL) and extracted with CHCl (3 × 100 mL). The combined organic layers were washed with brine (1 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0% to 40% gradient in 40 min)) to give tert-butyl 2-{5-[(1,5-dimethylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-oxoacetate (800 mg, 42.1%) as a yellow oil. LC-MS: (ES-H, m / z) [M+H] + =335.0. 1 H NMR(300MHz,CDCl3)δ7.63(dd,J=5.6,3.2Hz,1H),7.42-7.38(m,1H),7.17-7.08 (m,1H),5.61(d,J=0.8Hz,1H),3.71(s,3H),2.28(d,J=0.6Hz,3H),1.61(s,9H).

[0298] Step 4: Preparation of tert-butyl 2-{5-[(4-bromo-1,5-dimethylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-oxoacetate: To a stirred solution of tert-butyl 2-{5-[(1,5-dimethylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-oxoacetate (900 mg, 2.62 mmol, 1.00 equiv.) in MeCN (15 mL) was added NBS (479 mg, 2.69 mmol, 1.00 equiv.) in portions at room temperature. The resulting mixture was stirred at 40° C. under a nitrogen atmosphere for 1 hour and then cooled to room temperature. The resulting mixture was diluted with EtOAc (100 mL) and washed with water (2×50 mL). The organic layer was washed with brine (1×50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0% to 30% gradient in 40 min)) to give tert-butyl 2-{5-[(4-bromo-1,5-dimethylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-oxoacetate (1.1 g, 93.9%) as a yellow oil. LC-MS: (ES+H, m / z) [M+H] + =413.0. 1 H NMR (300MHz, CDCl3) δ7.50(dd,J=5.5,3.1Hz,1H),7.36-7.28(m,1H),7.04(dd,J=9.8,9.0Hz,1H),3.66(s,3H),2.21(s,3H),1.52(s,9H).

[0299] Step 5: Preparation of tert-butyl 2-{5-[(4-bromo-1,5-dimethylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-hydroxyacetate: To a stirred solution of tert-butyl 2-{5-[(4-bromo-1,5-dimethylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-oxoacetate (1.10 g, 2.66 mmol, 1.00 equiv.) in EtOH (12 mL) and HOAc (1.2 mL) was added NaBHCN (0.18 g, 2.92 mmol, 1.10 equiv.) in portions at room temperature. The resulting mixture was stirred at room temperature for 1 hour and then diluted with EtOAc (100 mL). The resulting mixture was washed with water (2 × 50 mL), brine (1 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated to give tert-butyl 2-{5-[(4-bromo-1,5-dimethylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-hydroxyacetate (1.1 g, crude) as a yellow solid. LC-MS: (ES+H, m / z) [M+H] + =415.0. 1 H NMR (300MHz, CDCl3) δ7.12-6.99(m,3H), 5.24(s,1H), 3.73(s,3H), 2.28(s,3H), 1.42(s,9H).

[0300] Step 6: Preparation of tert-butyl 2-{5-[(4-bromo-1,5-dimethylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-(methanesulfonyloxy)acetate (Intermediate 46): To a stirred solution of tert-butyl 2-{5-[(4-bromo-1,5-dimethylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-hydroxyacetate (1.10 g, crude) in DCM (15 mL) was added MsCl (0.45 g, 3.97 mmol, 1.50 equiv.) and EtN (0.80 g, 7.94 mmol, 3.00 equiv.) in portions at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 3 hours and then diluted with water (100 mL). The resulting mixture was extracted with CHCl (3 × 150 mL). The combined organic layers were washed with brine (1×50 mL), dried over anhydrous NaSO, filtered, and concentrated to give tert-butyl 2-{5-[(4-bromo-1,5-dimethylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-(methanesulfonyloxy)acetate (1.1 g, crude) as a yellow solid. LC-MS: (ES+H, m / z) [M+H] + =493.0. 1 H NMR (300MHz, CDCl3) δ7.21-7.05(m,3H),6.08(s,1H),3.74(s,3H),3.14(s,3H),2.29(s,3H),1.45(s,9H).

[0301] Step 7: Preparation of tert-butyl 2-{5-[(4-bromo-1,5-dimethylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (Intermediate 47): To a stirred solution of tert-butyl 2-{5-[(4-bromo-1,5-dimethylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-(methanesulfonyloxy)acetate (1.10 g, 2.23 mmol, 1.30 equiv.) in MeCN (15 mL), 5-[2-(3-fluoroazetidin-1-yl)ethyl]-4-(trifluoromethyl)-1H-pyridin-2-one (0.45 g, 1.71 mmol, 1.00 equiv.) and KCO (0.71 g, 5.14 mmol, 3.00 equiv.) were added dropwise at room temperature. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 3 hours and then cooled to room temperature. The resulting mixture was diluted with EtOAc (100 mL), washed with water (2 × 70 mL), brine (1 × 70 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by reverse-phase flash chromatography (C18 gel; mobile phase, MeCN / water (0.1% NH3.HO), 0% to 70% gradient in 30 min; detector: UV 220 nm) to give tert-butyl 2-{5-[(4-bromo-1,5-dimethylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (700 mg, 58.2%) as a white solid. LC-MS: (ES+H, m / z) [M+H] + =661.2. 1 H NMR(400MHz,CD3OD)δ7.36(s,1H),7.30-7.26(m,2H),7.05-7.03(m,1H),6.88(s,1H),6.59(s,1H),5.10-4. 92(m,1H),3.74(s,3H),3.54-3.44(m,2H),3.14-3.00(m,2H),2.60-2.47(m,4H),2.29(s,3H),1.44(s,9H). Intermediates 48 and 49 [ka]

[0302] Step 1: Preparation of 3-(3-methoxyazetidin-1-yl)-5-methylphenol: To a stirred mixture of 3-bromo-5-methylphenol (5.00 g, 26.73 mmol, 1.00 equiv.) and 3-methoxyazetidine hydrochloride (3.96 g, 32.08 mmol, 1.20 equiv.) in toluene (200 mL), Pd(dba) (1.22 g, 1.34 mmol, 0.05 equiv.), XPhos (1.27 g, 2.67 mmol, 0.10 equiv.), and t-BuONa (7.71 g, 80.20 mmol, 3.00 equiv.) were added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at 80 °C for 2 h and then concentrated. The residue was purified by reversed flash chromatography (C18 gel; mobile phase, MeCN / water (0.1% HCOOH), 10% to 50% gradient in 20 min; detector: UV 220 nm) to give 3-(3-methoxyazetidin-1-yl)-5-methylphenol (1.70 g, 32.9%) as a purple solid. LC-MS: (ES+H, m / z) [M+H] + =194.15.

[0303] Step 2: Preparation of 2-iodo-5-(3-methoxyazetidin-1-yl)-3-methylphenol: To a solution of 3-(3-methoxyazetidin-1-yl)-5-methylphenol (700 mg, 3.62 mmol, 1.00 equiv) in toluene (20 mL) was added sodium hydride (60% in oil, 290 mg, 7.24 mmol, 2.00 equiv) at 0 °C. The mixture was stirred at 0 °C for 1 h, and then I2 (873 mg, 3.44 mmol, 0.95 equiv) in toluene (30 mL) was added at 0 °C. After 1 h, the reaction mixture was quenched with water (30 mL). The mixture was acidified to pH 5 with HCl (1 M) and extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous NaSO, filtered, and concentrated to give 2-iodo-5-(3-methoxyazetidin-1-yl)-3-methylphenol (1 g, 86.5%) as a purple solid. LC-MS: (ES+H, m / z) [M+H] + =319.90. 1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),5.99(d,J=2.5Hz,1H),5.86(d,J=2.5Hz,1H),4.31(tt, J=6.2,4.3Hz,1H),4.05-3.95(m,2H),3.56(dd,J=8.1,4.2Hz,2H),3.27(s,3H),2.29(s,3H).

[0304] Step 3: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-fluoro-2'-hydroxy-4'-(3-methoxyazetidin-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3-yl]propanoate: A mixture of 2-iodo-5-(3-methoxyazetidin-1-yl)-3-methylphenol (500 mg, 1.57 mmol, 1.00 equiv.), ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (778 mg, 1.72 mmol, 1.10 equiv.), KCO (433 mg, 3.13 mmol, 2.00 equiv.), and Pd(dppf)Cl (115 mg, 0.16 mmol, 0.10 equiv.) in 1,4-dioxane (20 mL) and HO (1 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 h and then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc (0% to 50% in 20 min) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-fluoro-2'-hydroxy-4'-(3-methoxyazetidin-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3-yl]propanoate (300 mg, 37.1%) as a brown oil. LC-MS: (ES+H, m / z) [M+H] + =517.20. 1H NMR(300MHz,DMSO-d6)δ8.88(s,1H),7.50(d,J=8.9Hz,1H),6.96(dd,J=25. 0,7.0Hz,2H),5.87-5.82(m,1H),5.27(d,J=8.1Hz,1H),4.30(t,J=5.1Hz,1H ),4.02(ddd,J=14.3,7.6,5.9Hz,4H),3.55-3.51(m,2H),2.64(d,J=7.1Hz, 2H), 2.22(d,J=1.9Hz,3H),1.89(s,3H),1.34(s,9H),1.14(t,J=7.2Hz,3H). 19 F NMR(282MHz,DMSO-d6)δ-128.34.

[0305] Step 4: Preparation of ethyl (3S)-3-amino-3-[4-fluoro-2'-hydroxy-4'-(3-methoxyazetidin-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3-yl]propanoate: A solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-fluoro-2'-hydroxy-4'-(3-methoxyazetidin-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3-yl]propanoate (290 mg, 0.56 mmol, 1.00 equiv) and trifluoroacetic acid (5 mL) in CHCl (5 mL) was stirred at room temperature under a nitrogen atmosphere for 2 h and then concentrated. The residue was purified by reverse-phase flash chromatography (C18 gel; mobile phase, MeCN / water (0.1% NH3.HO), 0% to 100% gradient in 20 min; detector: UV 220 nm) to give ethyl (3S)-3-amino-3-[4-fluoro-2'-hydroxy-4'-(3-methoxyazetidin-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3-yl]propanoate (150 mg, 64.2%) as a purple oil. LC-MS: (ES+H, m / z) [M+H] + =417.15. Intermediate 50 [ka]

[0306] Step 1: Preparation of tert-butyl 2-(5-bromo-2-fluorophenyl)-2-[2-oxo-4-(trifluoromethyl)pyridin-1-yl]acetate: A mixture of tert-butyl 2-(5-bromo-2-fluorophenyl)-2-(methanesulfonyloxy)acetate (3.00 g, 7.83 mmol, 1.00 equiv.), 4-(trifluoromethyl)-1H-pyridin-2-one (1.28 g, 7.83 mmol, 1.00 equiv.), and K2CO3 (2.16 g, 15.66 mmol, 2.00 equiv.) in MeCN (60 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 hours and then cooled to room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc (0% to 50% in 20 min) to give tert-butyl 2-(5-bromo-2-fluorophenyl)-2-[2-oxo-4-(trifluoromethyl)pyridin-1-yl]acetate (3.20 g, 91.4%) as a colorless oil. LC-MS: (ES+H, m / z) [M+H] + =450.05. 1 H NMR(300MHz,DMSO-d6)δ7.79-7.68(m,2H),7.65(dd,J=6.5,2.5Hz,1H),7.34(dd,J=10. 1,8.8Hz,1H),6.94-6.90(m,1H),6.57(s,1H),6.52(dd,J=7.3,2.1Hz,1H),1.41(s,9H). 19 F NMR (282MHz, DMSO-d6) δ -65.49, -116.51.

[0307] Step 2: Preparation of (5-bromo-2-fluorophenyl)[2-oxo-4-(trifluoromethyl)pyridin-1-yl]acetic acid: To a stirred solution of tert-butyl 2-(5-bromo-2-fluorophenyl)-2-[2-oxo-4-(trifluoromethyl)pyridin-1-yl]acetate (2.00 g, 4.442 mmol, 1.00 equiv.) in CHCl (25 mL) was added dropwise under a nitrogen atmosphere at 0° C. Trifluoroacetic acid (25 mL) was added dropwise. The resulting mixture was stirred at room temperature for 4 hours and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C gel; mobile phase, MeCN / water (0.1% NH H O), 0% to 100% gradient in 20 minutes; detector: UV 220 nm) to afford (5-bromo-2-fluorophenyl)[2-oxo-4-(trifluoromethyl)pyridin-1-yl]acetic acid) (1.40 g, 82.4%) as a brown oil. LC-MS: (ES+H, m / z) [M+H] + =393.80. Intermediates 52 and 53 [ka]

[0308] Step 1: Preparation of 1-{2-fluoro-5-[(1-methylpyrazol-3-yl)oxy]phenyl}ethanone: To a stirred solution of 1-(2-fluoro-5-hydroxyphenyl)ethanone (5.00 g, 32.45 mmol, 1.00 equiv.) and 3-bromo-1-methylpyrazole (6.80 g, 42.15 mmol, 1.30 equiv.) in dioxane (150 mL), 2-(dimethylamino)acetic acid (3.34 g, 32.44 mmol, 1.00 equiv.), CuI (3.10 g, 16.20 mmol, 0.50 equiv.), and CsCO (21.15 g, 64.88 mmol, 2.00 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 120 °C under a nitrogen atmosphere. The resulting mixture was cooled to room temperature and filtered. The filter cake was washed with EtOAc (3 × 100 mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc (10% to 40% in 20 min) to give 1-{2-fluoro-5-[(1-methylpyrazol-3-yl)oxy]phenyl}ethanone (2.20 g, 28.9%) as a yellow liquid. 1 H NMR (300MHz, DMSO-d6) δ7.67(d,J=2.3Hz,1H),7.44-7.34(m,3H),5.87(d,J=2.3Hz,1H),3.75(s,3H),2.58(d,J=4.5Hz,3H).

[0309] Step 2: Preparation of {2-fluoro-5-[(1-methylpyrazol-3-yl)oxy]phenyl}(oxo)acetic acid: A solution of 1-{2-fluoro-5-[(1-methylpyrazol-3-yl)oxy]phenyl}ethanone (2.20 g, 9.39 mmol, 1.00 equiv.) and SeO (2.08 g, 18.78 mmol, 2.00 equiv.) in pyridine (30 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 hours, then cooled to room temperature and concentrated. The residue was acidified to pH 1 with HCl (3 M, aq.) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (1 × 200 mL), dried over anhydrous NaSO, filtered, and concentrated to give {2-fluoro-5-[(1-methylpyrazol-3-yl)oxy]phenyl}(oxo)acetic acid (2.20 g, 88.7%), which was used directly in the next step.

[0310] Step 3: Preparation of tert-butyl 2-{2-fluoro-5-[(1-methylpyrazol-3-yl)oxy]phenyl}-2-oxoacetate: To a stirred solution of {2-fluoro-5-[(1-methylpyrazol-3-yl)oxy]phenyl}(oxo)acetic acid (2.20 g, 8.33 mmol, 1.00 equiv.) in CHCl (25 mL) was added N,N'-diisopropyl tert-butoxymethaneimidamide (3.34 g, 16.65 mmol, 2.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight and then diluted with CHCl (100 mL). The resulting mixture was filtered, and the filter cake was washed with CHCl (3 × 100 mL). The combined filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc (20% to 50% in 30 min)) to give tert-butyl 2-{2-fluoro-5-[(1-methylpyrazol-3-yl)oxy]phenyl}-2-oxoacetate (2.10 g, 78.7%) as a pale yellow oil. LC-MS: (ES+H, m / z) [M+H] + =321.1. 1 H NMR (300MHz, DMSO-d6) δ7.69(d,J=2.3Hz,1H),7.61-7.58(m,1H),7.49-7.43(m,2H),5.94(d,J=2.4Hz,1H),3.76(s,3H),1.53(s,9H). 19 F NMR(282MHz,DMSO-d6)δ-118.67.

[0311] Step 4: Preparation of tert-butyl 2-{5-[(4-bromo-1-methylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-oxoacetate: A stirred solution of tert-butyl 2-{2-fluoro-5-[(1-methylpyrazol-3-yl)oxy]phenyl}-2-oxoacetate (2.05 g, 6.40 mmol, 1.00 equiv) and NBS (1.14 g, 6.40 mmol, 1.00 equiv) in CHCN (10 mL) was stirred under a nitrogen atmosphere at 60° C. for 1 h. The resulting mixture was diluted with EtOAc (500 mL), washed with water (2×300 mL), saturated aqueous NaCl (1×300 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc (15% to 50% in 30 min)) to give tert-butyl 2-{5-[(4-bromo-1-methylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-oxoacetate (2.46 g, 96.3%) as a white solid. LC-MS: (ES+H, m / z) [M+H] + =399.0. 1 H NMR(300MHz,DMSO-d6)δ8.02(s,1H),7.62-7.59(m,1H),7.51(dd,J=10.1,9.1Hz,1H),7.41(dd,J=5.5,3.1Hz,1H),3.78(s,3H),1.54(s,9H). 19 F NMR(282MHz,DMSO-d6)δ-118.18.

[0312] Step 5: Preparation of tert-butyl 2-{5-[(4-bromo-1-methylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-hydroxyacetate: To a stirred mixture of tert-butyl 2-{5-[(4-bromo-1-methylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-oxoacetate (2.40 g, 6.01 mmol, 1.00 equiv.) in EtOH (25 mL) and AcOH (2.5 mL) was added NaBHCN (416 mg, 6.61 mmol, 1.10 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 2 hours and quenched with water at room temperature. The resulting mixture was diluted with water (300 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc (15% to 40% in 40 min) to give tert-butyl 2-{5-[(4-bromo-1-methylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-hydroxyacetate (2.20 g, 91.2%) as a colorless oil. LC-MS: (ES+H, m / z) [M+H] + =401.1. 1 H NMR (300MHz, DMSO-d6) δ7.97(s,1H),7.97-7.16(m,1H),7.09-7.01(m,2H),6.13(d,J=5.9Hz,1H),5.16(d,J=5.9Hz,1H),3.76(s,3H),1.34(s,9H). 19 F NMR(282MHz,DMSO-d6)δ-125.24.

[0313] Step 6: Preparation of tert-butyl 2-{5-[(4-bromo-1-methylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-(methanesulfonyloxy)acetate: To a stirred solution of tert-butyl 2-{5-[(4-bromo-1-methylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-hydroxyacetate (2.20 g, 5.48 mmol, 1.00 equiv) and EtN (1.66 g, 16.45 mmol, 3.00 equiv) in CHCl (20 mL) was added MsCl (1.51 g, 6.58 mmol, 1.20 equiv) dropwise under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature for 2 h, then quenched with water (1 mL) at room temperature and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc (20% to 50% in 30 min)) to give tert-butyl 2-{5-[(4-bromo-1-methylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-(methanesulfonyloxy)acetate (2.27 g, 86.4%) as a white solid. LC-MS: (ES+H, m / z) [M+H] + =479.0.

[0314] Step 7: Preparation of tert-butyl 2-{5-[(4-bromo-1-methylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate To a stirred mixture of tert-butyl 2-{5-[(4-bromo-1-methylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-(methanesulfonyloxy)acetate (500 mg, 1.04 mmol, 1.00 equiv.) and 5-[2-(3-fluoroazetidin-1-yl)ethyl]-4-(trifluoromethyl)-1H-pyridin-2-one (276 mg, 1.04 mmol, 1.00 equiv.) in CHCN (10 mL) was added KCO (433 mg, 3.13 mmol, 3.00 equiv.) at room temperature. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours, then cooled to room temperature and diluted with EtOAc (5 mL). The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 5 mL). The combined organic layers were concentrated under reduced pressure, and the crude product was purified by reverse-phase flash chromatography (C18 gel; mobile phase, CH3CN / water (0.1% NH3.HO), 40% to 100% gradient in 30 min; detector: UV 254 nm) to give tert-butyl 2-{5-[(4-bromo-1-methylpyrazol-3-yl)oxy]-2-fluorophenyl}-2-{5-[2-(3-fluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (450 mg, 66.6%) as a colorless oil. LC-MS: (ES+H, m / z) [M+H] + =647.1. Intermediates 54 and 55 [ka]

[0315] Step 1: Preparation of 5-[2-(3,3-difluoroazetidin-1-yl)ethyl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one: To a stirred mixture of 2-{1-[(4-methoxyphenyl)methyl]-6-oxo-4-(trifluoromethyl)pyridin-3-yl}acetaldehyde (2.00 g, 6.14 mmol, 1.00 equiv.) and 3,3-difluoroazetidine hydrochloride (572 mg, 6.14 mmol, 1.00 equiv.) in EtOH (20 mL) was added CH3COOH (36 mg, 0.61 mmol, 1.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. To the above mixture was added NaBH3CN (772 mg, 12.29 mmol, 2.00 equiv.) in portions over 2 minutes at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours and then quenched by adding ice water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 × 100 mL), and the combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography using CHCl / MeOH (0–5%, 20 min) to give 5-[2-(3,3-difluoroazetidin-1-yl)ethyl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one (2 g, 80.8%) as a yellow oil. LC-MS: (ES+H, m / z) [M+H] + =403.0. 1 H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.35-7.30(m,2H),6.92-6.87(m,2H),6.75(s,1H),5.0 4(s,2H),3.72(s,3H),3.57(t,J=12.5Hz,4H),2.66(t,J=7.2Hz,2H),2.45(t,J=7.2Hz,2H). 19 F NMR (377MHz, DMSO-d6) δ -62.30, -97.86.

[0316] Step 2: Preparation of 5-[2-(3,3-difluoroazetidin-1-yl)ethyl]-4-(trifluoromethyl)-1H-pyridin-2-one: To a stirred mixture of 5-[2-(3,3-difluoroazetidin-1-yl)ethyl]-1-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)pyridin-2-one (2.00 g, 4.97 mmol, 1.00 equiv.) in TFA (10 mL) was added under a nitrogen atmosphere at 0° C. The resulting mixture was stirred overnight at 80° C. under a nitrogen atmosphere, then cooled to room temperature and concentrated. The residue was purified by reverse-phase flash chromatography (C18 gel; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 10% to 50% gradient in 20 min; detector: UV 254 / 220 nm) to give 5-[2-(3,3-difluoroazetidin-1-yl)ethyl]-4-(trifluoromethyl)-1H-pyridin-2-one (850 mg, 60.5%) as a yellow solid. LC-MS: (ES+H, m / z) [M+H] + =282.9. 1 H NMR (400MHz, DMSO-d6) δ12.12(s,1H),7.56(s,1H),6.68(s,1H),3.58(t,J=12.5Hz,4H),2.66(t,J=7.4Hz,2H),2.45(t,J=7.4Hz,2H). 19 F NMR (377MHz, DMSO-d6) δ -62.87, -97.55.

[0317] Step 3: Preparation of tert-butyl 2-(5-bromo-2-fluorophenyl)-2-{5-[2-(3,3-difluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate: To a stirred mixture of 5-[2-(3,3-difluoroazetidin-1-yl)ethyl]-4-(trifluoromethyl)-1H-pyridin-2-one (800 mg, 2.83 mmol, 1.00 equiv.) and tert-butyl 2-(5-bromo-2-fluorophenyl)-2-(methanesulfonyloxy)acetate (1.00 g, 2.83 mmol, 1.00 equiv.) in MeCN (5 mL) was added KCO (783 mg, 5.67 mmol, 2.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60° C. under a nitrogen atmosphere for 2 hours and then cooled to room temperature. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by reverse-phase flash chromatography (C18 gel; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 50% to 70% gradient in 20 min; detector: UV 254 / 220 nm) to give tert-butyl 2-(5-bromo-2-fluorophenyl)-2-{5-[2-(3,3-difluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (900 mg, 55.7%) as a yellow oil. LC-MS: (ES+H, m / z) [M+H] + =568.9. 1 H NMR(400MHz,DMSO-d6)δ7.75-7.68(m,1H),7.68-7.58(m,2H),7.33(t,J=10.0,8.8Hz,1H),6.89(s,1H),6 .53(s,1H),3.49(td,J=12.5,2.8Hz,4H),2.63(p,J=6.0,5.4Hz,2H),2.47(t,J=6.9Hz,2H),1.41(s,9H). 19 F NMR (377MHz, DMSO-d6) δ -62.70, -97.58, -116.58.

[0318] Step 4: Preparation of (5-bromo-2-fluorophenyl)({5-[2-(3,3-difluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl})acetic acid: To a stirred mixture of tert-butyl 2-(5-bromo-2-fluorophenyl)-2-{5-[2-(3,3-difluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl}acetate (900 mg, 1.58 mmol, 1.00 equiv.) in CHCl (10 mL) was added CFCOOH (10 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours and then concentrated. The residue was purified by reverse-phase flash chromatography (C18 gel; mobile phase, MeCN / water (0.1% NH3.HO), 10% to 50% gradient in 20 min; detector: UV 254 / 220 nm) to give (5-bromo-2-fluorophenyl)({5-[2-(3,3-difluoroazetidin-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1-yl})acetic acid (800 mg, 98.6%) as a colorless oil. LC-MS: (ES+H, m / z) [M+H] + =513.0. 1 H NMR(400MHz,DMSO-d6)δ7.63-7.52(m,3H),7.18-7.13(m,1H),6.71(s,1H), 6.36(s,1H),3.47(t,J=12.6Hz,4H),2.63-2.53(m,2H),2.47-2.39(m,2H). 19 F NMR (377MHz, DMSO-d6) δ -62.45, -97.35, -116.87. Intermediate 57 [ka]

[0319] Step 1: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4'-chloro-4-fluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate: To a stirred mixture of 5-chloro-2-iodo-3-methylphenol (2.14 g, 7.98 mmol, 1.20 equiv.) and ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (3.00 g, 6.65 mmol, 1.00 equiv.) in dioxane (20 mL) and water (1 mL), Pd(dppf)Cl.CHCl (542 mg, 0.66 mmol, 0.10 equiv.) and KCO (2.76 g, 19.94 mmol, 3.00 equiv.) were added at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours, then cooled to room temperature and diluted with water (100 mL). The aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0% to 20% in 30 min)) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4'-chloro-4-fluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate (2.1 g, 67.8%) as a yellow oil. LC-MS: (ES+H, m / z) [M+H-tBu] + =410.2. 1 H NMR(400MHz,DMSO-d6)δ9.63(s,1H),7.49(d,J=9.0Hz,1H),7.07-6.93(m,2H),6.83-6.76(m,2H),5.27(d,J=7.7Hz,1H),4 .03(dt,J=7.0,3.4Hz,2H),2.65(d,J=7.2Hz,2H),2.24(d,J=1.9Hz,3H),1.94(s,3H),1.33(s,9H),1.13(t,J=7.1Hz,3H). 19 F NMR (377MHz, DMSO-d6) δ-126.88.

[0320] Step 2: Preparation of ethyl (3S)-3-amino-3-{4'-chloro-4-fluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride: To a stirred mixture of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4'-chloro-4-fluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate (1.00 g, 2.12 mmol, 1.00 equiv.) in CHCl (2 mL) was added dropwise HCl (gas) in 1,4-dioxane (8 mL, 4 M) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at room temperature for 2 hours and then concentrated to give ethyl (3S)-3-amino-3-{4'-chloro-4-fluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride (800 mg, crude) as a colorless oil. LC-MS: (ES+H, m / z) [M+H] + =366.1. Intermediate 60 [ka]

[0321] Step 1: Preparation of 1-(4-bromo-3-hydroxy-5-methylphenyl)ethanone: To a stirred mixture of 1-(3-hydroxy-5-methylphenyl)ethanone (4.00 g, 26.63 mmol, 1.00 equiv) in CHCOOH (120 mL) was added Br (1.5 mL, 26.63 mmol, 1.00 equiv) in CHCOOH (120 mL) and HO (13.6 mL) dropwise under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h, diluted with EtOAc (1 L), washed with saturated NaSO(aq) (1 × 500 mL), saturated NaHCO(aq) (1 × 500 mL), and concentrated. The residue was purified by reverse-phase flash chromatography (C18 gel; mobile phase, MeCN / water (0.1% NH3.HO), 0% to 10% gradient in 30 min; detector: UV 254 nm) to give 1-(4-bromo-3-hydroxy-5-methylphenyl)ethanone (1.8 g, 29.5%, crude) as a yellow oil. LC-MS: (ES-H, m / z) [MH] - =226.9. 1H NMR (300MHz, CDCl3) δ7.31-7.20(m,2H),2.51(s,3H),2.28(s,3H).

[0322] Step 2: Preparation of 1-{4-bromo-3-[(3,4-dimethoxyphenyl)methoxy]-5-methylphenyl}ethanone: To a stirred mixture of 1-(4-bromo-3-hydroxy-5-methylphenyl)ethanone (700 mg, 3.05 mmol, 1.00 equiv.) and 4-(bromomethyl)-1,2-dimethoxybenzene (847 mg, 3.66 mmol, 1.20 equiv.) in MeCN (20 mL) was added KCO (1.2 g, 9.16 mmol, 3.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 2 hours and then cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 50 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc (0% to 30% in 30 min)) to give 1-{4-bromo-3-[(3,4-dimethoxyphenyl)methoxy]-5-methylphenyl}ethanone (375 mg, 32.3%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ7.61-7.57(m,1H),7.49(d,J=2.0Hz,1H),7.13(d,J=1.9 Hz, 1H), 7.06-6.95 (m, 2H), 5.21 (s, 2H), 3.77 (s, 6H), 2.58 (s, 3H), 2.44 (s, 3H).

[0323] Step 3: Preparation of 2-{4-bromo-3-[(3,4-dimethoxyphenyl)methoxy]-5-methylphenyl}propan-2-ol: To a stirred mixture of 1-{4-bromo-3-[(3,4-dimethoxyphenyl)methoxy]-5-methylphenyl}ethanone (850 mg, 2.24 mmol, 1.00 equiv.) in THF (45 mL) was added bromo(methyl)magnesium (4.5 mL, 4.48 mmol, 2.00 equiv., 1 M in THF) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h and then quenched by adding water (100 mL) at 0° C. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (1×100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0% to 50% gradient in 30 min)) to give 2-{4-bromo-3-[(3,4-dimethoxyphenyl)methoxy]-5-methylphenyl}propan-2-ol (650 mg, 73.3%) as a white solid. LC-MS: (ES-H, m / z) [MH] - =393.0. 1 H NMR (300MHz, DMSO-d6) δ7.13(t,J=2.5Hz,2H),7.06-6.93(m,3H),5.10(s,2H),5.06(s,1H),3.76(d,J=2.8Hz,6H),2.35(s,3H),1.41(s,6H).

[0324] Step 4: Preparation of (S)-ethyl 3-((tert-butoxycarbonyl)amino)-3-(2'-((3,4-dimethoxybenzyl)oxy)-4-fluoro-4'-(2-hydroxypropan-2-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate: To a stirred mixture of 2-{4-bromo-3-[(3,4-dimethoxyphenyl)methoxy]-5-methylphenyl}propan-2-ol (500 mg, 1.26 mmol, 1.00 equiv.) and ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (627 mg, 1.39 mmol, 1.10 equiv.) in dioxane (10 mL) and HO (1 mL), KCO (524 mg, 3.79 mmol, 3.00 equiv.) and Pd(dppf)Cl (92 mg, 0.12 mmol, 0.10 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 2 hours and then cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3×50 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc (gradient from 0% to 50% in 30 minutes)) to give ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2′-((3,4-dimethoxybenzyl)oxy)-4-fluoro-4′-(2-hydroxypropan-2-yl)-5,6′-dimethyl-[1,1′-biphenyl]-3-yl)propanoate (700 mg, 86.5%) as a white solid. LC-MS: (ES-H, m / z) [MH] - =640.4. 1 H NMR(300MHz,DMSO-d6)δ7.50(d,J=8.8Hz,1H),7.12-6.96(m,4H),6.87-6.78(m,3H),5.28(s,1H),5.01(s,1H),4.92(s,2H),4.10-3. 92(m,2H),3.71(s,3H),3.63(s,3H),2.64(brs,2H),2.23(d,J=1.9Hz,3H),1.99(s,3H),1.44(s,6H),1.31(s,9H),1.27-1.04(m,3H).

[0325] Step 5: Preparation of ethyl (3S)-3-amino-3-[4-fluoro-2'-hydroxy-4'-(2-hydroxypropan-2-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3-yl]propanoate: To a stirred mixture of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{2'-[(3,4-dimethoxyphenyl)methoxy]-4-fluoro-4'-(2-hydroxypropan-2-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate (500 mg, 0.46 mmol, 1.00 equiv.) in CHCl (5 mL) was added HCl (gas) in 1,4-dioxane (5 mL, 4 M) under a nitrogen atmosphere at 0°C. The resulting mixture was stirred under a nitrogen atmosphere at 0°C for 1 hour. The resulting mixture was diluted with water (20 mL), neutralized to pH 7 with NHHO, and extracted with CHCl (3 x 50 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by preparative TLC (CHCl / MeOH=15 / 1) to give ethyl (3S)-3-amino-3-[4-fluoro-2′-hydroxy-4′-(2-hydroxypropan-2-yl)-5,6′-dimethyl-[1,1′-biphenyl]-3-yl]propanoate (126 mg, 41.3%) as an off-white solid. LC-MS: (ES+H, m / z) [M+H] + =390.2. Intermediate 62 [ka]

[0326] Step 1: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4,5′-difluoro-2′-hydroxy-5-methyl-[1,1′-biphenyl]-3-yl}propanoate: To a stirred solution of 2-bromo-4-fluorophenol (635 mg, 3.33 mmol, 1.00 equiv.) and ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (1.65 g, 3.66 mmol, 1.10 equiv.) in dioxane (20 mL) and HO (2 mL), KCO (1.15 g, 8.31 mmol, 2.50 equiv.) and Pd(dppf)Cl (486 mg, 0.67 mmol, 0.20 equiv.) were added portionwise at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h and then cooled to room temperature. The reaction was quenched at room temperature by adding ice water (40 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (1 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc (gradient from 0% to 60% in 25 min)) to afford ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4,5'-difluoro-2'-hydroxy-5-methyl-[1,1'-biphenyl]-3-yl}propanoate (950 mg, 65.6%) as a yellow solid. LC-MS: (ES-H, m / z) [MH] - =434.2.

[0327] Step 2: Preparation of ethyl (3S)-3-amino-3-{4,5'-difluoro-2'-hydroxy-5-methyl-[1,1'-biphenyl]-3-yl}propanoate: A solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4,5'-difluoro-2'-hydroxy-5-methyl-[1,1'-biphenyl]-3-yl}propanoate (950 mg, 2.18 mmol, 1.00 equiv.) and HCl (gas) (4.5 mL, 4 M) in 1,4-dioxane in CHCl (9 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to give ethyl (3S)-3-amino-3-{4,5'-difluoro-2'-hydroxy-5-methyl-[1,1'-biphenyl]-3-yl}propanoate (900 mg, crude) as a yellow oil. LC-MS: (ES+H, m / z) [M+H] + =336.0. Intermediate 64 [ka]

[0328] Step 1: Preparation of 2-bromo-3,4-dimethylphenol: To a stirred mixture of 3,4-dimethylphenol (20.00 g, 163.71 mmol, 1.00 equiv.) in CH3COOH (300 mL) was added Br2 (8.4 mL, 163.71 mmol, 1.00 equiv.) in HO (35 mL) and CH3COOH (5 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h and then concentrated. The resulting mixture was diluted with diethyl ether (600 mL) and washed with Na2SO3 (aq., 0.63 M) (1 × 500 mL). The organic layer was washed with saturated NaHCO3 (aq.) (1 × 500 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / CHCl (0% to 30% in 50 min) to give 2-bromo-3,4-dimethylphenol (1 g, crude) as a white solid. The crude product (1 g) was purified by preparative SFC (column: CHIRALPAK IG, 3 × 25 cm, 5 μm; mobile phase A: CO; mobile phase B: MeOH:EtOH:Hexane = 1:1:2 (20 mM NH); flow rate: 100 mL / min; gradient: isocratic 10% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 284 / 220 nm; sample solvent: MeOH:CHCl = 16:1; injection volume: 0.3 mL) to give 2-bromo-3,4-dimethylphenol (725 mg, 2.2%) as a pale yellow solid. LC-MS: (ES-H, m / z) [MH] - =199.0. 1 H NMR (300MHz, DMSO-d6) δ9.80 (s, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 2.28 (s, 3H), 2.19 (s, 3H).

[0329] Step 2: Preparation of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4-fluoro-6'-hydroxy-2',3',5-trimethyl-[1,1'-biphenyl]-3-yl}propanoate: To a stirred mixture of 2-bromo-3,4-dimethylphenol (650 mg, 3.23 mmol, 1.00 equiv.) and ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (1.46 g, 3.23 mmol, 1.00 equiv.) in dioxane (30 mL) and HO (1.5 mL), Pd(dppf)ClCHCl (526 mg, 0.65 mmol, 0.20 equiv.) and KCO (1.34 g, 9.69 mmol, 3.00 equiv.) were added at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 3 h, then cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (10% to 30% gradient over 30 min)) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4-fluoro-6'-hydroxy-2',3',5-trimethyl-[1,1'-biphenyl]-3-yl}propanoate (476 mg, 33.1%) as a white solid. LC-MS: (ES-H, m / z) [MH] - =444.2. 1 H NMR(300MHz,CD3OD)δ6.96(dd,J=7.8,3.2Hz,3H),6.63(d,J=8.2Hz,1H),5.37(s,1H),4.17-4.08(m,2H),2. 79(q,J=8.0Hz,2H),2.32(d,J=2.1Hz,3H),2.21(s,3H),1.96-1.86(m,3H),1.42(s,9H),1.27-1.21(m,3H). 19 F NMR (282MHz, CD3OD) δ-128.20.

[0330] Step 3: Preparation of ethyl (3S)-3-amino-3-{4-fluoro-6'-hydroxy-2',3',5-trimethyl-[1,1'-biphenyl]-3-yl}propanoate, HCl salt: A mixture of (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4-fluoro-6'-hydroxy-2',3',5-trimethyl-[1,1'-biphenyl]-3-yl}propanoic acid (450 mg, 1.01 mmol, 1.00 equiv.) and HCl (gas) in 1,4-dioxane (5 mL, 20.00 mmol, 19.80 equiv., 4 M) in CHCl (5 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to give ethyl (3S)-3-amino-3-{4-fluoro-6'-hydroxy-2',3',5-trimethyl-[1,1'-biphenyl]-3-yl}propanoate, HCl salt (400 mg, crude) as a brown oil. LC-MS: (ES+H, m / z) [M+H] + =346.0. Intermediate 66 [ka]

[0331] Step 1: Preparation of ethyl (3S)-3-(4'-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-fluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((tert-butoxycarbonyl)amino)propanoate: A solution of (S)-ethyl 3-((tert-butoxycarbonyl)amino)-3-(4'-chloro-4-fluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate (200 mg, 0.43 mmol, 1.00 equiv.) and 3-oxa-8-azabicyclo[3.2.1]octane (437 mg, 3.86 mmol, 3. To a stirred mixture of {1,3-bis[2,6-bis(pentan-3-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H-imidazol-2-yl}dichloro(2-methyl-1lambda-4-pyridin-1-yl)palladium (108 mg, 0.13 mmol, 0.10 equiv.) and CsCO (1259 mg, 3.86 mmol, 3.00 equiv.) was added. The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 2 hours and then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (0-30% gradient in 30 min)) to give ethyl (3S)-3-(4'-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-fluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((tert-butoxycarbonyl)amino)propanoate (190 mg, 27.1%) as a yellow oil. LC-MS: (ES+H, m / z) [M+H] + =543.3. 1 H NMR(300MHz,CD3OD)δ7.01(t,J=5.5Hz,2H),6.35(s,1H),6.27(s,1H),5.40-5.31(m,1H),4.17-4.10(m,2H),4.07(s,2H),3.93(d,J=10 .7Hz,2H),3.53(d,J=10.8Hz,2H),2.86-2.72(m,2H),2.31(s,3H),2.06-2.04(m,4H),1.99(s,3H),1.43(s,9H),1.23(t,J=7.1Hz,3H).

[0332] Step 2: Preparation of ethyl (3S)-3-(4'-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-fluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-aminopropanoate hydrochloride: To a stirred solution of ethyl (3S)-3-(4'-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-fluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((tert-butoxycarbonyl)amino)propanoate (180 mg, 0.33 mmol, 1.00 equiv) in CHCl (3 mL) was added dropwise at room temperature under a nitrogen atmosphere with HCl (gas) in 1,4-dioxane (3 mL, 4 M). The resulting mixture was stirred at room temperature for 1 hour and then concentrated to give ethyl (3S)-3-(4'-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-fluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-aminopropanoate hydrochloride (170 mg, crude) as a yellow solid. LC-MS: (ES+H, m / z) [M+H] + =443.2. Intermediate 68 [ka]

[0333] Step 1: Preparation of (S)-ethyl 3-((tert-butoxycarbonyl)amino)-3-(4'-chloro-2'-((3,4-dimethoxybenzyl)oxy)-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate: To a stirred mixture of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4'-chloro-4-fluoro-2'-hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate (1.00 g, 2.14 mmol, 1.00 equiv.) and KCO (889 mg, 6.43 mmol, 3.00 equiv.) in DMF (10 mL), 4-(bromomethyl)-1,2-dimethoxybenzene (595 mg, 2.57 mmol, 1.20 equiv.) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 2 h, then cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0-30% gradient in 30 min)) to give ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-chloro-2'-((3,4-dimethoxybenzyl)oxy)-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate (1.00 g, 79.7%) as a white solid. LC-MS: (ES+H, m / z) [M+H] + =616.2. 1 H NMR(300MHz,DMSO-d6)δ7.50(s,1H),7.11-6.70(m,7H),5.27(s,1H),4.97(s,2H),4.04-3.95(m,2H),3.71 (s,3H),3.64(s,3H),2.64(s,2H),2.22(s,3H),1.98(d,J=3.3Hz,3H),1.30(s,9H),1.11(t,J=7.1Hz,3H).

[0334] Step 2: Preparation of (S)-ethyl 3-((tert-butoxycarbonyl)amino)-3-(2'-((3,4-dimethoxybenzyl)oxy)-4-fluoro-5,6'-dimethyl-4'-(oxetan-3-yl)-[1,1'-biphenyl]-3-yl)propanoate: Ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{4'-chloro-2'-[(3,4-dimethoxyphenyl)methoxy]-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate (800 mg, 1.29 mmol, 1.00 equiv.), 3-bromooxetane (355 mg, 2.59 mmol, 2.00 equiv.), octan-1-ol (338 mcg, 1.00 equiv.), in water (8 mL). A mixture of 100 mg (2.59 mmol, 2.00 equiv.), Zn (254 mg, 3.89 mmol, 3.00 equiv.), TMEDA (452 ​​mg, 3.89 mmol, 3.00 equiv.), XPhos (30 mg, 0.06 mmol, 0.05 equiv.), sodium octanoate (338 mg, 2.59 mmol, 2.00 equiv.), and NaCl (227 mg, 3.89 mmol, 3.00 equiv.) was stirred overnight at 70° C. under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (5:1)) to give ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{2'-[(3,4-dimethoxyphenyl)methoxy]-4-fluoro-5,6'-dimethyl-4'-(oxetan-3-yl)-[1,1'-biphenyl]-3-yl}propanoate (550 mg, 66.4%) as an off-white solid. LC-MS: (ES+H, m / z) [M+H] + =638.4. 1 H NMR(300MHz,DMSO-d6)δ7.49(d,J=8.8Hz,1H),7.15-6.96(m,3H),6.94-6.84(m,2H),6.7 9(d,J=10.0Hz,2H),5.28(s,1H),5.02-4.89(m,4H),4.66(dd,J=6.8,5.8Hz,2H),4.23(p ,J=7.6Hz,1H),4.01(ddt,J=11.3,7.0,3.7Hz,2H),3.71(s,3H),3.63(s,3H),2.64(s,2H) ),2.23(d,J=1.8Hz,3H),2.00(d,J=1.1Hz,3H),1.36-1.23(m,9H),1.12(t,J=7.1Hz,3H). 19 F NMR(282MHz,DMSO-d6)δ-127.19.

[0335] Step 3: Preparation of (S)-3-amino-3-(4-fluoro-2'-hydroxy-5,6'-dimethyl-4'-(oxetan-3-yl)-[1,1'-biphenyl]-3-yl)propanoate: A mixture of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-{2'-[(3,4-dimethylphenyl)methoxy]-4-fluoro-5,6'-dimethyl-4'-(oxetan-3-yl)-[1,1'-biphenyl]-3-yl}propanoate (200 mg, 0.33 mmol, 1.00 equiv.) (100 mg, 0.16 mmol, 1.00 equiv.) and TFA (1.00 mL, 13.45 mmol, 40.78 equiv.) in CHCl (2 mL) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was basified to pH 9 with saturated aqueous NaHCO and then c...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, 【Chemical 205】 During the ceremony, R １ However, hydrogen, deuterium, halogens, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R ２ is hydrogen, deuterium, halogen, -L-CN, -L-OH, -L-OR ａ , -LS(=O)R ａ , -L-S(=O) ２ R ａ , -L-S(=O) ２ NR ｃ R ｄ , -L-NR ｃ R ｄ , -LC(=O)R ａ , -LC(=O)OR ｂ , -LC(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, -L-cycloalkyl, or -L-heterocycloalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R ３ However, hydrogen, deuterium, halogens, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R ４ However, hydrogen, deuterium, halogens, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; L is absent or C １ ~C ６ is alkylene, Ring A is aryl or heteroaryl; Each R ５ are independently halogen, —CN, —NO ２ , —OH, —OR ａ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R's ５ together to form oxo, n is 0 to 4; X is -O-, -S-, -C(R ６ ) ２ -, -NR ７ -, -[C(R ６ ) ２ ] ２ -, -O-C(R ６ ) ２ -, -C(R ６ ) ２ -O-, -S-C(R ６ ) ２ -, or -C(R ６ ) ２ -S-, Each R ６ are independently hydrogen, deuterium, halogen, —OH, —OR ａ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ aminoalkyl, or C １ ~C ６ is heteroalkyl, or or two R's ６ together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; R ７ But hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl; Ring B is aryl or heteroaryl; Each R ８ are independently halogen, —CN, —NO ２ , —OH, —OR ａ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R's ８ together to form oxo, m is 0 to 4; Ring C is aryl or heteroaryl; Each R ９ are independently halogen, —CN, —NO ２ , —OH, —OR ａ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R's ９ together to form oxo, p is 0 to 4; Each R ａ But independently, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R ｂ are independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R ｃ and R ｄ are each independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Or, R ｃ and R ｄ together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently a halogen, —CN, —OH, —OC １ ~C ３ Alkyl, —OC １ ~C ３ Haloalkyl, -SC １ ~C ３ Alkyl, —S(═O)C １ ~C ３ Alkyl, —S(═O) ２ C １ ~C ３ Alkyl, —S(═O) ２ NH ２ , -S(=O) ２ NHC １ ~C ３ Alkyl, —S(═O) ２ N (C １ ~C ３ alkyl) ２ , -NH ２ , -NHC １ ~C ３ Alkyl, —N(C １ ~C ３ alkyl) ２ , -C(=O)C １ ~C ３ Alkyl, —C(═O)OH, —C(═O)OC １ ~C ３ Alkyl, —C(═O)NH ２ , -C(=O)NHC １ ~C ３ Alkyl, —C(═O)N(C １ ~C ３ alkyl) ２ , C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Deuteroalkyl, C １ ~C ３ Hydroxyalkyl, C １ ~C ３ Aminoalkyl, C １ ~C ３ Heteroalkyl, C ３ ~C ６ cycloalkyl or heterocycloalkyl; or two R on the same atom taken together form oxo, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

2. 2. The compound of claim 1, wherein the compound is of formula (Ia): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 【Chemical 206】

3. 2. The compound of claim 1, wherein the compound is of formula (Ib): 【Chemical 207】

4. 2. The compound of claim 1, wherein the compound is of formula (Ic): 【Chemical 208】

5. 2. The compound of claim 1, wherein the compound is of formula (Id): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 【Chemical Engineering 209】

6. 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is aryl.

7. 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is phenyl.

8. 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is heteroaryl.

9. 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is a 5- or 6-membered heteroaryl.

10. 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is a 5-membered heteroaryl.

11. 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is a 6-membered heteroaryl.

12. Each R ５ are independently halogen, —CN, —OH, —OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is heteroalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

13. Each R ５ are independently halogen, C １ ~C ６ Alkyl, C １ ~C ６ 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R is haloalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

14. Each R ５ are independently halogen, C １ ~C ６ Alkyl, C １ ~C ６ 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl or cycloalkyl.

15. 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 0 to 2.

16. 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1 or 2.

17. 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1.

18. X is -O-, -S-, -C(R ６ ) ２ - or -NR ７ 18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein

19. 19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is -O-.

20. 19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is -S-.

21. X is -C(R ６ ) ２ 19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein

22. X is -NR ７ 19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein

23. Each R ６ are independently hydrogen, deuterium, halogen, C １ ~C ６ Alkyl, or C １ ~C ６ 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

24. Each R ６ are independently hydrogen, halogen, or C １ ~C ６ 24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

25. Each R ６ 25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen.

26. Two R's ６ or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

27. R ７ But hydrogen, C １ ~C ６ Alkyl, or C １ ~C ６ 27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

28. R ７ 27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen.

29. 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is aryl.

30. 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is phenyl.

31. 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is heteroaryl.

32. 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is a 5- or 6-membered heteroaryl.

33. 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is a 5-membered heteroaryl.

34. 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is a 6-membered heteroaryl.

35. Each R ８ are independently halogen, —CN, —NO ２ , —OH, —OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ 35. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is heteroalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

36. Each R ８ are independently halogen, C １ ~C ６ Alkyl, or C １ ~C ６ 36. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

37. 37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 0 to 2.

38. 38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 1 or 2.

39. 39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 1.

40. 40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring C is aryl.

41. 40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring C is phenyl.

42. 40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring C is heteroaryl.

43. 40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring C is a 5- or 6-membered heteroaryl.

44. 40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring C is a 5-membered heteroaryl.

45. Each R ９ are independently halogen, —CN, —OH, —OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ 45. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is heteroalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

46. Each R ９ are independently halogen, —CN, —OH, —OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, or C １ ~C ６ 46. ​​The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

47. Each R ９ are independently halogen, C １ ~C ６ Alkyl, or C １ ~C ６ 47. The compound of any one of claims 1 to 46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

48. 48. The compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 0 to 2.

49. 49. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 1 or 2.

50. 50. The compound of any one of claims 1 to 49, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 2.

51. R １ However, hydrogen, deuterium, halogens, C １ ~C ６ Alkyl, or C １ ~C ６ 51. The compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: the alkyl is haloalkyl, wherein the alkyl is optionally substituted with one or more R.

52. R １ But hydrogen, halogen, C １ ~C ６ Alkyl, or C １ ~C ６ 52. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

53. R １ is hydrogen, halogen, or C １ ~C ６ 53. The compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

54. R １ 54. The compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen.

55. R ３ However, hydrogen, deuterium, halogens, C １ ~C ６ Alkyl, or C １ ~C ６ 55. The compound of any one of claims 1 to 54, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: the alkyl is haloalkyl, wherein the alkyl is optionally substituted with one or more R.

56. R ３ But hydrogen, halogen, C １ ~C ６ Alkyl, or C １ ~C ６ 56. The compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

57. R ３ is hydrogen or C １ ~C ６ 57. The compound of any one of claims 1 to 56, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

58. R ４ However, hydrogen, deuterium, halogens, C １ ~C ６ Alkyl, or C １ ~C ６ 58. The compound of any one of claims 1 to 57, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: the alkyl is haloalkyl, wherein the alkyl is optionally substituted with one or more R.

59. R ４ But hydrogen, halogen, C １ ~C ６ Alkyl, or C １ ~C ６ 59. The compound of any one of claims 1 to 58, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

60. R ４ is hydrogen or C １ ~C ６ 60. The compound of any one of claims 1 to 59, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

61. R ２ is -L-CN, -L-OH, -L-OR ａ , -L-NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ 61. The compound of any one of claims 1 to 60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R is heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R.

62. R ２ But -L-NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ 62. The compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R is an aminoalkyl, -L-cycloalkyl, or -L-heterocycloalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R.

63. R ２ But -L-NR ｃ R ｄ or -L-heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or more R, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

64. R ２ But -L-NR ｃ R ｄ 64. The compound of any one of claims 1 to 63, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

65. R ２ 64. The compound of any one of claims 1 to 63, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: is -L-heterocycloalkyl.

66. 66. The compound of any one of claims 1 to 65, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein L is absent.

67. L is C １ ~C ６ 66. The compound of any one of claims 1 to 65, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is alkylene.

68. A compound selected from the compounds of Table 1 or Table 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

69. 69. A pharmaceutical composition comprising a compound of any one of claims 1 to 68, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

70. 69. A method of treating a disease, comprising administering a compound of any one of claims 1 to 68, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

71. 71. The method of claim 70, wherein the disease is inflammatory bowel disease, ileoanal anastomosis, eosinophilic esophagitis, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholecititis, chronic bronchitis, chronic sinusitis, asthma, graft-versus-host disease, or chronic inflammatory disease of the lung.

72. 71. The method of claim 70, wherein the disease is inflammatory bowel disease.

73. 73. The method of claim 72, wherein the inflammatory bowel disease is colitis, Crohn's disease, ileitis, celiac disease, non-tropical sprue, seronegative arthropathy-associated enteropathy, gastroenteritis, or pouchitis.

74. 71. The method of claim 70, wherein the disease is colitis.

75. 75. The method of claim 74, wherein the colitis is ulcerative colitis, microscopic colitis, or collagenous colitis.

76. 71. The method of claim 70, wherein the disease is pouchitis, and the pouchitis is the result of a proctocolectomy.

77. 71. The method of claim 70, wherein the disease is gastroenteritis.

78. 78. The method of claim 77, wherein the gastroenteritis is eosinophilic gastroenteritis.

79. 71. The method of claim 70, wherein the disease is eosinophilic esophagitis.

80. 71. The method of claim 70, wherein the disease is a chronic inflammatory disease of the lung.

81. 81. The method of claim 80, wherein the chronic inflammatory disease of the lung is interstitial fibrosis.

82. 82. The method of claim 81, wherein the interstitial fibrosis is hypersensitivity pneumonitis, collagen disease, or sarcoidosis.

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