Quinoline derivatives as α4β7 integrin inhibitors

Abstract

To provide a method for treating disease.SOLUTION: The present disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof as described herein. The present disclosure also provides pharmaceutical compositions comprising a compound of Formula (I), processes for preparing compounds of Formula (I), and therapeutic methods for treating inflammatory disease. The present disclosure relates generally to novel compounds that have α4β7 integrin inhibitory action, prodrugs of compounds having α4β7 integrin inhibitory action, and methods of use and manufacture thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Citation of Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 752,805, filed October 30, 2018, and U.S. Provisional Patent Application No. 62 / 823,987, filed March 26, 2019, both of which are incorporated herein in their entirety for all purposes.

[0002] FIELD OF THE DISCLOSURE The present disclosure relates generally to novel compounds that have α4β7 integrin inhibitory activity, prodrugs of compounds that have α4β7 integrin inhibitory activity, and methods of use and preparation thereof. [Background technology]

[0003] Integrins are heterodimeric cell surface proteins involved in numerous cellular processes, including cell-cell and cell-extracellular matrix interactions. Upon binding to extracellular ligands, integrins mediate signal transduction to the interior of the cell, resulting in lymphocyte capture, adhesion, and infiltration into tissues.

[0004] Integrins are heterodimeric proteins composed of alpha and beta subunits. There are 18 known alpha subunits and 8 known beta subunits. α4β7 integrin is expressed on the surface of lymphocytes and recognizes the extracellular ligand mucosal addressin cell adhesion molecule-1 (MAdCAM-1). α4β7 integrin controls lymphocyte trafficking to and retention within intestinal tissue through its interaction with MAdCAM-1, which is expressed on arterioles in the intestinal mucosa and on high endothelial venules (HEV) in the gut-associated lymphoid tissue (GALT). Inhibiting the interaction between integrins and their respective ligands has been proposed as an effective method for treating various autoimmune and inflammatory diseases, and blocking α4β7-MAdCAM-1 interaction has shown therapeutic benefit in inflammatory bowel diseases (Crohn's disease and ulcerative colitis).

[0005] There is a need for improved α4β7 integrin antagonist molecules for the treatment of autoimmune and inflammatory diseases, including inflammatory bowel disease. Summary of the Invention [Means for solving the problem]

[0006] The present disclosure provides compounds that are inhibitors of α4β7 integrin. The present disclosure also provides compositions, including pharmaceutical compositions, kits containing the compounds, and methods of using (or administering) and making the compounds. The compounds provided herein are useful for treating diseases, disorders, or conditions mediated by α4β7 integrin. The present disclosure also provides compounds for use in therapy. The present disclosure further provides compounds for use in methods of treating diseases, disorders, or conditions mediated by α4β7 integrin. Furthermore, the present disclosure provides the use of compounds in the manufacture of a medicament for treating a disease, disorder, or condition mediated by α4β7 integrin.

[0007] In one aspect, a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof: [ka] is provided, L is a bond, -O-, or -OC(O)- * , -NH-, -C(O)-N(H)- * , and -N(H)-C(O)- * Selected from; where * is L's R 1 indicates the point of attachment to; R 1 is A 1 , A 2 , A 3 , and A 4 Selected from; A 1 is a 5- to 10-membered heteroaryl containing 1 to 5 heteroatoms independently selected from S, N, and O; 1optionally containing 1 to 3 C(O); and 1 is 1 to 6 R a with substitution as necessary; A 2 is 1 to 6 R a C substituted as needed 6~10 is aryl; A 3 is C 5~10 cycloalkyl or 5- to 14-membered heterocyclyl; 3 is oxo and R a and A 4 Ha-NR a1 R a2 and; where each R a are independently halo, cyano, hydroxyl, -NR a1 R a2 , C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxyl, -S(O) m -C 1~6 Alkyl, C 3~8 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6~10 Aryl, 5- to 6-membered heteroaryl, -OC 3~8 Cycloalkyl, -O-(3- to 6-membered heterocyclyl), -OC 1~4 Alkylene-C 3~8 cycloalkyl, and -O-phenyl; where R a C 3~8 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6~10 Aryl, 5- to 6-membered heteroaryl, -OC 3~8 Cycloalkyl, -O-(3- to 6-membered heterocyclyl), -OC 1~4 Alkylene-C 3~8cycloalkyl, and -O-phenyl each independently represent halo, cyano, hydroxyl, -NR a1 R a2 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, and C 1~6 optionally substituted with 1 to 3 groups independently selected from haloalkoxyl; and where R a C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxyl, and -S(O) m -C 1~6 Each alkyl is selected from 1 to 3 R a3 where each R is substituted as needed. a3 are independently halo, cyano, hydroxyl, -NR a1 R a2 , C 1~6 Alkoxyl, C 3~8 cycloalkyl, and 3- to 6-membered heterocyclyl; where R a3 C 3~8 Each of the cycloalkyl and 3- to 6-membered heterocyclyl groups has 1 to 3 R a4 and each R a4 are independently halo, cyano, hydroxyl, -NR a1 R a2 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 3~8 cycloalkyl, and 3- to 6-membered heterocyclyl; R 2 , R 3 , R 4 , R 5 , and R 6 each independently represents H, halo, cyano, hydroxy Sill, C.1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxyl, C 1~8 Haloalkyl, C 1~8 Haloalkoxyl, -NR b1 R b2 , -R b3 S(O) m R b4 , -S(O) m R b4 , -NR b1 S(O) n R b4 , -COOR b1 , -CONR b1 R b2 , -NR b1 COOR b2 , -NR b1 COR b4 , -R b3 NR b1 R b2 , -S(O) n NR b1 R b2 , C 3~12 Cycloalkyl, C 6~10 selected from aryl, 5- to 6-membered heteroaryl, and 3- to 12-membered heterocyclyl; where R 2 , R 3 , R 4 , R 5 , and R 6 C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxyl, C 1~8 Haloalkyl, and C 1~8 Each haloalkoxyl is one to two R c where each R c are independently azido, oxo, cyano, halo, hydroxyl, -NR a1 R a2 , C 1~4 Alkoxyl, C 3~8 Cycloalkyl, C 6~10aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl; c C 3~8 Cycloalkyl, C 6~10 Each of aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl is selected from halo, cyano, hydroxyl, -NR a1 R a2 , C 1~4 Alkyl, C 1~6 Haloalkyl, C 1~4 Alkoxyl, and C 3~6 optionally substituted with 1 to 3 groups independently selected from cycloalkyl; where R 2 , R 3 , R 4 , R 5 , and R 6 C 6~10 Each of the aryl and 5- to 6-membered heteroaryl independently has 1 to 5 R b with substitution as necessary; and where R 2 , R 3 , R 4 , R 5 , and R 6 C 3~12 Each of the cycloalkyl and the 3- to 12-membered heterocyclyl is independently ═CR b1 R b2 and R b optionally substituted with 1 to 6 groups independently selected from where each R b are independently azido, cyano, halo, hydroxyl, -NR a1 R a2 , C 1~6 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxyl, C 3~6 Cycloalkyl, C 6~10 aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl; b C 3~6 Cycloalkyl, C 6~10Each of the aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl independently is halo, cyano, hydroxyl, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Haloalkyl, and C 1~4 optionally substituted with 1 to 3 groups independently selected from alkoxyl; where R b1 and R b2 each independently represents H, C 1~8 Alkyl, C 1~8 Haloalkyl, C 3~8 Cycloalkyl, C 6~10 selected from aryl, 5- to 6-membered heteroaryl, and 3- to 8-membered heterocyclyl; where R b1 and R b2 C 3~8 Cycloalkyl, C 6~10 Each of the aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl independently is halo, cyano, hydroxyl, -NR a1 R a2 , C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxyl, C 3~6 Cycloalkyl, C 6~10 optionally substituted with 1 to 3 groups independently selected from aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl; and where R b1 and R b2 C 1~8 Alkyl and C 1~8 Each haloalkyl may be one to two R b5 with substitution as necessary; where R b3 is C 1~4 is alkylene; where R b4 is C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 6~10aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl; b4 C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~8 Cycloalkyl, C 6~10 Each of the aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl is selected from 1 to 3 R b6 with substitution as necessary; where each R b5 are independently cyano, hydroxyl, C 1~4 Alkoxyl, C 3~8 Cycloalkyl, C 6~10 aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl; and R b5 C 1~4 Alkoxyl, C 3~8 Cyclo Alkyl, C 6~10 Each of aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl is selected from halo, cyano, hydroxyl, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 optionally substituted with 1 to 3 groups independently selected from alkoxyl, and phenyl; and where each R b6 are independently halo, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxyl, C 3~6 cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; b6 C 3~6 Each of cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl is independently selected from halo, cyano, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Haloalkyl, and C 1~4optionally substituted with 1 to 3 groups independently selected from alkoxyl; or R 2 and R 3 , R 3 and R 4 , or R 5 and R 6 together with the atoms to which they are bonded, form C 6~10 Aryl, 5- to 6-membered heteroaryl, C 3~6 cycloalkyl, or 5- to 6-membered heterocyclyl; 6~10 Aryl, 5- to 6-membered heteroaryl, C 3~6 Each of the cycloalkyl and 5- to 6-membered heterocyclyl is independently halo, cyano, -NR a1 R a2 , C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6~10 Aryl, 5- to 6-membered heteroaryl, C 1~4 Alkylene-C 3~8 Cycloalkyl, C 1~4 Alkylene-C 6~10 Aryl, and C 1~4 optionally substituted with 1 to 3 groups independently selected from alkylene-(5- to 6-membered heteroaryl); R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 each independently represents H, halo, hydroxyl, cyano, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxyl, and -NR a1 R a2 Selected from; R 13 is H, C 1~4 Alkyl, and C 1~4 haloalkyl; and R14 is H, C 1~6 Alkyl, -C 1~4 Alkylene-NR a1 R a2 , -C 1~4 Alkylene-C(O)NR a1 R a2 , -C 1~4 Alkylene-OC(O)-C 1~4 Alkyl, -C 1~4 Alkylene-OC(O)-OC 1~4 Alkyl, -C 1~4 Alkylene-OC(O)-C 1~4 Alkylene-NR a1 R a2 , -C 1~4 Alkylene-OC 1~4 Alkyl, C 3~8 Cycloalkyl, -C 1~4 Alkylene-C 3~8 Cycloalkyl, 4- to 6-membered heterocyclyl, and -C 1~4 alkylene-(4- to 6-membered heterocyclyl); where R 14 C 3~8 Cycloalkyl, -C 1~4 Alkylene-C 3~8 Cycloalkyl, 4- to 6-membered heterocyclyl, and -C 1~4 Each alkylene-(4- to 6-membered heterocyclyl) is selected from halo, C 1~4 Alkyl, C 1~4 Alkoxyl, and C 1~4 optionally substituted with 1 to 3 groups independently selected from haloalkyl; or R 14 is R 13 together with the N to which it is attached to form a 5-membered heterocyclyl; wherein the 5-membered heterocyclyl is selected from the group consisting of halo, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, and C 6~10 aryl; 6~10 Aryl is halo, C 1~6 Alkyl, C 1~6Alkoxyl, and C 1~6 optionally substituted with 1 to 3 groups independently selected from haloalkyl; R a1 and R a2 each independently represents H, C 1~6 Alkyl, and C 1~6 haloalkyl; m is selected from 0, 1, and 2; and n is selected from 1 and 2. DETAILED DESCRIPTION OF THE INVENTION

[0008] Definitions and General Parameters The following description specifies exemplary methods, parameters, etc. However, such description It should be appreciated that the description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of exemplary embodiments.

[0009] As used herein, the following words, phrases, and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0010] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -CONH2 is attached through the carbon atom. Dashes before or at the end of a chemical group are for convenience; chemical groups can be represented with or without one or more dashes without losing their inherent meaning. A wavy line drawn through a line in a structure indicates the point of attachment of the group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which chemical groups are written or named.

[0011] Wavy lines on chemical groups, such as [ka] indicates a point of attachment, i.e., a broken bond by which the group is attached to the other depicted group.

[0012] Prefix “C” u~v " indicates that the following group has u to v carbon atoms. For example, "C 1~8 "Alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0013] Reference herein to "about" a value or parameter includes (and describes) embodiments that are directed to that value or parameter itself. In certain embodiments, the term "about" includes the stated amount ±10%. In other embodiments, the term "about" includes the stated amount ±5%. In certain other embodiments, the term "about" includes the stated amount ±1%. Also, the term "about X" includes the reference to "X." Additionally, the singular forms "a" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds, and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those of skill in the art.

[0014] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 1 to 20 carbon atoms (i.e., C 1~20 alkyl), 1 to 8 carbon atoms (i.e., C 1~8 alkyl), 1 to 6 carbon atoms (i.e., C 1~6 alkyl), or 1 to 4 carbon atoms (i.e., C 1~4alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylphenyl. When an alkyl residue having a specific number of carbons is named by a chemical name or specified by a molecular formula, all positional isomers having that number of carbons can be included; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0015] "Alkylene" (including those that are part of other groups) refers to branched and unbranched divalent "alkylene" groups. As used herein, alkylene refers to an alkyl group having 1 to 20 carbon atoms (i.e., C 1~20 alkylene), 1 to 8 carbon atoms (i.e., C 1~8 alkylene), 1 to 6 carbon atoms (i.e., C 1~6 alkylene), or 1 to 4 carbon atoms (i.e., C 1~4 The term "propylene" refers to a group consisting of propylene, butylene, 1-methylethylene, 1,1-dimethylethylene, and 1,2-dimethylethylene. Examples include methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, and 1,2-dimethylethylene. Unless otherwise indicated, the definitions propylene and butylene include all possible isomeric forms of the groups in question having the same number of carbons. Thus, for example, propylene also includes 1-methylethylene, and butylene includes 1-methylpropylene, 1,1-dimethylethylene, and 1,2-dimethylethylene.

[0016] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkenyl), 2 to 8 carbon atoms (i.e., C2~8 alkenyl), 2 to 6 carbon atoms (i.e., C 2~6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2~4 Alkenyl refers to an aliphatic group having an alkyl group. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0017] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkynyl), 2 to 8 carbon atoms (i.e., C 2~8 alkynyl), 2 to 6 carbon atoms (i.e., C 2~6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2~4 The term "alkynyl" refers to an aliphatic group having one triple bond and one double bond.

[0018] "Alkoxy" and "alkoxyl" are used interchangeably and refer to an "alkyl-O-" group. Examples of alkoxyl and alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. "Haloalkoxyl" refers to an alkoxyl group as defined above in which one or more hydrogen atoms have been replaced by halogen.

[0019] "Acyl" refers to the group -C(=O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0020] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl refers to an aromatic carbocyclic group having 6 to 20 ring carbon atoms (i.e., C 6~20 aryl), 6 to 12 carbon ring atoms (i.e., C 6~12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6~10 Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or overlap with heteroaryl, as defined below. When one or more aryl groups are fused to a heteroaryl ring, the resulting ring system is heteroaryl.

[0021] "Azido" refers to the group -N3.

[0022] "Cyano" or "carbonitrile" refers to the group --CN.

[0023] "Cycloalkyl" refers to a single ring or multiple rings, including fused ring systems, bridged ring systems and spiro rings. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl refers to a group having 3 to 20 ring carbon atoms (i.e., C 3~20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3~8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3~6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups also include partially unsaturated ring systems containing one or more double bonds, including fused ring systems having one aromatic and one non-aromatic ring, but not completely aromatic ring systems.

[0024] "Bridged" refers to a ring fusion in which non-adjacent ring atoms are joined by a divalent substituent, such as an alkylenyl or heteroalkylenyl group, or a single heteroatom. Quinuclidinyl and adamantanyl are examples of bridged ring systems.

[0025] The term "fused" refers to a ring that is joined to an adjacent ring.

[0026] "Spiro" refers to a ring substituent that is joined by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, where cyclopentane and piperidine, respectively, are spiro substituents.

[0027] "Spiro" also refers to a bicyclic moiety in which two rings are joined through a common atom. Spiro compounds can be fully carbocyclic or heterocyclic. Examples of spiro groups include 5-oxa-8-azaspiro[3.5]nonane, 7-oxa-4-azaspiro[2.5]octane, and 5λ 2 -azaspiro[2.4]heptane.

[0028] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodo. "Haloalkyl" refers to an unbranched or branched alkyl group as defined above in which one or more hydrogen atoms have been replaced by halogen. For example, if a residue is substituted with more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, which may, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0029] The term "heterocyclyl" or "heterocycle," as used herein, refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic ring system having at least one heteroatom in the ring (i.e., at least one ring heteroatom selected from O, N, S, S(O), S(O)2, and an N-oxide group). Unless otherwise specified, a heterocyclyl group has from 3 to about 20 ring atoms, e.g., from 3 to 12 ring atoms, e.g., from 3 to 10 ring atoms, e.g., from 5 to 10 ring atoms, or e.g., from 5 to 6 ring atoms. Thus, the term includes a single saturated or partially saturated ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) having from about 1 to 6 ring carbon atoms in the ring and from about 1 to 3 ring heteroatoms independently selected from the group consisting of O, N, S, S(O), S(O)2, and an N-oxide. The rings of fused polycyclic (e.g., bicyclic heterocyclyl) systems can be connected to each other through fused, spiro, and bridged bonds when permitted by valence requirements. Heterocycles include, but are not limited to, azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine. Heterocycles include groups derived from tetrahydropyridine, tetrahydro-2H-thiopyran 1,1-dioxide, quinuclidine, N-bromopyrrolidine, N-chloropiperidine, and the like. Heterocycles include spirocycles, such as aza or oxo-spiroheptane. Heterocyclyl groups also include partially unsaturated ring systems containing one or more double bonds, including fused ring systems having one aromatic and one non-aromatic ring, but not completely aromatic ring systems. Examples include dihydroquinolines, such as 3,4-dihydroquinoline, dihydroisoquinolines, such as 1,2-dihydroisoquinoline, dihydroimidazole, tetrahydroimidazole, indolines, isoindolines, isoindolones (e.g., isoindolin-1-one), isatins, dihydrophthalazines, quinolinones, spiro[cyclopropane-1,1'-isoindolin]-3'-one, and the like. Additional examples of heterocycles include, for example, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl, and hexahydropyrazino[2,1-c][1,4]oxazinyl.

[0030] "Hydroxyl" and "hydroxy" are used interchangeably and refer to -OH. "Oxo" refers to the (=O) or (O) group. When tautomeric forms of the compound exist, hydroxyl and oxo groups are interchangeable.

[0031] "Heteroaryl" refers to an aromatic group, including groups with aromatic tautomers, i.e., resonance structures, having a single ring, multiple rings, or fused-ring rings, and having at least one heteroatom in the ring, i.e., one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, where the nitrogen or sulfur may be oxidized. Thus, the term includes rings having one or more ring O, N, S, S(O), S(O)2, and N-oxide groups. The term includes rings having one or more ring C(O) groups. As used herein, heteroaryl includes 5 to 20 ring atoms (i.e., 5-20-membered heteroaryl), 5 to 12 ring atoms (i.e., 5-12-membered heteroaryl), or 5 to 10 ring atoms (i.e., 5-10-membered heteroaryl), and 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the oxidized forms of these heteroatoms. Examples of heteroaryl groups include pyridin-2(1H)-one, pyridazin-3(2H)-one, pyrimidin-4(3H)-one, quinolin-2(1H)-one, pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass or overlap with aryl, as defined above.

[0032] "Sulfonyl" refers to the group -S(O)R, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl include methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0033] Whenever a depiction of a group terminates in a single-bonded nitrogen atom, that group represents an —NH group unless otherwise specified. Similarly, unless otherwise stated, the presence of hydrogen atom(s) is implied and assumed to be present where necessary to complete valence or provide stability within the knowledge of one of ordinary skill in the art.

[0034] Certain commonly used alternative chemical names may be used. For example, divalent groups, such as divalent "alkyl" groups, divalent "aryl" groups, etc., may be referred to as "alkylene" or "alkylenyl" groups, "arylene" or "arylenyl" groups, respectively. Also, unless expressly stated otherwise, when a combination of groups is referred to herein as a single moiety, e.g., arylalkyl, the last-mentioned group is the one that attaches the moiety to the remainder of the molecule. Includes atoms that are bonded together.

[0035] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and non-occurrence of said event or circumstance. Also, the term "optionally substituted" refers to the fact that any one or more hydrogen atoms on a specified atom or group may or may not be replaced with a non-hydrogen moiety.

[0036] The term "substituted" means that any one or more hydrogen atoms on the specified atom or group are replaced with one or more non-hydrogen substituents, provided that the normal valence of the specified atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar indefinite structures resulting from defining an infinite number of additional substituents (e.g., substituted aryl having a substituted alkyl, which is itself substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.) are not intended to be encompassed herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, sequential substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., a methyl substituted with five fluorines or a heteroaryl group having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those of skill in the art. When used to modify a chemical group, the term "substituted" may also describe other chemical groups defined herein. For example, the term "substituted aryl" includes, but is not limited to, "alkylaryl." Unless otherwise specified, when a group is described as optionally substituted, any substituents on that group are not themselves substituted.

[0037] In some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In additional embodiments, "substituted cycloalkyl" refers to a cycloalkyl group having one or more substituents including alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl; "substituted heterocyclyl" refers to a heterocyclyl group having one or more substituents including alkyl, haloalkyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl; "substituted aryl" refers to an aryl group having one or more substituents including halo, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano; "substituted heteroaryl" refers to a heteroaryl group having one or more substituents including halo, alkyl, haloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano; and "substituted sulfonyl" refers to the group -S(O)R, wherein R is substituted with one or more substituents including alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, one or more of the substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted. The group may be further substituted with alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0038] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, a compound containing an amide may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among the tautomers, the compound will be understood by those skilled in the art to include both the amide and imidic acid tautomers. Thus, a compound containing an amide will be understood to include its imidic acid tautomer. Similarly, a compound containing an imidic acid will be understood to include its amide tautomer.

[0039] Any formula or structure shown herein is also intended to represent the unlabeled form and isotopically labeled form of these compounds.Isotopically labeled compounds have the structure represented by the formula given herein, except that one or more atoms are replaced by atoms with selected atomic mass or mass number.Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, including but not limited to: 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. Various isotopically labeled compounds of the present disclosure, including those containing radioactive isotopes, e.g. 3 H, 13 C and 14 C incorporated. Such isotopically labeled compounds may be useful in metabolism studies, kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or radiation treatment of patients.

[0040] The present disclosure also includes compounds of the present disclosure in which 1 to n hydrogens bonded to carbon atoms have been replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of any compound of the present disclosure when administered to mammals, particularly humans. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by methods well known in the art, for example, by utilizing starting materials in which one or more hydrogens have been replaced by deuterium.

[0041] Deuterium-labeled or substituted therapeutic compounds of the present disclosure can have improved DMPK (drug metabolism and pharmacokinetic) properties related to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, can result in certain therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F-labeled compounds can be useful for PET or SPECT testing.The isotope-labeled compounds of the present disclosure and their prodrugs can generally be prepared by carrying out the procedures disclosed in the schemes or examples and preparations described below, by using readily available isotope-labeled reagents instead of non-isotopically labeled reagents.It is understood that deuterium in this context is considered as a substituent of the compounds of the present disclosure.

[0042] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen in its naturally occurring isotopic composition. Thus, in the compounds of the present disclosure, deuterium ( Any atom specifically designated as D) is meant to represent deuterium.

[0043] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0044] The term "pharmaceutically acceptable salt" of a designated compound refers to a salt that retains the biological effectiveness and properties of the designated compound and is not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dialkenylamines, trialkenylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, mono-, di-, or tricycloalkylamines, mono-, di-, or triarylamines, or mixed amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0045] Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0046] Salts such as TFA salts can be converted to the free base / acid or other pharmaceutically acceptable salts.

[0047] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Except as long as any conventional media or agent is incompatible with the active substance, its use in therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0048] "Treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms caused by a disease or condition and / or reducing the severity of the disease or condition); b) delaying or halting the onset of one or more clinical symptoms associated with a disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition), and / or c) palliating the disease, i.e., causing a reduction in clinical symptoms (e.g., improving the disease state, causing partial or complete remission of the disease or condition, enhancing the effect of another drug, slowing the progression of the disease, increasing quality of life, and / or prolonging survival).

[0049] "Prevention" or "preventing" means any treatment of a disease or condition that keeps the clinical symptoms of the disease or condition from manifesting. The compounds may, in some embodiments, be administered to subjects (including humans) at risk for or who have a family history of the disease or condition.

[0050] "Subject" refers to an animal, e.g., a mammal (including a human), that has been or is the object of treatment, observation, or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0051] The term "therapeutically effective amount" or "effective amount" of a compound described herein or its pharmaceutically acceptable salt, isomer, or mixture means an amount sufficient for effective treatment when administered to a subject to provide a therapeutic benefit, such as improving symptoms or delaying disease progression. For example, a therapeutically effective amount may be an amount sufficient to reduce the symptoms of a disease or condition that responds to the inhibition of α4β7 integrin activity. The therapeutically effective amount may vary depending on the subject being treated and the disease or condition, the weight and age of the subject, the severity of the disease or condition, and the mode of administration, and can be easily determined by those skilled in the art.

[0052] The term "inhibition" refers to a reduction in the baseline activity of a biological activity or process. "Inhibition of the activity of α4β7 integrin" or variations thereof refers to a reduction in the activity of α4β7 integrin as a direct or indirect response to the presence of a compound of the present application, compared to the activity of α4β7 integrin in the absence of a compound of the present application. "Inhibition of α4β7" refers to a reduction in α4β7 integrin activity as a direct or indirect response to the presence of a compound described herein, relative to the activity of α4β7 integrin in the absence of a compound described herein. In some embodiments, the inhibition of α4β7 integrin activity may be compared in the same subject before treatment, or in another subject not receiving treatment. compound

[0053] Provided herein are compounds that function as inhibitors of α4β7 integrin. In one aspect, compounds of formula (I) [ka] (R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12, R 13 , R 14 , and L is as defined above) or a pharmaceutically acceptable salt thereof.

[0054] In another aspect, a compound of formula (II), or a pharmaceutically acceptable salt thereof: [ka] is provided, L is a bond, -O-, or -OC(O)- * , -NH-, -C(O)-N(H)- * , and -N(H)-C(O)- * Selected from; where * is L's R 1 indicates the point of attachment to; R 1 is A 1 , A 2 , and A 3 Selected from; A 1 is a 5- to 10-membered heteroaryl containing 1 to 5 heteroatoms independently selected from S, N, and O; 1 optionally containing 1 to 3 C(O); and 1 is 1 to 6 R a with substitution as necessary; A 2 is 1 to 6 R a C substituted as needed 6~10 is aryl; and A 3 is C 5~10 cycloalkyl or 5- to 14-membered heterocyclyl; 3 is oxo and R a and where each R a are independently halo, cyano, hydroxyl, -NR a1 R a2 , C 1~6 Alkyl, C 2~6Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxyl, -S(O) m -C 1~6 Alkyl, C 3~8 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6~10 Aryl, 5- to 6-membered heteroaryl, -OC 3~8 Cycloalkyl, -O-(3- to 6-membered heterocyclyl), -OC 1~4 Alkylene-C 3~8 cycloalkyl, and -O-phenyl; where R a C 3~8 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6~10 Aryl, 5- to 6-membered heteroaryl, -OC 3~8 Cycloalkyl, -O-(3- to 6-membered heterocyclyl), -OC 1~4 Alkylene-C 3~8 cycloalkyl, and -O-phenyl each independently represent halo, cyano, hydroxyl, -NR a1 R a2 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, and C 1~6 optionally substituted with 1 to 3 groups independently selected from haloalkoxyl; and where R a C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxyl, and -S(O) m -C 1~6 Each alkyl is selected from 1 to 3 R a3 where each R is substituted as needed. a3 are independently halo, cyano, hydroxyl, -NR a1 R a2 , C 1~6 Alkoxyl, C3~8 cycloalkyl, and 3- to 6-membered heterocyclyl; where R a3 C 3~8 Each of the cycloalkyl and 3- to 6-membered heterocyclyl groups has 1 to 3 R a4 and each R a4 are independently halo, cyano, hydroxyl, -NR a1 R a2 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 3~8 cycloalkyl, and 3- to 6-membered heterocyclyl; R 2 , R 3 , R 4 , R 5 , and R 6 each independently represents H, halo, cyano, hydroxy Sill, C. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxyl, C 1~8 Haloalkyl, C 1~8 Haloalkoxyl, -NR b1 R b2 , -R b3 S(O) m R b4 , -S(O) m R b4 , -NR b1 S(O) n R b4 , -COOR b1 , -CONR b1 R b2 , -NR b1 COOR b2 , -NR b1 COR b4 , -R b3 NR b1 R b2 , -S(O) n NR b1 R b2 , C 3~12 Cycloalkyl, C6~10 selected from aryl, 5- to 6-membered heteroaryl, and 3- to 12-membered heterocyclyl; where R 2 , R 3 , R 4 , R 5 , and R 6 C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxyl, C 1~8 Haloalkyl, and C 1~8 Each haloalkoxyl is one to two R c where each R c are independently azido, oxo, cyano, halo, hydroxyl, -NR a1 R a2 , C 1~4 Alkoxyl, C 3~8 Cycloalkyl, C 6~10 aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl; c C 3~8 Cycloalkyl, C 6~10 Each of aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl is selected from halo, cyano, hydroxyl, -NR a1 R a2 , C 1~4 Alkyl, C 1~6 Haloalkyl, C 1~4 Alkoxyl, and C 3~6 optionally substituted with 1 to 3 groups independently selected from cycloalkyl; where R 2 , R 3 , R 4 , R 5 , and R 6 C 6~10 Each of the aryl and 5- to 6-membered heteroaryl independently has 1 to 5 R b with substitution as necessary; and where R 2 , R 3 , R 4 , R 5 , and R6 C 3~12 Each of the cycloalkyl and the 3- to 12-membered heterocyclyl independently represents ═CR b1 R b2 and R b optionally substituted with 1 to 6 groups independently selected from where each R b are independently azido, cyano, halo, hydroxyl, -NR a1 R a2 , C 1~6 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxyl, C 3~6 Cycloalkyl, C 6~10 aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl; b C 3~6 Cycloalkyl, C 6~10 Each of the aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl independently is halo, cyano, hydroxyl, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Haloalkyl, and C 1~4 optionally substituted with 1 to 3 groups independently selected from alkoxyl; where R b1 and R b2 each independently represents H, C 1~8 Alkyl, C 1~8 Haloalkyl, C 3~8 Cycloalkyl, C 6~10 selected from aryl, 5- to 6-membered heteroaryl, and 3- to 8-membered heterocyclyl; where R b1 and R b2 C 3~8 Cycloalkyl, C 6~10 Each of the aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl independently is halo, cyano, hydroxyl, -NR a1 R a2 , C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~6Alkoxyl, C 3~6 Cycloalkyl, C 6~10 optionally substituted with 1 to 3 groups independently selected from aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl; and where R b1 and R b2 C 1~8 Alkyl and C 1~8 Each haloalkyl may be one to two R b5 with substitution as necessary; where R b3 is C 1~4 is alkylene; where R b4 is C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 6~10 aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl; b4 C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~8 Cycloalkyl, C 6~10 Each of the aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl is selected from 1 to 3 R b6 with substitution as necessary; where each R b5 are independently cyano, hydroxyl, C 1~4 Alkoxyl, C 3~8 Cycloalkyl, C 6~10 aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl; and R b5 C 1~4 Alkoxyl, C 3~8 Cyclo Alkyl, C 6~10 Each of aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl is selected from halo, cyano, hydroxyl, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4optionally substituted with 1 to 3 groups independently selected from alkoxyl, and phenyl; and where each R b6 are independently halo, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxyl, C 3~6 cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; b6 C 3~6 Each of cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl is independently selected from halo, cyano, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Haloalkyl, and C 1~4 optionally substituted with 1 to 3 groups independently selected from alkoxyl; or R 2 and R 3 , R 3 and R 4 , or R 5 and R 6 together with the atoms to which they are bonded, form C 6~10 Aryl, 5- to 6-membered heteroaryl, C 3~6 cycloalkyl, or 5- to 6-membered heterocyclyl; 6~10 Aryl, 5- to 6-membered heteroaryl, C 3~6 Each of the cycloalkyl and 5- to 6-membered heterocyclyl is independently halo, cyano, -NR a1 R a2 , C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6~10 Aryl, 5- to 6-membered heteroaryl, C 1~4 Alkylene-C 3~8 Cycloalkyl, C 1~4 Alkylene-C 6~10 Aryl, and C 1~4optionally substituted with 1 to 3 groups independently selected from alkylene-(5- to 6-membered heteroaryl); R 7 , R 8 , R 9 , R 10 , and R 11 each independently represents H, halo, hydroxyl, cyano, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxyl, and -NR a1 R a2 Selected from; R 13 is H, C 1~4 Alkyl, and C 1~4 haloalkyl; and R 14 is H, C 1~6 Alkyl, -C 1~4 Alkylene-NR a1 R a2 , -C 1~4 Alkylene-C(O)NR a1 R a2 , -C 1~4 Alkylene-OC(O)-C 1~4 Alkyl, -C 1~4 Alkylene-OC(O)-OC 1~4 Alkyl, -C 1~4 Alkylene-OC(O)-C 1~4 Alkylene-NR a1 R a2 , -C 1~4 Alkylene-OC 1~4 Alkyl, C 3~8 Cycloalkyl, -C 1~4 Alkylene-C 3~8 Cycloalkyl, 4- to 6-membered heterocyclyl, and -C 1~4 alkylene-(4- to 6-membered heterocyclyl); where R 14 C 3~8 Cycloalkyl, -C 1~4 Alkylene-C 3~8 Cycloalkyl, 4- to 6-membered heterocyclyl, and -C 1~4Alkylene-(4- to 6-membered heterocyclyl) is a 4- to 6-membered heterocyclyl, halo, C 1~4 Alkyl, C 1~4 Alkoxyl, and C 1~4 optionally substituted with 1 to 3 groups independently selected from haloalkyl; or R 14 is R 13 together with the N to which it is attached to form a 5-membered heterocyclyl; wherein the 5-membered heterocyclyl is selected from the group consisting of halo, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, and C 6~10 aryl; 6~10 Aryl is halo, C 1~6 Alkyl, C 1~6 Alkoxyl, and C 1~6 optionally substituted with 1 to 3 groups independently selected from haloalkyl; R a1 and R a2 each independently represents H, C 1~6 Alkyl, and C 1~6 haloalkyl; m is selected from 0, 1, and 2; and n is selected from 1 and 2.

[0055] In another aspect, a compound of formula (IIa), or a pharmaceutically acceptable salt thereof: [ka] wherein in formula (IIa), R 1 , R 2 , R 3 , R 5 , R 6 , R 14 , R b1 , and R b2 is as defined above in formula (I), (II), or elsewhere in this disclosure.

[0056] In another aspect, a compound of formula (IIb), or a pharmaceutically acceptable salt thereof: [ka] wherein in formula (IIb), R 1 , R 2 , R 3 , R 5 , R 6 , R 14 , and R b is as defined above in formula (I), (II), or elsewhere in this disclosure. 1 is CR x1 and N; and X 2 is CR x1 R x2 , N.R. x2 , O, and S(O)2. x1 H, and R b and R x2 is H, C 1~4 Alkyl, and C 1~4 haloalkyl. p is selected from 0, 1, and 2. q is selected from 0, 1, 2, 3, and 4.

[0057] In another aspect, a compound of formula (IIc), or a pharmaceutically acceptable salt thereof: [ka] wherein in formula (IIc), R 1 , R 2 , R 3 , R 5 , R 6 , R 14 , and R b4 is as defined above in formula (I), (II), or elsewhere in this disclosure. do.

[0058] In another aspect, a compound of formula (IId), or a pharmaceutically acceptable salt thereof: [ka] is provided, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 Each of these is independently y , and N. R y H, and R a Selected from: R a , R 2 , R 3 , R 4 , R 5 , R 6 , and R 14 is as defined above in formula (I), (II), or elsewhere in this disclosure.

[0059] In another aspect, a compound of formula (IIe), or a pharmaceutically acceptable salt thereof: [ka] wherein in formula (IIe), R a , R 2 , R 4 , R 6 , and R 14 is as defined above in formula (I), (II), or elsewhere in this disclosure. u is selected from 0, 1, 2, 3, 4, and 5.

[0060] In another aspect, a compound of formula (IIf), or a pharmaceutically acceptable salt thereof: [ka] wherein in formula (IIf) R y are independently H, and R a Selected from: R a , R 2 , R 4 , R 6 , and R 14 is as defined above in formula (I), (II), or elsewhere in this disclosure.

[0061] In another aspect, a compound of formula (IIg), or a pharmaceutically acceptable salt thereof: [ka] wherein in formula (IIg), R a , R 2 , R 3 , R 4 , R 5 , R 6 , and R 14 is as defined above in formula (I), (II), or elsewhere in this disclosure. 3 , Y 4 , and Y 5 is as defined above in formula (IId) or elsewhere in this disclosure. y are independently H, and R a is selected from.

[0062] In another aspect, a compound of formula (IIh), or a pharmaceutically acceptable salt thereof: [ka] wherein in formula (IIh), R 2 , R 3 , R 4 , R 5 , R 6 , and R 14 is as defined above in formula (I), (II), or elsewhere in this disclosure. y are independently as defined above in formula (IId) or elsewhere in this disclosure.

[0063] In another aspect, a compound of formula (IIi), or a pharmaceutically acceptable salt thereof: [ka] wherein in formula (IIi), R a , R 2 , R 3 , R 4 , R 5 , R 6 , and R14 is as defined above in formula (I), (II), or elsewhere in this disclosure. r is selected from 0, 1, 2, 3, 4, 5, and 6.

[0064] In some embodiments of Formula (I) or (II), L is a bond. In some embodiments, L is -O-. In some embodiments, L is -C(O)-N(H)-. * is.

[0065] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 is selected from phenyl, naphthyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, isoxazolyl, triazolyl, pyrazolyl, benzothiazolyl, pyridinonyl, quinolinonyl, isoquinolinonyl, quinazolindionyl, pyrazinonyl, pyrimidinonyl, pyrimidinedionyl, pyridazinonyl, quinazolinonyl, benzofuranyl, tetrahydrocyclopenta[b]pyridinonyl, naphthyridinonyl, chromanyl, isochromanyl, and chromenonyl. 1 are independently 1 to 4 R a In some embodiments, R 1 is selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, quinolinyl, isoxazolyl, pyridinonyl, quinolinonyl, quinazolinedionyl, pyrazinonyl, pyrimidinonyl, pyridazinonyl, quinazolinonyl, benzofuranyl, and chromenonyl, and each R 1 are independently 1 to 4 R a has been substituted as necessary.

[0066] In some embodiments of formula (I) or (II), "R 1 -L-" is [ka] Each "R 1 -L-" is 1 to 4 Ra In some embodiments, each R a are independently halo, cyano, hydroxyl, NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, C 1~4 Haloalkoxyl, C 3~6 Cycloalkyl, -OC 3~6 In some embodiments, each R is selected from cycloalkyl, 3- to 6-membered heterocyclyl, —O-(3- to 6-membered heterocyclyl), and phenyl. a are independently selected from F, Cl, CN, OH, —NH 2 , —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCH 3 , and —OCF 3 .

[0067] In some embodiments of formula (I) or (II), "R 1 -L-" is [ka] Each "R 1 -L-" is 1 to 4 R a In some embodiments, each R a are independently halo, cyano, hydroxyl, NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, C 1~4 Haloalkoxyl, C 3~6 Cycloalkyl, -OC 3~6 In some embodiments, each R a are independently selected from F, Cl, CN, OH, —NH 2 , —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCH 3 , and —OCF 3 .

[0068] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 teeth, [ka] [ka] Each R 1 is 1 to 4 R a has been substituted as necessary.

[0069] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 teeth, [ka] [ka] Each R 1 is 1 to 4 R a has been substituted as necessary.

[0070] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 teeth, [ka] Each R is selected from 1 is 1 to 4 R a In some embodiments, each R a are independently halo, CN, -OH, NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, C 1~4 Haloalkoxyl, C 3~6 Cycloalkyl, -OC 3~6 In some embodiments, each Ra are independently selected from F, Cl, OH, CN, —NH 2 , —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCH 3 , and —OCF 3 .

[0071] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 teeth, [ka] Each R is selected from 1 is 1 to 4 R a In some embodiments, each R a are independently halo, CN, -OH, NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, C 1~4 Haloalkoxyl, C 3~6 Cycloalkyl, -OC 3~6 In some embodiments, each R a is independently selected from F, Cl, OH, CN, —NH, —NH(CH), —N(CH), —CH, —CHF, —CHF, —CF, —OCH, and —OCF. a are independently selected from F, Cl, —N(CH3)2, —CH3, —OCH3, and —CF3.

[0072] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 is 1 to 3 R a , substituted as necessary with [ka] In some embodiments, each R ais independently selected from F, Cl, —N(CH), —CH, —OCH, and —CF. In some embodiments, R 1 is substituted with -CH3.

[0073] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 Halo, CN, OH, NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, C 1~4 Haloalkoxyl, and C 3~6 1 to 3 R independently selected from cycloalkyl a In some embodiments, each R a are independently F, Cl, CN, OH, -NH2, -N(CH3)2, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CN, -CH2CH2CN, -CH2OH, -CH2CH2OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -OC(CH3)3, -C H2OCH3, -CH2OCH2CH3, -CH2OCH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -SO2CH3, -S O2CH2CH3, [ka] In some embodiments, each R is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, -O-cyclopropyl, -O-CH-cyclopropyl, -O-cyclobutyl, -O-CH-cyclobutyl, -O-cyclopentyl, -O-CH-cyclopentyl, -O-cyclohexyl, -O-CH-cyclohexyl, and -O-phenyl. aare independently selected from F, Cl, CN, —NH2, —CH3, —CH2F, —CHF2, —CF3, —OCH3, —CH2OCH2CH3, and —OCF3.

[0074] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 teeth, [ka] [ka] [ka] is selected from.

[0075] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 teeth, [ka] is selected from.

[0076] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 teeth, [ka] [ka] is selected from.

[0077] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 teeth, [ka] is selected from.

[0078] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 teeth, [ka] [ka] In some embodiments, R 1 teeth, [ka] is.

[0079] In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc), "R 1 -L-" is -OC(O)-NR a1 R a2 In some embodiments, R a1 and R a2 each independently represents H, and C 1~4 In some embodiments, R a1 and R a2 is independently selected from H, CH, —CHCH, —CH(CH), and —C(CH). a1 and R a2 is independently selected from H, CH, and —CHCH. a1 and R a2 and are both CH. In some embodiments, "R 1 -L-" is -OC(O)-N(CH3)2.

[0080] In some embodiments of formula (I) or (II), R 2 and R 3 What is C 3~6In some embodiments, the 5- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl contains 1 or 2 N. In some embodiments, C 3~6 Cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, and C 1~4 In some embodiments, C is substituted with one or two groups independently selected from alkylene-phenyl. 3~6 The cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl is substituted with one or two groups independently selected from Cl, —CH 3 , cyclopropyl, and —CH 2 -phenyl.

[0081] In some embodiments of formula (I) or (II), R 3 and R 4 What is C 3~6 In some embodiments, the 5- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl contains 1 or 2 N. In some embodiments, C 3~6 Cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, and C 1~4 In some embodiments, C is substituted with one or two groups independently selected from alkylene-phenyl. 3~6 The cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl is substituted with one or two groups independently selected from Cl, —CH 3 , cyclopropyl, and —CH 2 -phenyl.

[0082] In some embodiments of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIg), (IIh), or (IIi), R 2 , R 3 , R 4 , R 5 , and R 6 each independently represents H, halo, CN, OH, -NR b1 R b2 , C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, and C 1~6 In some embodiments, R is selected from haloalkoxyl. 2 , R 3 , R 4 , R 5 , and R 6 each independently represents H, halo, CN, OH, -NR b1 R b2 , C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, and C 1~4 In some embodiments, R is selected from haloalkoxyl. 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from H, F, Cl, CN, OH, —NH, —N(CH), —CH, CD, —CHF, —CHF, —CF, —OCH, and —OCF. 2 and R 6 each independently represents H, halo, CN, OH, -NR b1 R b2 , C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, and C 1~4 In some embodiments, R is selected from haloalkoxyl. 2 and R 6are each independently selected from F, Cl, CN, OH, —NH, —N(CH), —CH, —CHF, —CHF, —CF, —OCH, and —OCF. 2 and R 6 and are both F. In some embodiments, R 6 is —CH3. In some embodiments, R 3 and R 5 each independently represents H, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxyl, and C 3~6 In some embodiments, R 3 and R 5 each independently represents H, C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, and C 1~4 In some embodiments, R is selected from haloalkoxyl. 3 and R 5 is independently selected from H, F, —NH, —CH, —CHF, —CHF, —CF, and —OCH. 3 and R 5 Both are H.

[0083] In some embodiments of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIg), (IIh), or (IIi), R 2 is F, and R 6 is -CH3.

[0084] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 -H, -NR b1 R b2 , -NR b1 S(O) n R b4and 3- to 8-membered heterocyclyl. 4 The 3- to 8-membered heterocyclyl contains 1 to 2 heteroatoms or groups independently selected from S, N, O, and S(O)2.

[0085] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 Ha-NR b1 R b2 In some embodiments, R b1 and R b2 each independently represents H, C 1~8 Alkyl, C 1~8 Haloalkyl, C 3~6 Cycloalkyl, phenyl, and 3- to 8-membered heterocycles In some embodiments, the 3- to 8-membered heterocyclyl contains 1 to 2 atoms independently selected from N and O. In some embodiments, R b1 is H, C 1~4 Alkyl, and C 1~6 In some embodiments, R is selected from haloalkyl. b1 is selected from H, and CH. In some embodiments, R b2 is C 1~6 Alkyl, C 1~8 Haloalkyl, C 3~6 Cycloalkyl, C 3~6 cycloalkyl, and 4- to 6-membered heterocyclyl. In some embodiments, R b2 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 cycloalkyl, and 4- to 6-membered heterocyclyl. In some embodiments, R b1 is H, and R b2 is C 1~6 Alkyl, C 1~8 Haloalkyl, C 3~6cycloalkyl, and 5- to 6-membered heterocyclyl. b1 is H, and R b2 is C 1~6 In some embodiments, R b2 Ha-C 1~5 In some embodiments, R b2 is selected from -methylene-CF3, -ethylene-CF3, -propylene-CF3, -butylene-CF3, and -pentylene-CF3. In some embodiments, R b2 is one or two R b5 -C replaced with 1~5 In some embodiments, each R b5 are independently hydroxyl, C 1~4 Alkoxyl, C 3~6 In some embodiments, each R b5 independently, C 3~6 R is selected from cycloalkyl, 4- to 6-membered heterocyclyl, and phenyl. b5 C 3~6 Each of cycloalkyl, 4- to 6-membered heterocyclyl, and phenyl is independently selected from halo, hydroxyl, cyano, -NR b1 R b2 , C 1~4 Alkyl, C 1~4 Alkoxyl, and C 1~4 In some embodiments, R is optionally substituted with 1 or 3 groups independently selected from haloalkyl. b5 is selected from cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl, tetrahydrofuranyl, and phenyl; and each R b5 is optionally substituted with one group selected from F, Cl, CN, —CH, —CHF, —CHF, and —CF. In some embodiments, R b5 is phenyl. In some embodiments, R b5is phenyl substituted with 1 or 2 groups independently selected from F, Cl, CN, —CH, —CHF, —CHF, and —CF. In some embodiments, R b5 is phenyl substituted with 1 or 2 groups independently selected from F, Cl, CN, and —CF. In some embodiments, R b5 is unsubstituted phenyl.

[0086] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 teeth, [ka] is selected from.

[0087] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 teeth, [ka] [ka] is selected from.

[0088] In some embodiments, in Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 teeth [ka] is.

[0089] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 is 1 to 3 R b and each R is a 3- to 8-membered heterocyclyl optionally substituted withb are independently halo, hydroxyl, cyano, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl, and C 1~4 In some embodiments, each R 4 is optionally substituted with 1 to 2 groups independently selected from F, Cl, CN, —OH, —CH 3 , —CH(CH 3 ) 2 , and —CF 3 .

[0090] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 is a 3- to 8-membered spiro, fused, or bridged heterocyclyl. 4 is selected from azetidinyl, aziridinyl, imidazolidinyl, morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrazolidinyl, piperidinyl, pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydropyridinyl, tetrahydropyridinyl, 1,1-dioxide-thiomorpholinyl, and quinuclidinyl; and each R 4 is 1 to 3 R b In some embodiments, R 4 is selected from morpholinyl, piperidinyl, tetrahydropyranyl, and pyrrolidinyl; each R 4 is 1 to 3 R b In some embodiments, each R b are independently halo, hydroxyl, cyano, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl, and C 1~4 In some embodiments, each R b are independently selected from F, Cl, CN, —OH, —CH 3 , —CH(CH 3 ) 2 , and —CF 3 .

[0091] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 is 1 to 3 R b In some embodiments, R is a spirocyclyl optionally substituted with 4 is azaspiroheptanyl. In some embodiments, R 4 is azaspiro[3.3]heptanyl. In some embodiments, R 4 is azaspiro[2.4]heptanyl In some embodiments, each R b are independently halo, hydroxyl, cyano, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl, and C 1~4 In some embodiments, each R b are independently selected from F, Cl, CN, —OH, —CH 3 , —CH(CH 3 ) 2 , and —CF 3 .

[0092] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 is 1 to 3 R b In some embodiments, each R 4 is independently selected from azabyicyclo[3.1.0]hexanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.2.2]octanyl, and oxa-azabicyclo[2.2.2]octanyl; each R 4 is 1 to 3 R b Each R b are independently halo, hydroxyl, cyano, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl, and C1~4 In some embodiments, each R b are independently selected from F, Cl, CN, —OH, —CH 3 , —CH(CH 3 ) 2 , and —CF 3 .

[0093] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 teeth, [ka] and each R 4 Halo, OH, CN, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl, and C 1~4 and optionally substituted with 1 to 3 groups independently selected from haloalkyl.

[0094] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 teeth, [ka] and each R 4 is F, Cl, OH, CN, NH2, -CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, C 3~6 Cycloalkyl, and -CHC 3~6 and optionally substituted with 1 to 3 groups independently selected from cycloalkyl.

[0095] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 teeth, [ka] [ka] is selected from.

[0096] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 teeth, [ka] is selected from.

[0097] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 teeth, [ka] [ka] is selected from.

[0098] In some embodiments, R 4 teeth, [ka] is.

[0099] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 Ha-NHS(O)2R b4 In some embodiments, R b4 is C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 In some embodiments, R b4is selected from -CH3, -CH2F, -CHF2, -CF3, and phenyl. In some embodiments, phenyl is selected from halo, and C 1~4 In some embodiments, the pyridinyl is optionally substituted with 1 or 2 groups independently selected from alkyl, F, and -CH.

[0100] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 teeth, [ka] is selected from.

[0101] In some embodiments of Formula (IIb), X 1 is CH or N. In some embodiments, X 1 is N. In some embodiments, X 2 CH2, NR x2 , O, and S(O). In some embodiments, X 1 is N, and X 2 is O. In some embodiments, X 1 is N, and X 2 is CH2. In some embodiments, X 1 is N, and X 2 is S(O). In some embodiments, each R b are independently selected from F, OH, —CH, —CH(CH), —CHF, —CHF, and —CF.

[0102] In some embodiments of Formula (IIb), p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, q is 1. In some embodiments, q is 2.

[0103] In some embodiments of Formula (IId), Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 is CR y In some embodiments, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 At least one of Y is N. In some embodiments, 1 is N; and Y 2 , Y 3 , Y 4 , and Y 5 is CR y In some embodiments, Y 2 is N; and Y 1 , Y 3 , Y 4 , and Y 5 is CR y In some embodiments, Y 3 is N; and Y 1 , Y 2 , Y 4 , and Y 5 is CR y In some embodiments, Y 1 and Y 5 is N; and Y 1 , Y 2 , and Y 3 is CR y is.

[0104] In some embodiments of Formula (IId), (IIf), (IIg), or (IIh), each R y are independently H, halo, hydroxyl, CN, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl, and C 1~4 In some embodiments, each R yare independently H, F, Cl, CN, OH, -NH2, -N(CH3)2, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CN, -CH2CH2CN, -CH2OH, -CH2CH2OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -OC(CH3)3, -CH2O CH3, -CH2OCH2CH3, -CH2OCH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -SO2CH3, -SO2CH2CH3, [ka] In some embodiments, each R is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, -O-cyclopropyl, -O-CH-cyclopropyl, -O-cyclobutyl, -O-CH-cyclobutyl, -O-cyclopentyl, -O-CH-cyclopentyl, -O-cyclohexyl, -O-CH-cyclohexyl, and -O-phenyl. y is independently selected from H, F, Cl, OH, CN, —NH, —CH, —CHF, —CHF, —CF, —OCH, —CHOCHCH, and —OCF. In some embodiments, each R y are independently selected from H, F, —CH3, —CH2F, —CHF2, —CF3, —OCH3, —CH2OCH2CH3, and —OCF3.

[0105] In some embodiments of Formula (IIe), u is selected from 1, 2, and 3. In some embodiments, u is 3.

[0106] In some embodiments of Formula (IIg), Y 3 , Y 4 , and Y 5 independently, CR y , and N; where R y H, and R aIn some embodiments, Y 3 is N; and Y 4 and Y 5 is CR y In some embodiments, Y 5 is N; and Y 3 , and Y 4 is CR y In some embodiments, each R y is independently selected from H, F, Cl, CN, —NH, —N(CH), —CH, —CHF, —CHF, —CF, and —OCH. x1 are independently selected from H, F, Cl, —NH 2 , —N(CH 3 ) 2 , —CH 3 , —CF 3 , —OCH 3 , and —OCF 3 .

[0107] In some embodiments of Formula (IIi), r is selected from 1, 2, and 3. In some embodiments, r is 3.

[0108] In some embodiments of Formula (I) or (II), R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from H, F, Cl, CN, —NH, —N(CH), —CH, —CHF, —CHF, —CF, —OCH, and —OCF. 7 , R 8 , R 9 , R 10 , and R 11 Each of R is selected from H, F, CN, —N(CH) , —CH , and —CF . 7 ~R 11 Each of is selected from H, F, and -N(CH3)2. In some embodiments, R 7 ~R 11 is H. In some embodiments, R 7is selected from H, F, CN, —N(CH) , —CH , and —CF . In some embodiments, R 7 is F. In some embodiments, R 8 is selected from H, F, CN, —N(CH) , —CH , and —CF . In some embodiments, R 8 is F. In some embodiments, R 10 is selected from H, F, CN, —N(CH) , —CH , and —CF . In some embodiments, R 10 is F, or —N(CH). In some embodiments, R 11 is -CH3.

[0109] In some embodiments of Formula (I), R 12 is H. In some embodiments, R 12 is -CH3.

[0110] In some embodiments of Formula (I), R 13 is H. In some embodiments, R 13 is -CH3.

[0111] In some embodiments of Formula (I), R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 Each of is H.

[0112] In some embodiments of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 14 is C 1~6 Alkyl, C 3~8 cycloalkyl, and 4- to 6-membered heterocyclyl. In some embodiments, R 14 C 3~8 Each of cycloalkyl and 4- to 6-membered heterocyclyl is selected from halo, C1~4 Alkyl, and C 1~4 In some embodiments, R is optionally substituted with 1 to 3 groups independently selected from haloalkyl. 14 -C 1~4 Alkylene-NR a1 R a2 , -C 1~4 Alkylene-C(O)NR a1 R a2 , -C 1~4 Alkylene-OC(O)-C 1~4 Alkyl, -C 1~4 Alkylene-OC(O)-OC 1~4 Alkyl, -C 1~4 Alkylene-OC(O)-C 1~4 Alkylene-NR a1 R a2 , and -C 1~4 Alkylene-OC 1~4 In some embodiments, when administered to a biological system, the provided esters are selected from R alkyl as a result of chemical reaction(s), enzyme-catalyzed chemical reaction(s), and / or metabolic chemical reaction(s). 14 produces the active ingredient, which is hydrogen.

[0113] In some embodiments of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 14 is H, methyl, ethyl, propyl, butyl, -CH2C(O)N(CH3)2, -(CH2)2N(CH2CH3)2, -CH2-OC(O)CH3, -(CH2)2-OC(O)CH3, -CH2-OC(O)C(CH)3, -(CH2)2-OC(O)C(CH)3, -CH2-OC(O)-O-CH3, -CH(CH3)-OC(O)-O-CH3, -CH2-OC(O)-O-CH2CH3, -CH2-OC(O)-O-CH(CH3)2, -CH2-OC(O)-OC(CH3)3, -(CH2)2C(O)CH3, [ka] In some embodiments, R 14 is H, -CH2-OC(O)C(CH)3, -CH(CH3)-OC(O)-O-CH3, [ka] is selected from.

[0114] In some embodiments, R 14 is R 13 together with the N to which it is attached to form a 5-membered heterocyclyl. In some embodiments, the 5-membered heterocyclyl is C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, and C 6~10 In some embodiments, the 5-membered heterocyclyl is substituted with 1 to 2 groups independently selected from CH, CHCH, -OCH, -OCHCH, and phenyl. In some embodiments, the 5-membered heterocyclyl is substituted with phenyl, and the phenyl is substituted with halo, C 1~6 Alkyl, C 1~6 Alkoxyl, and C 1~6 and optionally substituted with 1 to 3 groups independently selected from haloalkyl.

[0115] In some embodiments, R 14 is H.

[0116] In some embodiments, R 14 is CH, or CHCH. In some embodiments, R 14 is CH3. In some embodiments, R 14 is CH2CH3.

[0117] In some embodiments, the compound of the present disclosure is selected from Examples 1-354.

[0118] In some embodiments, the compound of the present disclosure is selected from Examples 355 to 406. In some embodiments, the compound of the present disclosure is selected from Examples 407 to 496.

[0119] In some embodiments, the compounds of the present disclosure are [ka] [ka] [ka] is selected from.

[0120] In another aspect, a compound of formula (J), or a pharmaceutically acceptable salt thereof: [ka] or a pharmaceutically acceptable salt thereof, wherein: L is a bond, -O-, or -OC(O)- * , -NH-, -C(O)-N(H)- * , and -N(H)-C(O)- * Selected from; where * is L's R 1 indicates the point of attachment to; R 1 is A 1 , A 2 , A 3 , and A 4 Selected from; A 1 is a 5- to 10-membered heteroaryl containing 1 to 5 heteroatoms independently selected from S, N, and O; 1 optionally containing 1 to 3 C(O); and 1 is 1 to 6 R a with substitution as necessary; A 2 is 1 to 6 R a C substituted as needed6~10 is aryl; A 3 is C 5~10 cycloalkyl or 5- to 14-membered heterocyclyl; 3 is oxo and R a and A 4 Ha-NR a1 R a2 and; where each R a are independently halo, cyano, hydroxyl, -NR a1 R a2 , C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxyl, -S(O) m -C 1~6 Alkyl, C 3~8 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6~10 Aryl, 5- to 6-membered heteroaryl, -OC 3~8 Cycloalkyl, -O-(3- to 6-membered heterocyclyl), -OC 1~4 Alkylene-C 3~8 cycloalkyl, and -O-phenyl; where R a C 3~8 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6~10 Aryl, 5- to 6-membered heteroaryl, -OC 3~8 Cycloalkyl, -O-(3- to 6-membered heterocyclyl), -OC 1~4 Alkylene-C 3~8 cycloalkyl, and -O-phenyl each independently represent halo, cyano, hydroxyl, -NR a1 R a2 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, and C 1~6 Haloal optionally substituted with 1 to 3 groups independently selected from coxyl; and where R a C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxyl, and -S(O) m -C 1~6 Each alkyl is selected from 1 to 3 R a3 where each R is substituted as needed. a3 are independently halo, cyano, hydroxyl, -NR a1 R a2 , C 1~6 Alkoxyl, C 3~8 cycloalkyl, and 3- to 6-membered heterocyclyl; where R a3 C 3~8 Each of the cycloalkyl and 3- to 6-membered heterocyclyl groups has 1 to 3 R a4 and each R a4 are independently halo, cyano, hydroxyl, -NR a1 R a2 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 3~8 cycloalkyl, and 3- to 6-membered heterocyclyl; R 2 , R 3 , R 4 , R 5 , and R 6 each independently represents H, halo, cyano, hydroxyl, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxyl, C 1~8 Haloalkyl, C 1~8 Haloalkoxyl, -NR b1 R b2 , -R b3S(O) m R b4 , -S(O) m R b4 , -NR b1 S(O) n R b4 , -COOR b1 , -CONR b1 R b2 , -NR b1 COOR b2 , -NR b1 COR b4 , -R b3 NR b1 R b2 , -S(O) n NR b1 R b2 , C 3~12 Cycloalkyl, C 6~10 selected from aryl, 5- to 6-membered heteroaryl, and 3- to 12-membered heterocyclyl; where R 2 , R 3 , R 4 , R 5 , and R 6 C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxyl, C 1~8 Haloalkyl, and C 1~8 Each haloalkoxyl is one to two R c where each R c are independently azido, oxo, cyano, halo, hydroxyl, -NR a1 R a2 , C 1~4 Alkoxyl, C 3~8 Cycloalkyl, C 6~10 aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl; c C 3~8 Cycloalkyl, C 6~10 Each of aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl is selected from halo, cyano, hydroxyl, -NR a1 R a2 , C 1~4 Alkyl, C1~6 Haloalkyl, C 1~4 Alkoxyl, and C 3~6 optionally substituted with 1 to 3 groups independently selected from cycloalkyl; where R 2 , R 3 , R 4 , R 5 , and R 6 C 6~10 Each of the aryl and 5- to 6-membered heteroaryl independently has 1 to 5 R b with substitution as necessary; and where R 2 , R 3 , R 4 , R 5 , and R 6 C 3~12 Each of the cycloalkyl and the 3- to 12-membered heterocyclyl independently represents ═CR b1 R b2 and R b optionally substituted with 1 to 6 groups independently selected from where each R b are independently azido, cyano, halo, hydroxyl, -NR a1 R a2 , C 1~6 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxyl, C 3~6 Cycloalkyl, C 6~10 aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl; b C 3~6 Cycloalkyl, C 6~10 Each of the aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl independently is halo, cyano, hydroxyl, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Haloalkyl, and C 1~4 optionally substituted with 1 to 3 groups independently selected from alkoxyl; where R b1 and R b2each independently represents H, C 1~8 Alkyl, C 1~8 Haloalkyl, C 3~8 Cycloalkyl, C 6~10 selected from aryl, 5- to 6-membered heteroaryl, and 3- to 8-membered heterocyclyl; where R b1 and R b2 C 3~8 Cycloalkyl, C 6~10 Each of the aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl independently is halo, cyano, hydroxyl, -NR a1 R a2 , C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- to 6-membered hetero optionally substituted with 1 to 3 groups independently selected from aryl, and 4- to 6-membered heterocyclyl; and where R b1 and R b2 C 1~8 Alkyl and C 1~8 Each haloalkyl may be one to two R b5 with substitution as necessary; where R b3 is C 1~4 is alkylene; where R b4 is C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 6~10 aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl; b4 C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~8 Cycloalkyl, C 6~10 Each of the aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl is selected from 1 to 3 R b6 with substitution as necessary; where each Rb5 are independently cyano, hydroxyl, C 1~4 Alkoxyl, C 3~8 Cycloalkyl, C 6~10 aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl; and R b5 C 1~4 Alkoxyl, C 3~8 Cycloalkyl, C 6~10 Each of aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl is selected from halo, cyano, hydroxyl, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 optionally substituted with 1 to 3 groups independently selected from alkoxyl, and phenyl; and where each R b6 are independently halo, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxyl, C 3~6 cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; b6 C 3~6 Each of cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl is independently selected from halo, cyano, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Haloalkyl, and C 1~4 optionally substituted with 1 to 3 groups independently selected from alkoxyl; or R 2 and R 3 , R 3 and R 4 , or R 5 and R 6 together with the atoms to which they are bonded, form C 6~10 Aryl, 5- to 6-membered heteroaryl, C 3~6 cycloalkyl, or 5- to 6-membered heterocyclyl; 6~10Aryl, 5- to 6-membered heteroaryl, C 3~6 Each of the cycloalkyl and 5- to 6-membered heterocyclyl is independently halo, cyano, -NR a1 R a2 , C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6~10 Aryl, 5- to 6-membered heteroaryl, C 1~4 Alkylene-C 3~8 Cycloalkyl, C 1~4 Alkylene-C 6~10 Aryl, and C 1~4 optionally substituted with 1 to 3 groups independently selected from alkylene-(5- to 6-membered heteroaryl); R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 each independently represents H, halo, hydroxyl, cyano, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxyl, and -NR a1 R a2 Selected from; R 13 is H, C 1~4 Alkyl, and C 1~4 haloalkyl; R 15 is H, C 1~10 Alkyl, C 1~10 Haloalkyl, C 3~10 Cycloalkyl, 3- to 14-membered heterocyclyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, -C 1~4 Alkylene-NR a1 R a2 , -C 1~4 Alkylene-C(O)NR a1 R a2 , and -L 1 -R 16 Selected from; Here, L 1 -C 1~4 Alkylene-, -C 1~4 Alkylene -O-, -C 1~4 Alkylene-C(O)-, -C 1~4 Alkylene-OC(O)-, -C 1~4 Alkylene-OC(O)-C 1~4 Alkylene-, -C 1~4 Alkylene-C(O)-O-, -C 1~4 Alkylene-C(O)-OC 1~4 Alkylene, -C 1~4 Alkylene-OC(O)-O-, -C 1~4 Alkylene-OC(O)-OC 1~4 Alkylene-, -C 1~4 Alkylene-NR a1 C(O)-O-, and -C 1~4 Alkylene-OC(O)-NR a1 - selected from; and where R 16 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 3- to 14-membered heterocyclyl, C 6~10 Aryl and 5- to 10-membered heteroaryl Selected from the reels; where R 15 and R 16 C 3~10 Cycloalkyl, 3- to 14-membered heterocyclyl, C 6~10 Each of aryl and 5- to 10-membered heteroaryl is selected from halo, hydroxyl, -COOR b7 , -NR a1 R a2 , -S(O)2R a5 , C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, C 1~4 Haloalkoxyl, and -C 1~4 Alkylene-NR a1 R a2 optionally substituted with 1 to 4 groups independently selected from Ra1 and R a2 each independently represents H, C 1~6 Alkyl, and C 1~6 haloalkyl; R a5 is C 1~6 is alkyl; R b7 are independently H and C 1~6 alkyl; m is selected from 0, 1, and 2; and n is selected from 1 and 2.

[0121] In some embodiments of Formula (J) or a pharmaceutically acceptable salt thereof, the compound has the formula (Ja): [ka] In the formula (Ja), Y 1 , Y 2 , Y 3 , and Y 4 Each of these is independently y , and N; where each R y are independently H and R a and R z is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 cycloalkyl, and 3- to 6-membered heterocyclyl.

[0122] In some embodiments of Formula (J) or (Ja), or a pharmaceutically acceptable salt thereof, the compound has the formula (Jb): [ka] In the formula (Jb), Y 2 and Y 4 Each of these is independently y , and N. Each R yare independently H and R a Selected from: R z is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 cycloalkyl, and 3- to 6-membered heterocyclyl. X 1 is CR x1 , and N. 2 is CR x1 R x2 , N.R. x2 , O, and S(O)2. x1 H, and R b and R x2 is H, C 1~4 Alkyl, and C 1~4 haloalkyl, q is selected from 0, 1, 2, and 3; and r is selected from 0, 1, and 2.

[0123] In some embodiments of Formula (J) or (Ja), or a pharmaceutically acceptable salt thereof, the compound has the formula (Jc): [ka] In the formula (Jc), R z is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 cycloalkyl, and 3- to 6-membered heterocyclyl; and r is selected from 0, 1, 2, and 3.

[0124] In some embodiments of Formula (J), (Ja), (Jb), or (Jc), or a pharmaceutically acceptable salt thereof, the compound has the formula (Jd): [ka] In the formula (Jd), R z is selected from H, -CH3, -CD3-CH2F, -CHF2, -CF3, and -CH2CH3; X 1 is CR x1 , and N. X 2 is CR x1 R x2 , N.R. x2 , O, and S(O)2. x1 H, and R b and R x2 is H, C 1~4 Alkyl, and C 1~4 haloalkyl, q is selected from 0, 1, 2, and 3; and r is selected from 0, 1, 2, and 3.

[0125] In some embodiments of Formula (J), (Ja), (Jb), (Jc), or (Jd), or a pharmaceutically acceptable salt thereof, the compound has the formula (Je): [ka] In the formula (Je), X 1 is CR x1 , and N. X 2 is CR x1 R x2 , N.R. x2 , O, and S(O)2. x1 H, and R b and R x2 is H, C 1~4 Alkyl, and C 1~4 haloalkyl; q is selected from 0, 1, 2, and 3.

[0126] In some embodiments of Formula (J), or (Ja), or a pharmaceutically acceptable salt thereof, the compound has the formula (Jf): [ka] In the formula (Jf), Y1 and Y 4 Each of these is independently y , and N. Each R y are independently H and R a Selected from: R z is selected from H, —CH3, —CD3—CH2F, —CHF2, —CF3, and —CH2CH3. 1 is CR x1 , and N. 2 is CR x1 R x2 , N.R. x2 , O, and S(O)2. x1 H, and R b and R x2 is H, C 1~4 Alkyl, and C 1~4 haloalkyl, q is selected from 0, 1, 2, and 3; and r is selected from 0, 1, and 2.

[0127] In some embodiments of Formula (J) or a pharmaceutically acceptable salt thereof, the compound has the formula (Jg): [ka] In the formula (Jg), Z 1 , Z 2 , Z 3 , and Z 4 Each of these is independently y1 R y2 , N.R. z1 , and O; where R y1 and R y2 each independently represents H and R a and R z and R z1 each independently represents H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 cycloalkyl, and 3- to 6-membered heterocyclyl.

[0128] In some embodiments of Formula (I), or (J), or a pharmaceutically acceptable salt thereof, R 1 teeth, [ka] where each R 1 is 1 to 4 R a In some embodiments, R a is C 1~4 In some embodiments, R a is —CH3. In some embodiments, R 1 teeth, [ka] is selected from.

[0129] In some embodiments of Formula (I) or (J), or a pharmaceutically acceptable salt thereof, R 1 teeth, [ka] Each R is selected from 1 is 1 to 4 R a In some embodiments, each R a are independently halo, CN, -OH, NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, C 1~4 Haloalkoxyl, C 3~6 Cycloalkyl, -OC 3~6 In some embodiments, each R a is independently selected from F, Cl, OH, CN, —NH, —NH(CH), —N(CH), —CH, —CHF, —CHF, —CF, —OCH, and —OCF. aare independently selected from —N(CH 3 ) 2 , —CH 3 , —OCH 3 , and —CF 3 .

[0130] In some embodiments of Formula (I), or (J), R 1 teeth, [ka] [ka] In some embodiments, R 1 teeth [ka] is.

[0131] In some embodiments of Formula (I), or (J), or a pharmaceutically acceptable salt thereof, R 1 is 1 to 2 R a replaced with [ka] Each R a independently, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxyl, and C 3~6 In some embodiments, R 1 teeth [ka] is.

[0132] In some embodiments of Formula (J), (Ja), or (Jc), or a pharmaceutically acceptable salt thereof, R 3 and R 5 is H.

[0133] In some embodiments of Formula (J), (Ja), (Jb), (Jc), (Jd), (Je), or (Jf), or a pharmaceutically acceptable salt thereof, R2 and R 6 each independently represents H, halo, C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, C 1~4 Haloalkoxyl, C 3~6 cycloalkyl, and 3- to 7-membered heterocyclyl. In some embodiments, R 2 and R 6 is independently selected from F, Cl, —CH, —CD, —CHCH, —OCH, —OCHCH, —CHF, —CHF, —CF, —CHCHF, —CHCHF, —CHCF, —NH, and —N(CH). 2 and R 6 is independently selected from F, Cl, and —CH. 2 is F, and R 6 is —CH3. In some embodiments, R 2 and R 6 is independently selected from F, and Cl. 2 and R 6 is F.

[0134] In some embodiments of Formula (J), (Ja), (Jb), (Jc), (Jd), (Je), or (Jf), or a pharmaceutically acceptable salt thereof, R 4 is 1 to 3 R b replaced with [ka] In some embodiments, each R b independently, C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, and C 1~4 In some embodiments, R is selected from haloalkoxyl. bis independently selected from -CH3, -CF3, and -OCF3. In some embodiments, R b is —CF. In some embodiments, R 4 teeth, [ka] is.

[0135] In some embodiments of formula (Ja) or (Jb), Y 2 is N. In some embodiments of formula (Ja) or (Jb), Y 2 is N and Y 4 In some embodiments of Formula (Ja), Y 1 , Y 3 , and Y 4 is CR y In some embodiments of (Ja), Y 1 , Y 2 , Y 3 , and Y 4 At least one of Y is N. In some embodiments, 4 In some embodiments of (Ja), Y 1 , Y 2 , Y 3 , and Y 4 is CR y is.

[0136] In some embodiments of Formula (Jf), Y 1 is N. In some embodiments, Y 4 is N. In some embodiments, Y 1 and Y 4 Both and are N.

[0137] In some embodiments of Formula (Ja), (Jb), (Jc), (Jd), or (Jf), or a pharmaceutically acceptable salt thereof, R z is -CH3.

[0138] In some embodiments of Formula (Jb), (Jd), (Je), or (Jf), or a pharmaceutically acceptable salt thereof, X 1 is N.

[0139] In some embodiments of Formula (Jb), (Jd), (Je), or (Jf), or a pharmaceutically acceptable salt thereof, X 2 is O. In some embodiments, X 1 is N, and X 2 is O.

[0140] In some embodiments of Formula (Jb), (Jd), (Je), or (Jf), or a pharmaceutically acceptable salt thereof, q is 1.

[0141] In some embodiments of formula (Jb), (Jd), (Je), or (Jf), each R b independently, C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, and C 1~4 In some embodiments, R is selected from haloalkoxyl. b is C 1~4 In some embodiments, R b is independently selected from -CHF, -CHF, and -CF. In some embodiments, R b is CF3.

[0142] In some embodiments of Formula (J), (Ja), (Jb), (Jc), (Jd), (Je), or (Jf), or a pharmaceutically acceptable salt thereof, R 15 is H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 4- to 10-membered heterocyclyl, and C 6~10 In some embodiments, R 15 is H, C 1~6 alkyl, and phenyl; and phenyl is selected from halo, C1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, and C 1~4 In some embodiments, R is optionally substituted with 1 to 3 groups independently selected from haloalkoxyl. 15 is selected from H, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl, and phenyl. 15 is selected from H, methyl, ethyl, and phenyl. In some embodiments, R 15 is H. In some embodiments, R 15 is methyl. In terms of form, R 15 is ethyl. In some embodiments, R 15 is phenyl. In some embodiments, R 15 is phenyl substituted with one group selected from F, —CH, —CF, —OCF, and —(CH)N(CHCH). In some embodiments, R 15 is -CH2CH2N(CH2CH3)2.

[0143] In some embodiments of Formula (J), (Ja), (Jb), (Jc), (Jd), (Je), or (Jf), or a pharmaceutically acceptable salt thereof, R 15 Ha-L 1 -R 16 In some embodiments, L 1 -CH2-, -CH2CH2-, -CH(CH3)-, -CH2-OC(O)-C 1~4 Alkyl, and -CH2-OC(O)-OC 1~4 In some embodiments, R 16is selected from -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH3, phenyl, pyridinyl, imidazolyl, tetrahydrofuranyl, morpholinyl, and tetrahydropyranyl. 16 Each of the phenyl, pyridinyl, imidazolyl, tetrahydrofuranyl, morpholinyl, and tetrahydropyranyl is optionally substituted with 1 to 2 groups independently selected from F, —CH 3 , —CH 2 CH 3 , hydroxyl, and —COOH.

[0144] In some embodiments of Formula (J), (Ja), (Jb), (Jc), (Jd), (Je), or (Jf), or a pharmaceutically acceptable salt thereof, R 15 is H, -CH3, -CH2CH3, [ka] is selected from.

[0145] In some embodiments of Formula (J), (Ja), (Jb), (Jc), (Jd), (Je), or (Jf), or a pharmaceutically acceptable salt thereof, R 15 is selected from H, —CH, and —CHCH. In some embodiments, R 15 is H In some embodiments, R 15 is -CH2CH3.

[0146] In some embodiments of Formula (Jg), or a pharmaceutically acceptable salt thereof, Z 1 is O. In some embodiments, Z 2 is O. In some embodiments, Z 3 is O. In some embodiments, Z 4 is O. In some embodiments, Z 1 is NR z1 In some embodiments, Z 2 is NR z1 In some embodiments, Z 3is NR z1 In some embodiments, Z 4 is NR z1 In some embodiments, R z1 is selected from H, —CH, and —CHCH. In some embodiments, R z1 is H.

[0147] In some embodiments of Formula (Jg), or a pharmaceutically acceptable salt thereof, R z is -CH3.

[0148] In some embodiments of Formula (Jg), or a pharmaceutically acceptable salt thereof, R 3 and R 5 is H.

[0149] In some embodiments of Formula (Jg), or a pharmaceutically acceptable salt thereof, R 2 and R 6 each independently represents H, halo, C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, C 1~4 Haloalkoxyl, C 3~6 cycloalkyl, and 3- to 7-membered heterocyclyl. In some embodiments, R 2 and R 6 is independently selected from F, Cl, —CH, —CD, —CHCH, —OCH, —OCHCH, —CHF, —CHF, —CF, —CHCHF, —CHCHF, —CHCF, —NH, and —N(CH). 2 and R 6 is independently selected from F, Cl, and —CH. 2 is F, and R 6 is —CH3. In some embodiments, R 2 and R 6 is independently selected from F, and Cl.2 and R 6 is F.

[0150] In some embodiments of Formula (Jg), or a pharmaceutically acceptable salt thereof, R 4 is 1 to 3 R b replaced with [ka] In some embodiments, each R b independently, C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, and C 1~4 In some embodiments, R is selected from haloalkoxyl. b is independently selected from -CH3, -CF3, and -OCF3. In some embodiments, R b is —CF. In some embodiments, R 4 teeth, [ka] is.

[0151] In some embodiments of Formula (Jg), or a pharmaceutically acceptable salt thereof, R 15 is selected from H, —CH, —CHCH, and —CHCHCH. In some embodiments, R 15 is H. In some embodiments, R 15 teeth- In some embodiments, R 15 is -CH2CH3. In some embodiments, R 15 is -CH2CH2CH3.

[0152] In some embodiments, the compounds of the present disclosure are [ka] [ka] [ka] is selected from.

[0153] In some embodiments, the compounds of the present disclosure are [ka] is selected from.

[0154] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein 1 to n hydrogen atoms bonded to a carbon atom may be replaced by deuterium atoms or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds may increase resistance to metabolism and thus may be useful for increasing the half-life of the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by methods well known in the art, for example, by utilizing starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0155] In some embodiments, compounds of the present disclosure contain 1 to 6 deuterium ( 2 H, or D). In some embodiments, R 2 , R 3 , R 4 , R 5 , and R 6 In some embodiments, one of R 6 contains 1 to 6 D. In some embodiments, R 6is CD3.

[0156] Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. "Physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. In addition, if a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize a variety of synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts.

[0157] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0158] A "prodrug" is a biologically inactive derivative of a drug that, upon administration to the human body, is converted into the biologically active parent drug following some chemical or enzymatic pathway.

[0159] In certain embodiments, the compounds described herein or their pharmaceutically acceptable salts or mixtures thereof are provided as optical isomers, racemates, or other mixtures thereof. In these circumstances, single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be achieved, for example, by conventional methods, such as crystallization in the presence of a resolving agent, or chromatography using, for example, a chiral high-pressure liquid chromatography (HPLC) column. In addition, Z and E forms (or cis and trans forms) of the hydroxyamidine compounds described herein are also provided. Specifically, Z and E forms are included even when only one name is given for both the carbon-carbon double bond and the hydroxyamidine bond.

[0160] Where chirality is not specified, but is present, it is understood that this embodiment is directed to either a particular diastereomeric or enantiomerically enriched form, or a racemic or scalemic mixture of such compound(s).

[0161] "Enantiomers" are pairs of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. A mixture of enantiomers in a ratio other than 1:1 is a "scalic" mixture.

[0162] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0163] "Atropisomers" are stereoisomers that arise due to hindered rotation about a single bond, when the barrier to rotation about that bond is high enough to isolate individual stereoisomers.

[0164] In certain embodiments, atropisomers of the compounds or pharmaceutically acceptable salts described herein are provided.

[0165] The compositions provided herein containing the compounds described herein or pharmaceutically acceptable salts, isomers, or mixtures thereof may be used in the form of racemic mixtures, or mirror-image mixtures. All such isomeric forms of these compounds may include mixtures containing an isomeric excess of one enantiomer or a single diastereomer or mixtures of diastereomers, and are expressly included herein the same as if each and every isomeric form were specifically and individually listed.

[0166] In certain embodiments, the present invention also provides chelates, non-covalent complexes, and mixtures thereof of the compounds described herein or their pharmaceutically acceptable salts, isomers, or mixtures thereof. A "chelate" is formed by the coordination of a compound to a metal ion at two (or more) points. A "non-covalent complex" is formed by the interaction of a compound with another molecule, where no covalent bond is formed between the compound and the molecule. For example, complex formation can occur through van der Waals interactions, hydrogen bonds, and electrostatic interactions (also called ionic bonds). Therapeutic Uses of the Compounds

[0167] The methods described herein can be applied to in vivo or ex vivo cell populations. "In vivo" refers to within an individual organism, such as an animal or human. In this context, the methods described herein can be used therapeutically in individuals. "Ex vivo" refers to outside an individual organism. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from individuals. Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and their biopsies. In this context, the present invention can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the present invention can be used ex vivo to determine the optimal schedule and / or dosage of administration of an α4β7 integrin inhibitor for a given indication, cell type, individual, and other parameters. Information gathered from such use can be used for experimental purposes or to design in vivo treatment protocols in the clinic. Other ex vivo uses to which the present invention may be adapted are described below or will become apparent to those skilled in the art. Selected compounds can be further characterized to determine their safety or tolerability in human or non-human subjects. Such properties can be determined using methods commonly known to those skilled in the art.

[0168] In some embodiments, the compounds described herein, such as compounds of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIIf), (IIg), (IIh), or (IIi), or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analog thereof, can be used to treat subjects having or suspected of having disease states, disorders, and conditions (collectively referred to as "indications") that respond or are thought to respond to inhibition of α4β7 integrin activity. In some embodiments, the compounds described herein can be used to inhibit the activity of α4β7 integrin. In some embodiments, the compounds described herein can be used to inhibit excessive or destructive immune responses, or the growth or proliferation of cells, such as cancer cells, or to inhibit immunosuppression.

[0169] In some embodiments, the compounds described herein, e.g., compounds of Formula (J), (Ja), (Jb), (Jc), (Jd), (Je), or (Jf), or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analog thereof, are used to treat or inhibit disease states, disorders, and conditions (collectively also referred to as "indications") that respond or are thought to respond to inhibition of α4β7 integrin activity. The compounds described herein can be used to treat subjects suspected of having these disorders. In some embodiments, the compounds described herein can be used to inhibit the activity of α4β7 integrin. In some embodiments, the compounds described herein can be used to inhibit excessive or destructive immune responses, or the growth or proliferation of cells, such as cancer cells, or to inhibit immunosuppression. method

[0170] In some embodiments, the present disclosure provides compounds described herein that are useful as inhibitors of α4β7 integrin. In some embodiments, the present disclosure provides a method for treating an inflammatory disease or condition, comprising administering a compound described herein.

[0171] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier.

[0172] In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound described herein and at least one additional therapeutic agent and at least one pharmaceutically acceptable excipient.

[0173] The present disclosure provides compounds described herein for use in therapy.

[0174] In another embodiment, the present disclosure provides a compound described herein for use in the manufacture of a medicament for treating a disease or condition presented herein.

[0175] In some embodiments, the compounds described herein are useful for treating diseases or conditions in patients suitable for treatment by inhibiting α4β7 integrin. Diseases or conditions that can be treated using the compounds described herein include solid tumors, diabetes, inflammatory diseases, graft-versus-host disease, primary sclerosing cholangitis, HIV, autoimmune diseases, inflammatory bowel disease (IBD), alcoholic hepatitis, systemic lupus erythematosus (SLE), and lupus nephritis.

[0176] In some embodiments, there are provided compounds described herein that are useful for treating an inflammatory disease or condition in a patient that is mediated, at least in part, by α4β7 integrin.

[0177] "Administering" or "administration" refers to the delivery of one or more therapeutic agents to a patient. In some embodiments, administration is monotherapy, in which the compound described herein is the only active ingredient administered to a patient in need of treatment. In another embodiment, administration is simultaneous administration, in which two or more therapeutic agents are delivered together during the course of treatment. In some embodiments, two or more therapeutic agents may be formulated simultaneously into a single dosage form or "combined dosage unit," or may be formulated separately as a single-layer or bilayer tablet or capsule, as is typical for intravenous or oral administration, and then combined into a combined dosage unit.

[0178] In some embodiments, the compounds described herein are administered to a human patient in need thereof in an effective amount, e.g., about 0.1 mg to about 1000 mg of the compound per dose. In some embodiments, the effective amount is about 0.1 mg to about 400 mg per dose. In some embodiments, the effective amount is about 0.1 mg to about 300 mg per dose. In some embodiments, the effective amount is about 0.1 mg to about 200 mg per dose. In some embodiments, the effective amount is about 1 mg to about 100 mg per dose. In other embodiments, the effective amount is about 1 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 18 mg, about 20 mg, about 30 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 200 mg, or about 300 mg per dose.

[0179] In some embodiments, a compound described herein and at least one additional therapeutic agent are administered to a human patient in need thereof in an effective amount of each agent, independently, from about 0.1 mg to about 1000 mg per compound per dose, per dose of compound or formulation. In some embodiments, the effective amount of a combination treatment of a compound described herein and an additional compound is independently from about 0.1 mg to about 200 mg per compound per dose. In some embodiments, the effective amount of a combination treatment of a compound described herein and an additional compound is independently from about 1 mg to about 100 mg per compound per dose. In other embodiments, the effective amount of a combination treatment of a compound described herein and an additional compound is, for each component, about 1 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 18 mg, about 20 mg, about 30 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 200 mg, or about 500 mg per dose.

[0180] In some embodiments, the dose of the compound described herein and / or the combination of doses of the compound described herein and / or the dose of the additional therapeutic agent is administered once daily, twice daily, or three times daily. In yet another embodiment, the dose of the compound described herein and / or the dose of the additional therapeutic agent is administered as a loading dose of about 0.1 mg to about 1000 mg per compound on Day 1, followed by a regular regimen of the compound described herein and / or one or more additional therapeutic agents or treatments each day, every other day, or weekly for up to one month. Maintenance doses may be about 0.1 mg to about 1000 mg for each component of the multi-component drug regimen once daily, twice daily, three times daily, or weekly. A qualified caregiver or attending physician will know which dosing regimen is best for a particular patient or a particular presenting condition and will make the appropriate treatment regimen judgment for that patient. Thus, in another embodiment, a qualified caregiver can tailor the dosage regimen of the compounds described herein and / or the additional therapeutic agent(s) as disclosed herein to suit the particular needs of the patient. Thus, it will be understood that the amount of the dose of the compounds described herein and the amount of the dose of the additional therapeutic agent actually administered will typically be determined by a physician in light of the relevant circumstances, including the condition(s) to be treated, the selected route of administration, the actual compound (e.g., salt or free base) administered and its associated activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0181] Coadministration can also include administration of component drugs, such as one or more compounds described herein and one or more additional (second, third, fourth, or fifth) therapeutic agents. Such combinations of one or more compounds described herein and one or more additional therapeutic agents can be administered simultaneously or sequentially (one after the other) within a reasonable time period (e.g., about 1 minute to 24 hours) between each administration, depending on the pharmacokinetic and / or pharmacodynamic properties of each agent or combination. Coadministration can also involve treatment with a fixed combination, in which the agents of the treatment regimen can be combined at a fixed dosage or in a combined administration vehicle, such as a solid, liquid, or aerosol. In some embodiments, a kit can be used to administer drugs or drug components.

[0182] Thus, some embodiments of the present disclosure are methods of treating a disease or condition mediated at least in part by α4β7 integrin, comprising administering, including, for example, via a kit, a formulation of a therapeutically effective amount of one or more compounds described herein and one or more additional therapeutic agents to a patient in need thereof. It will be understood that a qualified caregiver will administer or direct the administration of a therapeutically effective amount of any of the disclosed compound(s) or combination of compounds.

[0183] "Intravenous administration" refers to the direct administration of a substance into a vein, or "intravenous." Compared to other routes of administration, the intravenous (IV) route delivers fluids and medications throughout the body more quickly. Infusion pumps can precisely control the flow rate and total amount of medication delivered. However, if changes in flow rate would not have significant consequences or if a pump is not available, dripping is often simply allowed to flow by placing the bag above the patient's level and using a clamp to adjust the rate. Alternatively, if the patient requires a high flow rate and the IV access device is large enough in diameter to accommodate it, a rapid injector can be used. This is either an inflatable cuff placed around the fluid bag to push the fluid into the patient, or a similar electrical device that can also heat the fluid being injected. When a patient needs medication only at certain times, intermittent injections, which do not require additional fluid, are used. This can use the same techniques as intravenous drip (pump or gravity drip), but the tubing is disconnected from the IV access device after the full dose of medication is given. Some medications can be given by IV push or IV bolus; that is, a syringe is connected to an IV access device and the medication is injected directly (slowly if it would irritate the vein or cause an overly rapid effect). When a medication is injected into the fluid stream of the IV tubing, there will be some means to ensure that the medication reaches the patient from the tubing. Usually, this is accomplished by allowing the fluid stream to flow normally, thereby carrying the medication into the bloodstream, although a second fluid injection is sometimes used as a "flush" to push the medication into the bloodstream more rapidly following the injection. Thus, in some embodiments, the compounds or combinations of compounds described herein can be administered by IV administration alone or in combination with the administration of certain components of a treatment regimen by oral or parenteral routes.

[0184] "Oral administration" refers to a route of administration in which a substance is taken by mouth, including buccal, sublabial, and sublingual administration, as well as enteral administration, and administration through the respiratory tract unless the agent is administered, for example, through a tube, so as not to come into direct contact with any of the oral mucosa. Typical forms of oral administration of therapeutic agents include the use of tablets or capsules. Thus, in some embodiments, the compounds or combinations of compounds described herein can be administered orally alone or in combination with the administration of certain components of a treatment regimen by IV or parenteral routes. Pharmaceutical preparations

[0185] The compounds described herein can be administered in pharmaceutical preparations.The pharmaceutical preparations / compositions contemplated by the present disclosure include, in addition to a carrier, the compounds described herein, or the combinations of the compounds described herein, optionally combined with additional therapeutic agents.

[0186] The pharmaceutical formulations / compositions contemplated by the present disclosure may be intended for administration by injection and may include aqueous solutions, oil suspensions, emulsions (with sesame oil, corn oil, cottonseed oil, or peanut oil), and elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, Other suitable additives include cyclodextrin derivatives, cyclodextrin derivatives, and vegetable oils (and suitable mixtures thereof). Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and / or by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0187] Sterile injection solution is prepared by incorporating the compound of component (single or multiple) in the required amount into a suitable solvent with various other components as listed above, or optionally followed by filtration sterilization.Generally, dispersion is prepared by incorporating various sterilized active components into a sterile vehicle that contains a basic dispersion medium and other required components from those listed above.For the preparation of sterile powder for sterile injection solution, the preferred preparation method is vacuum drying and freeze-drying technology, which obtains powder of active component (single or multiple) and any additional desired components from its solution that has been previously sterilized and filtered.

[0188] In preparing pharmaceutical compositions containing the compounds described herein or their pharmaceutically acceptable salts, optionally in combination with additional agents / treatments useful for the purpose, the active ingredient is usually diluted with an excipient or carrier, and / or enclosed in or mixed with a carrier, such as a capsule, sachet, paper, or other container.When an excipient plays the role of a diluent, this excipient can be a solid, semi-solid, or liquid material (as described above), and acts as a vehicle, carrier, or medium for the active ingredient.Thus, the composition can be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), for example, an ointment containing up to 20% by weight of the active compound, soft and hard gelatin capsules, sterile injection solution, and sterile packaged powder.

[0189] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulation may further include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propylhydroxybenzoates; sweeteners; and flavoring agents.

[0190] The compositions of the present disclosure can be formulated by utilizing procedures known in the art to provide rapid, sustained or delayed release of active ingredients after administration to patients.In some embodiments, sustained release formulations are used.The sustained release drug delivery system for oral administration includes osmotic pump system and dissolution system, which comprises polymer-coated reservoir or drug-polymer matrix formulation.

[0191] Certain compositions are preferably formulated into unit dosage forms. The term "unit dosage form" or "combination dosage unit" refers to a physically separate unit suitable as a unit dosage for human subjects and other mammals, each unit containing a predetermined amount of one or more active materials (for example, the compound described herein, optionally combined with additional therapeutic agents calculated to produce the desired effect in association with suitable pharmaceutical excipients, such as tablets, capsules, ampoules or vials for injection). However, it is understood that the amount of each active agent actually administered will be determined by a physician in light of the relevant circumstances, including the condition to be treated, the selected administration route, the actual compound administered and its relative activity, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. It would be.

[0192] To prepare solid compositions, such as tablets, the primary active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present disclosure. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0193] Tablets or pills containing the compounds described herein of the present disclosure, optionally in combination with a second agent, may be coated or otherwise formulated to provide a dosage form that provides the advantage of sustained release or to protect against the acidic conditions of the stomach.For example, a tablet or pill may contain an internal dosage element and an external dosage element, the latter being in the form of a shell that covers the former.In some embodiments, the internal dosage element may contain the compounds described herein, and the external dosage element may contain a second or additional therapeutic agent, or vice versa.Alternatively, a combination dosage unit may be in a side-by-side configuration, such as in a capsule or tablet, where one part or half of the tablet or capsule is filled with a formulation of the compounds described herein, and the other part or half of the tablet or capsule contains an additional therapeutic agent.

[0194] A variety of materials can be used for such enteric layers or coatings, including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate. One skilled in the art will be aware of the techniques and materials used in preparing dosages of the formulations disclosed herein.

[0195] A "sustained release formulation" or "sustained release formulation" is a formulation designed to slowly release a therapeutic agent into the body over an extended period of time, while an "immediate release formulation" is a formulation designed to rapidly release a therapeutic agent into the body over a shortened period of time. In some cases, an immediate release formulation can be coated so that the therapeutic agent is released only when it reaches the desired target in the body (e.g., the stomach). One of ordinary skill in the art can develop sustained release formulations of the compounds of the present disclosure without undue experimentation. Thus, in some embodiments, the compounds or combinations of compounds described herein can be delivered via sustained release formulations alone or in combination with the administration of certain components of a treatment regimen by oral, IV, or parenteral routes.

[0196] Lyophilized formulations can also be used to administer the compounds described herein alone or in combination with additional therapeutic agents. Those skilled in the art will know how to make and use lyophilized formulations of drug substances that are suitable for lyophilization.

[0197] Spray-dried preparations can also be used to administer the compounds described herein alone or in combination with additional therapeutic agents.Those skilled in the art will recognize how to make and use the spray-dried preparations of active pharmaceutical ingredients that are suitable for spray-drying.Other known formulation techniques can also be used to formulate the compounds or combinations of compounds disclosed herein.

[0198] The compounds disclosed herein are useful for treating diseases or conditions mediated at least in part by α4β7 integrin. Non-limiting examples of diseases or conditions mediated at least in part by α4β7 integrin include, but are not limited to, acne, acid-induced lung injury, Addison's disease, adrenal hyperplasia, adrenal insufficiency, adult-onset Still's disease, adult respiratory distress syndrome (ARDS), age-related macular degeneration, aging, and alcohol. Hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopneumonia, allergic conjunctivitis, allergic contact dermatitis, allergy, allergic encephalomyelitis, allergic neuritis, transplant rejection, alopecia, alopecia areata, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, angina pectoris, angioedema, angiofibroma, anhidrotic ectodermal dysplasia type ill, anti-glomerular basement membrane disease, antigen-antibody complex-mediated disease, ankylosing spondylitis, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, ascites, aspergillosis, asthma, arteriosclerosis, atherosclerotic plaque, atopic dermatitis, atrophic thyroiditis, autoimmune disease, autoimmune hemolytic anemia (immune pancytopenia, paroxysmal night syndrome) hemoglobinuria), autoimmune polyendocrine insufficiency, autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia), autoimmune hepatitis, autoimmune thyroid disorder, autoinflammatory disease, back pain, Bacillus anthracis infection, Behçet's disease, bee sting-induced inflammation, Behçet's syndrome, Bell's palsy, beryllium poisoning, Blau syndrome, bone pain, bronchitis, bullous pemphigoid (BP) asthma, burns, bursitis, cardiomegaly, carpal tunnel syndrome, Castleman's disease, catabolic disorders, cataracts, celiac disease, cerebral aneurysms, chemical irritant-induced inflammation, chorioretinitis, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated body temperature (CANDLE) syndrome, chronic heart failure, chronic lung disease of prematurity, chronic obstructive pulmonary disease (COPD), chronic pancreatitis, chronic prostatitis, chronic recurrent multifocal osteomyelitis, cicatricial alopecia, colitis, complex regional pain syndrome, complications of organ transplantation, conjunctivitis, connective tissue diseases, contact dermatitis, keratinitis Membrane graft neovascularization, corneal ulcer, Crohn's disease, cryopyrin-associated periodic syndrome, cutaneous lupus erythematosus (CLE), cryptococcosis, cystic fibrosis, interleukin-1 receptor antagonist deficiency (DIRA), dermatitis, endotoxemic dermatitis, dermatomyositis, diabetic macular edema, diverticulitis, eczema, encephalitis, endometriosis, endotoxemia, eosinophilic pneumonia, epicondylitis, epidermolysis bullosa, erythema multiforme, erythroblastopenia, esophagitis, familial amyloidosis polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth retardation, fibromyalgia, fistulous Crohn's disease, food allergy, giant cell arteritis, glaucoma, glioblastoma, glomerular disease, glomerular nephritisGlomerulonephritis, gluten-sensitive enteropathy, gout, gouty arthritis, graft-versus-host disease (GVHD), granulomatous hepatitis, Graves' disease, growth plate injury, Guillain-Barré syndrome, intestinal disease, hair loss, Hashimoto's thyroiditis, head trauma, headache, hearing loss, heart disease, hemangioma, hemolytic anemia, hemophilic arthropathy, Henoch-Scholein purpura, hepatitis, hereditary periodic fever syndromes, hereditary connective tissue disorders, shingles and herpes simplex, hidradenitis suppurativa (HS), total hip replacement, Hodgkin's disease, Huntington's disease, hyaline membrane disease, hyperactive inflammatory response, hyperammonemia, hyper Calcemia, hypercholesterolemia, hypereosinophilic syndrome (HES), hyper-IgDemia with relapsing fever (HIDS), hypersensitivity pneumonitis, hypertrophic bone formation, hypoplastic and other anemias, hypoplastic anemia, ichthyosis, idiopathic demyelinating polyneuropathy, idiopathic inflammatory myopathies (dermatomyositis, polymyositis), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, immunoglobulin nephropathy, immune complex nephritis, immune thrombocytopenic purpura (ITP), incontinentia pigmenti (IP, Bloch-Siemens syndrome), infectious mononucleosis, viral diseases such as AIDS (HIV infection), hepatitis A, B, C, D, E, and herpes infections, including inflammation, inflammation of the CNS, inflammatory bowel disease (IBD), inflammatory diseases of the lower respiratory tract including bronchitis or chronic obstructive pulmonary disease, inflammatory diseases of the upper respiratory tract including the nose and sinuses, e.g. rhinitis or sinusitis, inflammatory diseases of the airways, inflammatory ischemic events such as stroke and cardiac arrest, inflammatory lung diseases, inflammatory muscle diseases such as myocarditis, inflammatory liver diseases, inflammatory neuropathy, inflammatory pain, insect bite-induced inflammation, interstitial cystitis, interstitial lung disease, iritis, irritant-induced inflammation, ischemia / reperfusion, artificial joint replacement, juvenile arthritis, juvenile rheumatoid arthritis, keratitis, kidney damage due to parasitic infection, kidney transplant rejection, Leptospirosis, leukocyte adhesion deficiency, lichen sclerosus (LS), Lambert-Eaton myasthenic syndrome, Loeffler syndrome, lupus, lupus nephritis, Lyme disease, Marfan syndrome (MFS), mast cell activation syndrome, mastocytosis, meningitis, meningioma, mesothelioma, mixed connective tissue disease, Muckle-Wells syndrome (urticarial deafness amyloidosis), mucositis, multisystem injury syndrome, multiple sclerosis, muscle wasting, muscular dystrophy, myasthenia gravis (MG), myelodysplastic syndrome, myocarditis, myositis, rhinosinusitis, necrotizing enterocolitis, neonatal-onset multisystem inflammatory disease (NOMID), neovascular glaucoma,Nephrosis, Syndrome, neuritis, neuropathological diseases, non-allergen-induced asthma, obesity, ocular allergy, optic neuritis, organ transplant rejection, Osler-Weber syndrome, osteoarthritis, osteogenesis imperfecta, osteonecrosis, osteoporosis, osterarthritis, otitis, congenital pachyonychia, Paget's disease, Paget's disease of bone, pancreatitis, Parkinson's disease, childhood rheumatism, pelvic inflammatory disease, pemphigus, pemphigus vulgaris (PV), bullous pemphigoid (BP), pericarditis, periodic fever, periodontitis, peritoneal endometriosis, pernicious anemia (Addison's disease), whooping cough, PFAPA (periodic fever with aphthous pharyngitis and cervical adenitis), pharyngitis and adenitis (PFAPA syndrome), plant irritant-induced inflammation, pneumocystis infection, pneumonia, interstitial pneumonia, poison ivy / urushiol oil-induced inflammation, nodular polyarthritis, polychondritis, polycystic kidney disease, polymyalgia rheumatica, giant cell arteritis, polymyositis, pouchitis, reperfusion injury and transplant rejection, primary biliary cirrhosis, primary pulmonary hypertension, primary sclerosing cholangitis (PSC), proctitis, psoriasis, plaque psoriasis, psoriatic arthritis, psoriatic epidermis, psychosocial stress disorders, lung diseases, pulmonary fibrosis, pulmonary hypertension, pyoderma gangrenosum, pyogenic granulomaRetrolental fibroplasia, suppurative aseptic arthritis, Raynaud's syndrome, Reiter's disease, reactive arthritis, kidney disease, renal transplant rejection, reperfusion injury, respiratory distress syndrome, retinal disease, retrolental fibroplasia, Raynaud's syndrome, rheumatic carditis, rheumatic disease, rheumatic fever, rheumatoid arthritis, rhinitis, psoriatic rhinitis, rosacea, sarcoidosis, Schnitzler's syndrome, scleritis, sclerosis, scleroderma, scoliosis, seborrhea, sepsis, septic shock, severe pain, Sézary syndrome, sickle cell anemia, silica-induced disease (silicosis), Sjögren's syndrome, skin disease, skin irritation, skin rash, skin sensitization (contact dermatitis or allergic contact dermatitis), sleep apnea, spinal cord injury, spinal stenosis, spondyloarthropathy, sports injuries, sprains and strains, Stevens-Jones syndrome These include Stevens-Johnson syndrome (SJS), stroke, subarachnoid hemorrhage, sunburn, synovitis, systemic inflammatory response syndrome (SIRS), systemic lupus erythematosus, systemic mastocytosis (SMCD), systemic vasculitis, systemic juvenile idiopathic arthritis, temporal arteritis, tendinitis, tenosynovitis, thrombocytopenia, thyroditis, thyroiditis, tissue transplant, toxoplasmosis, trachoma, transplant rejection, traumatic brain injury, tuberculosis, tubulointerstitial nephritis, tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), type 1 diabetes, type 2 diabetes, complications of type 1 or type 2 diabetes, ulcerative colitis, urticaria, uterine fibroids, uveitis, uveoretinitis, vascular restenosis, vasculitis, vasculitis (NHLBI), vitiligo, Wegener's granulomatosis, and Whipple's disease.

[0199] In further embodiments, the methods are provided for ameliorating symptoms of a disease or condition mediated at least in part by α4β7 integrin. In some embodiments, the methods include identifying a mammal having symptoms of a disease or condition mediated at least in part by α4β7 integrin, and providing to the mammal an amount of a compound as described herein effective to ameliorate (i.e., reduce the severity of) the symptoms.

[0200] In some embodiments, the disease or condition mediated at least in part by α4β7 integrin is an inflammatory disease or LPS-induced endotoxic shock. In some embodiments, the disease is an autoimmune disease. In certain embodiments, the autoimmune disease is systemic lupus erythematosus (SLE), myasthenia gravis, rheumatoid arthritis (RA), acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis (MS), inflammatory bowel disease (IBD), sepsis, psoriasis, Sjögren's syndrome, autoimmune hemolytic anemia, asthma, or chronic obstructive pulmonary disease (COPD), ankylosing spondylitis, acute gout and ankylosing spondylitis, reactive arthritis, monoarthritis, osteoarthritis, gouty arthritis, juvenile arthritis, juvenile-onset rheumatoid arthritis, juvenile rheumatoid arthritis, or psoriatic arthritis. In another embodiment, the disease is inflammation. In yet another embodiment, the disease is an excessive or destructive immune response, such as asthma, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease (COPD), and lupus.

[0201] In some embodiments, the disease is mediated at least in part by α4β7 integrin. Or the condition is inflammatory bowel disease (IBD).The term "inflammatory bowel disease" or "IBD" as used herein is a general term that describes inflammatory disorders of the gastrointestinal tract, the most common forms of which are ulcerative colitis and Crohn's disease.Other types of IBD that can be treated using the compounds, compositions and methods of the present disclosure include diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autistic colitis, indeterminate colitis, Behcet's disease, gastroduodenal CD, jejunoileitis, ileitis, ileocolitis, Crohn's (granulomatous) colitis, irritable bowel syndrome, mucositis, radiation-induced enteritis, short bowel syndrome, celiac disease, gastric ulcer, diverticulitis, pouchitis, proctitis, chronic diarrhea.

[0202] Treatment or prevention of IBD also includes the improvement or reduction of one or more symptoms of IBD. As used herein, the term "symptoms of IBD" refers to detected symptoms, such as upper abdominal pain, diarrhea, rectal bleeding, weight loss, fever, loss of appetite, and other more serious complications, such as dehydration, anemia, and malnutrition. Many such symptoms are amenable to quantitative analysis (e.g., weight loss, fever, anemia, etc.). Some symptoms are easily determined from blood tests (e.g., anemia) or tests that detect the presence of blood (e.g., rectal bleeding). The term "when the symptoms are reduced" refers to a qualitative or quantitative reduction of the detected symptoms, including, but not limited to, the detected effect on the rate of recovery from the disease (e.g., weight gain rate). Diagnosis is typically determined through endoscopic observation of the mucosa and pathological examination of endoscopic biopsy specimens.

[0203] The course of IBD is variable, and is often associated with the intermittent cycle of disease remission and disease exacerbation.Various methods have been described for characterizing the disease activity and severity of IBD, and the response of the subject with IBD to treatment.Treatment by this method is generally applicable to the subject with IBD of any level or degree of disease activity.

[0204] In some embodiments, diseases or conditions that may be treated by administration of the compounds of the compositions described herein include acute gout and ankylosing spondylitis, allergic disorders, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis and multiple sclerosis, atherosclerosis, bacterial infections, bone cancer pain and endometriosis, BRAF-resistant melanoma, pain caused by brainstem glioma or pituitary adenoma, burns, bursitis, anal cancer, endocrine system cancer, kidney or ureter cancer (e.g., renal cell carcinoma, and renal pelvis cancer), penile cancer, small intestine cancer, thyroid cancer, urethral cancer, blood cancers such as acute myeloid leukemia, tongue cancer, cervical cancer, endometrial cancer, fallopian tube cancer, renal pelvis cancer, vaginal cancer, or vulvar cancer, chronic myeloid leukemia, and the like. Blood diseases, chronic or acute leukemia, chronic pain, classic Bartter's syndrome, cold-related conjunctivitis, coronary artery disease, cutaneous or intraocular melanoma, dermatitis, dysmenorrhea, eczema, endometriosis, familial adenomatous polyposis, fibromyalgia, fungal infections, gout, gynecological tumors, uterine sarcoma, fallopian tube cancer, headache, hemophilic arthropathy, Parkinson's disease, AIDS, shingles, Hodgkin's disease, Huntington's disease, hyperprostaglandin E syndrome, influenza, iritis, juvenile arthritis, juvenile-onset rheumatoid arthritis, juvenile rheumatoid arthritis, low back and neck pain, lymphocytic lymphoma, myofascial disorders, myositis, neuralgia, neurodegenerative diseases such as Alzheimer's disease, neuroinflammatory disorders, neuropathic pain, vulvar cancer, Parkinson's disease, childhood malignancies, pulmonary fibrosis These include rectal cancer, rhinitis, sarcoidosis, soft tissue sarcoma, scleritis, skin cancer, childhood solid tumors, spinal axis tumors, sprains and strains, gastric cancer, stroke, subacute and chronic musculoskeletal pain syndromes such as bursitis, surgical or dental procedures, symptoms associated with influenza or other viral infections, synovitis, toothache, ulcers, uterine cancer, uterine sarcoma, uveitis, vasculitis, viral infections, viral infections (e.g., influenza), and wound healing.

[0205] Criteria useful for assessing disease activity in subjects with ulcerative colitis include, for example, those described by Truelove et al. (1955) Br Med J 2:1041-1048 Using these criteria, disease activity can be characterized as mild or severe in subjects with IBD. Subjects who do not meet all the criteria for severe disease activity but exceed the criteria for mild disease activity are classified as having moderate disease activity.

[0206] The therapeutic method of the present disclosure can also be applied at any point in the course of the disease. In some embodiments, the method is applied to a subject with IBD in remission (i.e., inactive disease). In such embodiments, the method provides benefit by extending the period of remission (e.g., extending the period of inactive disease) or by preventing, reducing, or delaying the onset of active disease. In other embodiments, the method can be applied to a subject with IBD in the period of active disease. Such a method provides benefit by reducing the duration of the period of active disease, reducing or ameliorating one or more symptoms of IBD, or treating IBD.

[0207] The scales for determining the effectiveness of IBD treatment in clinical practice have been described, and include, for example: symptom control; fistula closure; the level of corticosteroid therapy required; and improvement in quality of life.Health-related quality of life (HRQL) can be evaluated using the Inflammatory Bowel Disease Questionnaire (IBDQ), which is widely used in clinical practice to evaluate the quality of life in subjects with IBD.(See Guyatt et al. (1989) Gastroenterology 96:804-810) In some embodiments, disease or condition is immune-mediated liver injury, disease or condition.

[0208] In some embodiments, the disease or condition mediated at least in part by α4β7 integrin is alcoholic hepatitis. Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver failure that occurs in subjects with chronic and active alcohol abuse. (See Akriviadis E. et. al, Ann Gastroenterol. 2016 Apr-Jun;29(2):236-237.) Alcoholic hepatitis can cause cirrhosis and fibrosis of liver cells. Glucocorticoids (e.g., prednisolone) and phosphodiesterase inhibitors (e.g., pentoxifylline) can be used to treat alcoholic hepatitis. The compounds herein can be used as stand-alone treatments or in combination with existing treatments for alcoholic hepatitis.

[0209] In one aspect, the present disclosure provides a method of treating or preventing human immunodeficiency virus (HIV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0210] In some embodiments, the disease or condition mediated at least in part by α4β7 integrin is systemic lupus erythematosus (SLE), lupus nephritis, lupus-related or other autoimmune disorders, or symptoms of SLE. Symptoms of systemic lupus erythematosus include joint pain, joint swelling, arthritis, fatigue, hair loss, mouth sores, swollen lymph nodes, sun sensitivity, skin rash, headache, numbness, tingling, convulsions, blurred vision, personality changes, upper abdominal pain, nausea, vomiting, abnormal heart rate, coughing up blood and difficulty breathing, mottled skin color, and Raynaud's phenomenon. Combination therapy

[0211] Also provided are methods of treatment in which the compounds described herein are given to a patient in combination with one or more additional active agents or therapies.

[0212] Thus, in some embodiments, a method for treating a disease or condition mediated at least in part by α4β7 integrin, and / or a disease or symptom coexisting with, or exacerbated or caused by, a disease or condition mediated at least in part by α4β7 integrin, such as an allergic disorder and / or an autoimmune and / or inflammatory disease and / or an acute inflammatory response, comprises administering to a patient in need thereof an effective amount of a compound described herein, optionally in combination with an additional agent (e.g., a second, third, fourth, or fifth active agent) that may be useful for treating a disease or condition mediated at least in part by α4β7, an allergic disorder and / or an autoimmune and / or inflammatory disease associated with, or coexisting with, a disease or condition mediated at least in part by α4β7 integrin. Treatment with the second, third, fourth, or fifth active agent can be performed before, simultaneously with, or subsequent to treatment with a compound described herein. In some embodiments, a compound described herein is combined with another active agent into a single dosage form. Suitable therapeutic agents that can be used in combination with the compounds described herein include, but are not limited to, any therapeutic agent provided herein, or a combination comprising at least one therapeutic agent provided herein.

[0213] The present disclosure includes methods of treatment in which the compounds described herein are administered in combination with an agent for the treatment of an inflammatory disease or condition. Examples of agents for the treatment of inflammatory diseases or conditions that can be used in combination with the compounds described herein include alpha-fetoprotein modulators; adenosine A3 receptor antagonists; adrenomedullin ligands; AKT1 gene inhibitors; antibiotics; antifungals; ASK1 inhibitors; ATPase inhibitors; beta-adrenergic receptor antagonists; BTK inhibitors; calcineurin inhibitors; carbohydrate metabolism modulators; cathepsin S inhibitors; CCR9 chemokine antagonists; CD233 modulators; CD29 modulators; CD3 antagonists; CD40 ligand inhibitors; CD40 ligand receptor antagonists; chemokine CXC ligand inhibitors; CHST15 gene inhibitors; collagen modulators; CSF-1 antagonists; CX3CR1 chemokine modulators; ecobiotics; eotaxin ligand inhibitors; EP4 prostanoid receptor agonists; F1F0 ATP synthase modulators; farnesoid X receptor (FXR and NR1H4) agonists or modulators; fecal microbial transplantation (FMT); fractalkine ligand inhibitors; free fatty acid receptor 2 antagonists; GATA3 transcription factor inhibitors; glucagon-like peptide 2 agonists; glucocorticoid agonists; glucocorticoid receptor modulators; guanylate cyclase receptor agonists; HIF prolyl hydroxylase inhibitors; histone deacetylase inhibitors; HLA class II antigen modulators; hypoxia-inducible factor-1 stimulators ;ICAM1 gene inhibitor;IL-1 beta ligand modulator;IL-12 antagonist;IL-13 antagonist;IL-18 antagonist;IL-22 agonist;IL-23 antagonist;IL-23A inhibitor;IL-6 antagonist;IL-7 receptor antagonist;IL-8 receptor antagonist;Integrin alpha-4 / beta-1 antagonist;Integrin alpha-4 / beta-7 antagonist;Integrin antagonist;Interleukin ligand inhibitor;Interleukin receptor 17A antagonist;Interleukin-1 beta ligand; interleukin-1-like receptor 2 inhibitor; IL-6 receptor modulator; JAK tyrosine kinase inhibitor; Jak1 tyrosine kinase inhibitor; Jak3 tyrosine kinase inhibitor; lactoferrin stimulator; LanC-like protein 2 modulator; leukocyte elastate inhibitor; leukocyte proteinase-3 inhibitor; MAdCAM inhibitor; melanin-concentrating hormone (MCH-1) antagonist; melanocortin agonist; metalloproteinase-9 inhibitor; microbiome target; Therapies; Natriuretic peptide receptor C agonists; Neuregulin-4 ligands; NLPR3 inhibitors; NKG2 D-activated NK receptor antagonists; Nuclear factor kappa B inhibitors; Opioid receptor antagonists; OX40 ligand inhibitors; Oxidoreductase inhibitors; P2X7 purinergic receptor modulators; PDE4 inhibitors; Pellino homolog 1 inhibitors; PPAR alpha / delta agonists; PPAR gamma agonists; Protein fimH inhibitors; P-selectin glycoprotein ligand-1 inhibitors; Ret tyrosine kinase receptor inhibitors; RIP-1 kinase inhibitors; RIP-2 kinase inhibitors; RNA polymerase inhibitors; Sphingosine 1-phosphate phosphatase 1 stimulators; Sphingosine-1-phosphate receptor-1 agonists; Sphingosine-1-phosphate receptor-5 agonists; Sphingosine-1-phosphate receptor-1 antagonists; sphingosine-1-phosphate receptor-1 modulators; stem cell antigen-1 inhibitors; superoxide dismutase modulators; SYK inhibitors; tissue transglutaminase inhibitors; TLR-3 antagonists; TLR-4 antagonists; Toll-like receptor 8 (TLR8) inhibitors; TLR-9 agonists; TNF alpha ligand inhibitors; TNF ligand inhibitors; TNF alpha ligand modulators; TNF antagonists; TPL-2 inhibitors; tumor necrosis factor 14 ligand modulators; tumor necrosis factor 15 ligand inhibitors; Tyk2 tyrosine kinase inhibitors; type I IL-1 receptor antagonists; vanilloid VR1 agonists; and zonulin inhibitors, and combinations thereof.

[0214] Adenosine A3 receptor antagonists include PBF-677.

[0215] Adrenomedullin ligands include adrenomedullin.

[0216] Antibiotics include ciprofloxacin, clarithromycin, metronidazole, vancomycin, rifamycin, rifaximin, and tosufloxacin.

[0217] ASK1 inhibitors include GS-4997.

[0218] Alpha-fetoprotein modulators include ACT-101.

[0219] Anti-CD28 inhibitors include JNJ-3133 and abatacept.

[0220] Beta adrenergic receptor antagonists include NM-001.

[0221] BTK inhibitors include GS-4059.

[0222] Calcineurin inhibitors include tacrolimus and cyclosporine.

[0223] Carbohydrate metabolism modulators include ASD-003.

[0224] Cathepsin S inhibitors include VBY-129.

[0225] CCR9 chemokine antagonists include CCX-507.

[0226] CD233 modulators include GSK-2831781.

[0227] CD29 modulators include PF-06687234.

[0228] CD3 antagonists include NI-0401.

[0229] CD4 antagonists include IT-1208.

[0230] CD40 ligand inhibitors include SAR-441344 and letolizumab.

[0231] CD40 gene inhibitors include NJA-730.

[0232] CD40 ligand receptor antagonists include FFP-104 and BI-655064.

[0233] Chaperonin-binding immunoglobulin proteins include IRL-201805.

[0234] Chemokine CXC ligand inhibitors include LY-3041658.

[0235] CHST15 gene inhibitors include STNM-01.

[0236] Collagen modulators include ECCS-50 (DCCT-10).

[0237] COT protein kinase inhibitors include GS-4875.

[0238] CSF-1 antagonists include JNJ-40346527 (PRV-6527), and SNDX-6352.

[0239] CX3CR1 chemokine modulators include E-6130.

[0240] Ecobiotics include SER-287.

[0241] Eotaxin ligand inhibitors include bertilimumab.

[0242] EP4 prostanoid receptor agonists include KAG-308.

[0243] F1F0 ATP synthase modulators include LYC-30937 EC.

[0244] Fractalkine ligand inhibitors include quetmolimab (E-6011).

[0245] Free fatty acid receptor 2 antagonists include GLPG-0974.

[0246] GATA3 transcription factor inhibitors include SB-012.

[0247] Glucagon-like peptide 2 agonists include teduglutide and apraglutide.

[0248] Glucocorticoid receptor agonists include budesonide, beclomethasone dipropionate, and dexamethasone sodium phosphate.

[0249] Glucocorticoid receptor modulators / TNF ligand inhibitors include ABBV-3373.

[0250] Guanylate cyclase receptor agonists include dolucatide.

[0251] HIF prolyl hydroxylase inhibitors include DS-1093 and AKB-4924.

[0252] HIF prolyl hydroxylase-2 inhibitors / hypoxia inducible factor-1 stimulators include GB-004.

[0253] Histone deacetylase inhibitors include gibinostat.

[0254] Histone deacetylase-6 inhibitors include CKD-506.

[0255] HLA class II antigen modulators include HLA class II protein modulators.

[0256] ICAM1 gene inhibitors include alicaforsen.

[0257] IL-12 antagonists include ustekinumab (IL12 / IL23).

[0258] IL-13 antagonists include tralokinumab.

[0259] IL-18 antagonists include GSK-1070806.

[0260] IL-22 agonists include RG-7880.

[0261] IL-23 antagonists include tildrakizumab, risankizumab (BI-655066), mirikizumab (LY-3074828), brazikumab (AMG-139), and PTG-200.

[0262] IL-23A inhibitors include guselkumab.

[0263] IL-6 antagonists include olokizumab.

[0264] IL-7 receptor antagonists include OSE-127.

[0265] IL-8 receptor antagonists include clotrimazole.

[0266] Integrin alpha-4 / beta-1 antagonists include natalizumab.

[0267] Integrin alpha-4 / beta-7 antagonists include etrolizumab (a4b7 / aEb7), vedolizumab, carotegast methyl, TRK-170 (a4b7 / a4b1), PN-10943, and PTG-100.

[0268] Integrin antagonists include E-6007.

[0269] Interleukin ligand inhibitors include bimekizumab (IL-17A / IL-17F) Examples include:

[0270] Interleukin receptor 17A antagonists include brodalumab.

[0271] Interleukin-1 beta ligands include K(D)PT.

[0272] Interleukin-1-like receptor 2 inhibitors include BI-655130.

[0273] IL-6 receptor modulators include olamkicept.

[0274] JAK tyrosine kinase inhibitors include tofacitinib(1 / 3), peficitinib(1 / 3), TD-3504, and TD-1473. Jak1 tyrosine kinase inhibitors include compounds disclosed in WO2008 / 109943. Examples of other JAK inhibitors include, but are not limited to, AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110, lestaurtinib, momelotinib (CYT0387), NS-018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), XL019, upadacitinib (ABT-494), filgotinib, GLPG-0555, SHR-0302, and brepositinib (PF-06700841) (JAK1 / Tyk2).

[0275] Jak3 tyrosine kinase inhibitors include PF-06651600.

[0276] Lactoferrin stimulators include recombinant human lactoferrin (VEN-100).

[0277] LanC-like protein 2 modulators include BT-11.

[0278] Leukocyte elastase inhibitors / leukocyte proteinase-3 inhibitors include tiprelestat.

[0279] MAdCAM inhibitors include SHP-647 (PF-547659).

[0280] Melanin-concentrating hormone (MCH-1) antagonists include CSTI-100.

[0281] Melanocortin MC1 receptor agonists include ASP-3291 and PL-8177.

[0282] Metalloprotease-9 inhibitors include GS-5745.

[0283] Microbiome modulators include ABI-M201.

[0284] Natriuretic peptide receptor C agonists include plecanatide.

[0285] Neuregulin-4 ligands include NRG-4.

[0286] NKG2 D-activating NK receptor antagonists include JNJ-4500.

[0287] NLPR3 inhibitors include dapanstril, BMS-986299, SB-414, MCC-950, IFM-514, JT-194, PELA-167, and NBC-6.

[0288] Farnesoid X receptor (FXR and NR1H4) agonists or modulators include AGN-242266, cilofexor tromethamine (GS-9674), EDP-305, EYP-001, GNF-5120, MET-409, nidufexor (LMB-763), obeticholic acid, TERN-101, and tropifexor.

[0289] Nuclear factor kappa B inhibitors include Thetanix.

[0290] Opioid receptor antagonists include naltrexone and IRT-103.

[0291] OX40 ligand inhibitors include KHK-4083.

[0292] Oxidoreductase inhibitors include olsalazine.

[0293] Pellino homolog 1 inhibitors include BBT-401.

[0294] P2X7 purinergic receptor modulators include SGM-1019.

[0295] PDE4 inhibitors include apremilast.

[0296] PPAR alpha / delta agonists include elafibranor (GFT-1007).

[0297] PPAR gamma agonists include GED-0507-34-Levo.

[0298] Protein fimH inhibitors include sibofimroc (EB-8018).

[0299] P-selectin glycoprotein ligand-1 inhibitors include SEL-K2, AbGn-168H and neflizumab.

[0300] Ret tyrosine kinase receptor inhibitors include GSK-3179106.

[0301] RIP-1 kinase inhibitors include GSK-2982772.

[0302] RIP-2 kinase inhibitors include GSK-2983559.

[0303] Sphingosine-1-phosphate phosphatase 1 stimulators include etrasimod.

[0304] Sphingosine-1-phosphate receptor-1 agonists include ozanimod, moclavimod (KRP-203), and BMS-986166.

[0305] Sphingosine-1-phosphate receptor-1 agonists / sphingosine-1-phosphate receptor-5 agonists include ozanimod.

[0306] Sphingosine-1-phosphate receptor-1 antagonists include amiselimod (MT-1303).

[0307] Sphingosine-1-phosphate receptor-1 modulators include OPL-002.

[0308] Stem cell antigen-1 inhibitors include Ampion (DMI-9523).

[0309] Superoxide dismutase modulators include midismase.

[0310] Syk inhibitors include GS-9876.

[0311] Tissue transglutaminase inhibitors include zampilimab.

[0312] TLR-3 antagonists include PRV-300.

[0313] TLR-4 antagonists include JKB-122.

[0314] Toll-like receptor 8 (TLR8) inhibitors include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, VTX-1463, and VTX-763.

[0315] TLR-9 agonists include cobitolimod, IMO-2055, IMO-2125, lefitolimod, ritenimod, MGN-1601, and PUL-042.

[0316] TNF-alpha ligand inhibitors include adalimumab, certolizumab pegol, infliximab, golimumab, DLX-105, Debio-0512, HMPL-004, CYT-020-TNFQb, Hemay-007, and V-565.

[0317] TNF antagonists include AVX-470, tulinercept, and etanercept.

[0318] TPL-2 inhibitors include GS-4875.

[0319] Tumor necrosis factor 14 ligand modulators include AEVI-002.

[0320] Tumor necrosis factor 15 ligand inhibitors include PF-06480605.

[0321] Tyk2 tyrosine kinase inhibitors include PF-06826647 and BMS-986165.

[0322] TrkA receptor antagonists include SNA-125.

[0323] Type I IL-1 receptor antagonists include anakinra.

[0324] Zonulin inhibitors include larazotide acetate.

[0325] The present disclosure provides a method for treating rheumatoid arthritis in which the compounds described herein are administered in combination with an anti-inflammatory agent. Anti-inflammatory agents include, but are not limited to, NSAIDs, nonspecific and COX-2 specific cyclooxygenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptor antagonists, immunosuppressants, and methotrexate.

[0326] Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, a combination of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, nabumetone sodium, sulfasalazine, tolmetin sodium, and hydroxychloroquine. Examples of NSAIDs include COX-2 specific inhibitors (i.e., inhibitors of COX-1 specificity, i.e., inhibitors of COX-2 specificity, i ... 50 IC is less than 1 / 50 of 50 and compounds which inhibit COX-2 in the presence of steroids such as celecoxib, valdecoxib, lumiracoxib, etoricoxib and / or rofecoxib.

[0327] In a further embodiment, the anti-inflammatory agent is a salicylate, including but not limited to acetylsalicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylates.

[0328] The anti-inflammatory agent may also be a corticosteroid, for example, the corticosteroid may be selected from cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, and prednisone.

[0329] In some embodiments, the anti-inflammatory therapeutic agent is a gold compound, such as gold sodium thiomalate or auranofin.

[0330] In some embodiments, the anti-inflammatory agent is a metabolic inhibitor, for example, a dihydrofolate reductase inhibitor, such as methotrexate, or a dihydroorotate dehydrogenase inhibitor, such as leflunomide.

[0331] In some embodiments, the anti-inflammatory compound is an anti-C5 monoclonal antibody (eg, eculizumab or pexelizumab), a TNF antagonist such as etanercept, or the anti-TNF alpha monoclonal antibody infliximab.

[0332] The present disclosure includes methods of treatment in which a compound described herein is administered in combination with an immunosuppressant. In some embodiments, the immunosuppressant is methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, or mycophenolate mofetil.

[0333] The present disclosure includes methods of treatment in which the compounds described herein are administered in combination with a class of agents for the treatment of IBD.Examples of classes of agents for the treatment of IBD that can be used in combination with the compounds described herein include ASK1 inhibitors, beta-adrenergic receptor antagonists, BTK inhibitors, beta-glucuronidase inhibitors, bradykinin receptor modulators, calcineurin inhibitors, calcium channel inhibitors, cathepsin S inhibitors, CCR3 chemokine antagonists, CD40 ligand receptor antagonists, chemokine CXC ligand inhibitors, CHST15 gene inhibitors, collagen modulators, CSF-1 antagonists, cyclooxygenase inhibitors, cytochrome P450 3A4 inhibitors, eotaxin ligand inhibitors, EP4 prostanoid receptor agonists, erythropoietin receptor agonists, fractalkine ligand inhibitors, free fatty acid receptor 2 antagonists, GATA3 transcription factor inhibitors. agents, glucagon-like peptide 2 agonists, glucocorticoid agonists, guanylate cyclase receptor agonists, histone deacetylase inhibitors, HLA class II antigen modulators, IL-12 antagonists, IL-13 antagonists, IL-23 antagonists, IL-6 antagonists, IL-6 receptor modulators, interleukin-7 receptor modulators, IL-7 antagonists, IL-8 antagonists, integrin alpha-4 / beta-1 antagonists, integrin alpha-4 / beta-7 antagonists, integrin alpha-E antagonists, integrin antagonists, integrin beta -7 antagonist, interleukin ligand inhibitor, interleukin-2 ligand, interleukin receptor 17A antagonist, interleukin-1 beta ligand, interleukin-1 beta ligand modulator, IRAK4 inhibitor, JAK tyrosine kinase inhibitor, Jak1 tyrosine kinase inhibitor, Jak3 tyrosine kinase inhibitor, LanC-like protein 2 modulator, lipoxygenase modulator, MAdCAM inhibitor, matrix metalloproteinase inhibitor, melanocortin agonist, metalloproteinase-9 inhibitor, natriuretic peptide receptor C agonist, neuregulin-4 ligand, NKG2D-activated NK receptor antagonists, opioid receptor antagonists, opioid receptor delta antagonists, oxidoreductase inhibitors, P2X7 purinergic receptor agonists, PDE4 inhibitors, phagocytosis-stimulating peptide modulators, potassium channel inhibitors, PPAR alpha agonists, PPAR delta agonists, PPAR gamma agonists, protein fimH inhibitors, P-selectin glycoprotein ligand-1 inhibitors, RNA polymerase inhibitors, sphingosine 1-phosphate phosphatase 1 stimulators, sphingosine 1-phosphate phosphatase modulators, sphingosine-1-phosphate receptor-1 agonists , sphingosine-1-phosphate receptor-1 antagonists, sphingosine-1-phosphate receptor-1 modulators, sphingosine-1-phosphate receptor-5 modulators, STAT3 gene inhibitors, stem cell antigen-1 inhibitors, superoxide dismutase modulators, superoxide dismutase stimulators, SYK inhibitors, TGF beta 1 ligand inhibitors, thymulin agonists, TLR antagonists, TLR agonists, TNF alpha ligand inhibitors, TNF antagonists, tumor necrosis factor 14 ligand modulators, type II TNF receptor modulators, Tpl2 inhibitors, and zonulin inhibitors.

[0334] The present disclosure includes methods of treatment in which the compounds described herein are administered in combination with agents for the treatment of IBD. Examples of agents for the treatment of IBD that can be used in combination with the compounds described herein or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analog thereof include those provided herein for the treatment of inflammatory diseases or conditions, and include ABX-464, adalimumab; alicaforsen, ALLO-ASC-CD, AMG-966, anakinra, apremilast; Alequel; AMG-139; amiselimod, ASD-003, ASP-3291, AX-1505, BBT-401, balsalazide; beclomethasone dipropionate; BI-655130, BMS-986184; budesonide; CEQ-508; certolizumab; ChAdOx2-HAV, dexamethasone sodium phosphate, DNVX-078, etanercept; sibirine; Clostridium nitrate; butyricum; ETX-201, golimumab; GS-4997, GS-9876, GS-4875, GS-4059, infliximab; mesalazine, HLD-400, LYC-30937 EC; IONIS-JBI1-2.5Rx, JNJ-64304500, JNJ-4447, naltrexone; natalizumab; neflizumab, olsalazine; PH-46-A, propionyl-L-carnitine; PTG-100; remestemcel-L; tacrolimus; teduglutide; tofacitinib; ASP-1002; ustekinumab; vedolizumab; AVX-470; INN-108; SGM-1019; PF-06480605; PF-06651600; PF-06687234; RBX-8225, SER-287; Tetanix; TOP-1288; VBY-129; 99mTc-anephrine Xyn V-128; bertilimumab; DLX-105; dolucanatide; FFP-104; filgotinib; foralarumab; GED-0507-34-Levo; gibinostat; GLPG-0974; iberogast; JNJ-40346527; K(D)PT; KAG-308; KHK-4083; KRP-203; larazotide acetate; LY-3074828, midismase; olokizumab; OvaSave; P-28-GST; PF-547659; prednisolone; QBECO; RBX-2660, RG-7835; JKB- 122; SB-012; STNM-01; Debio-0512; TRK-170; zucapsaicin; ABT-494; Ampion; BI-655066; carotegrast methyl; cobitolimod; elafibranor; etrolizumab; GS-5745; HMPL-004; LP-02, ozanimod; peficitinib; quetomolimab (E-6011); RHB-104; rifaximin; tildrakizumab; tralokinumab; brodalumab; laquinimod; plecanatide; bidofludimus; and AZD-058.

[0335] The present disclosure includes methods of treatment in which the compounds described herein are administered in combination with an agent for the treatment of graft-versus-host disease. Examples of agents for the treatment of graft-versus-host disease that can be used in combination with the compounds described herein include those provided herein for the treatment of inflammatory diseases or conditions, as well as [18F]F-AraG, AM-01, alpha-1 antitrypsin stimulators: AAT-IV and CSL-964; Allocetra, efabaleukin alfa (AMG-592), arsenic trioxide, ATIR-101, belatacept, belimumab, beta-lactamase modulators: ribaxamase, bovine serum albumin (BSA), and erythropoietin (EGFR). Lutezomib, brentuximab vedotin, brimonidine, brimonidine tartrate, cannabidiol, cyclosporine, CYP-001, um, dilanubicel, dornase alfa, DSM-9843, eculizumab, EDP-1066, everolimus, Furestem, GL-101, ibrutinib, IMSUT-CORD, IRX-4204, itolizumab, KD-025, MaaT-013, milatuzumab, mizoribine, mycophenolate mofetil, MSCTC-0010, nalotimagene Carmaleucel, MET-2, nilotinib, narsoplimab (OMS-721), pacritinib, PF-05285401, ProTmune, QPI-1002, remestemcel-L, RGI-2001, saratin, SCM-CGH, ​​sirolimus, T-allo10, telmisartan, TOP-1288, TZ-101, voclosporin; CCR5 chemokine antagonist: leronlimab (PRO-140); CD40 ligand receptor antagonist: iscalimab; complement C1s subcomponent inhibitor : CE-1145, stimulimab, Cinryze, BIVV-009; B-lymphocyte antigen CD20 inhibitors: obinutuzumab, rituximab; CASP9 gene stimulators: ribogenlecleucel; CD3 antagonists or CD7 inhibitors: T-Guard; complement C5a factor inhibitors: orendalizumab; dipeptidyl peptidase IV inhibitors: begelomab; JAK1 / 2 tyrosine kinase inhibitors: ruxolitinib; Jak1 tyrosine kinase inhibitors: itacitinib; interleukin-2 ligand: aldesleukin;Interleukin-22 ligand: F-652; IL-2 receptor alpha subunit inhibitor: basiliximab and inolimomab; IL-6 receptor agonist: PLX-1; IL-6 receptor antagonist: clazakizumab; OX40 ligand inhibitor: KY-1005; examples of such OX40 inhibitors are the compounds disclosed in US 8,450,460, the entire contents of which are incorporated herein by reference; signal transducer CD24 modulator: CD24-IgFc; somatostatin receptor agonist: thymoglobulin; and sphingosine-1-phosphate receptor-1 agonist: ponesimod.

[0336] The present disclosure includes methods of treatment in which the compounds described herein are administered in combination with an agent for the treatment of primary sclerosing cholangitis. Agents for the treatment of primary sclerosing cholangitis that can be used in combination with the compounds described herein Examples of inflammatory diseases or conditions include those provided herein for the treatment of inflammatory diseases or conditions, as well as BTT-1023, CM-101, Doconexent, GRI-0124, HTD-1801, HTD-2802, hymecromone, IDN-7314, NGM-282, norursodeoxycholic acid, ORBCEL-C, integrin alpha-V / beta-1 and beta-6 antagonist: PLN-74809; PPAR delta agonist: seradelparlysin; SCT-5-27, PTGS2 gene and TGF beta 1 gene antagonists. gene inhibitors: SCT-5-27, and STP-705; farnesoid X receptor (FXR, NR1H4) agonists or modulators: AGN-242266, cilofexor tromethamine (GS-9674), EDP-305, EYP-001, GNF-5120, MET-409, nidufexor (LMB-763), obeticholic acid, TERN-101, tropifexor; liver X receptor antagonists: DUR-928; and CCR5 / CCR2 chemokine antagonists: cenicriviroc.

[0337] In some embodiments, the one or more additional therapeutic agents are: combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reactivators, compounds targeting the HIV capsid, immune-based therapies, phosphatidylinositol-3 kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic cell ICAM-3-binding nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV selected from the group consisting of POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or a pharmaceutically acceptable salt of any of the preceding, or any combination thereof.

[0338] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of HIV protease inhibitor compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for the treatment of HIV, or pharmaceutically acceptable salts of any of the foregoing, or any combination thereof.

[0339] In some embodiments, the one or more additional therapeutic agents are immunomodulatory agents, such as immunostimulatory agents or immunosuppressants. In certain other embodiments, the immunomodulatory agent may alter the function of immune checkpoints, including the CTLA-4, LAG-3, B7-H3, B7-H4, Tim3, BTLA, KIR, A2aR, CD200, and / or PD-1 pathways. In other embodiments, the immune modulator is an immune checkpoint modulator. Exemplary immune checkpoint modulators include anti-CTLA-4 antibodies (e.g., ipilimumab), anti-LAG-3 antibodies, anti-B7-H3 antibodies, anti-B7-H4 antibodies, anti-Tim3 antibodies, anti-BTLA antibodies, anti-KIR antibodies, anti-A2aR antibodies, anti-CD200 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CD28 antibodies, anti-CD80 or anti-CD86 antibodies, anti-B7RP1 antibodies, anti-B7-H3 antibodies, anti-HVEM antibodies, anti-CD137 or anti-CD137L antibodies, anti-OX40 or anti-OX40L antibodies, anti-CD40 or anti-CD40L antibodies, anti-GAL9 antibodies, anti-IL-10 antibodies, and A2aR drugs. For certain such immune pathway gene products, the use of either antagonists or agonists of such gene products is contemplated, as are small molecule modulators of such gene products. In some embodiments, immunomodulatory agents include agents capable of altering the function of mediators in cytokine-mediated signaling pathways.

[0340] In some embodiments, the compounds disclosed herein (e.g., compounds described herein) can be combined with one or more (e.g., 1, 2, 3, 4, 1 or 2, 1-3, or 1-4) additional therapeutic agents, at any dosage of the compounds described herein (e.g., 10 mg to 1000 mg of compound).

[0341] The compounds described herein can be combined with the agents provided herein in any dosage of the compound (e.g., 50 mg to 500 mg of compound) as if each dosage combination were specifically and individually listed.

[0342] In some embodiments, kits are provided that include pharmaceutical compositions comprising a compound described herein, or a compound described herein and at least one additional therapeutic agent, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, kits are provided that include a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analog thereof, in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents. Any pharmaceutical composition provided in this disclosure can be used in the kit, as if each and every composition were specifically and individually listed for use in the kit. In some embodiments, the kit includes instructions for use in treating an inflammatory disease or condition. In some embodiments, the instructions in the kit are directed to using the pharmaceutical composition for the treatment of IBD. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] synthesis

[0343] The compounds of the present disclosure can be prepared using the methods disclosed herein, and routine modifications thereof that will become apparent in light of the disclosure herein, as well as methods well known in the art. Conventional and well-known synthetic methods can be used in addition to the teachings herein. The synthesis of exemplary compounds of formula (I), such as compounds having a structure described by one or more of formula (I) or other formulas, or compounds disclosed herein, or their pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, or deuterated analogs, can be achieved as described in the following examples.

[0344] Salts such as TFA salts can be converted to the free base / acid or other pharmaceutically acceptable salts. General scheme

[0345] Exemplary embodiments of compounds according to the present disclosure can be synthesized using the general reaction schemes and / or examples described below. It will be apparent in light of the description herein that the general schemes can be modified by replacing the starting materials with other materials having similar structures, resulting in correspondingly different products. The syntheses are described below to provide numerous examples of how the starting materials can be modified to yield corresponding products. Starting materials are typically obtained from commercial sources or synthesized using published methods for synthesizing compounds that are embodiments of the present disclosure, and inspection of the structure of the synthesized compound will reveal the identity of each substituent. The identity of the final product will generally be apparent by simple inspection of the necessary starting materials in light of the examples herein. General Scheme 1 [ka]

[0346] Scheme 1 describes a general route used to prepare several compounds of formula (I). From intermediate AA1, which has a hydroxyl or halogen group as Z and a halogen group as X, amino acid esters (AA2) can be prepared under a variety of conditions (e.g., Schollkopf, Maruoka, etc.). After appropriate protection of the free amine with a protecting group (PG), such as trityl, Boc, etc., AA2 was converted to boronic acid or boronic esters (AA3) under standard conditions (e.g., Miyaura). 1 was introduced under various cross-coupling conditions to give AA4. After removal of the amine protecting group (PG) under appropriate conditions, the amine was coupled with an acid to generate the heterocyclic compound AA5. General Scheme 2 [ka]

[0347] Scheme 2 describes the general route used to prepare some compounds of formula (I). From intermediate BB1 ​​bearing a halogen group as Z, amino acid ester (BB2) can be prepared under various conditions (mainly according to Negishi). After appropriate removal of the protecting group (e.g., benzyloxycarbonyl, CBZ), BB2 was converted to its free amine (BB3) under standard conditions (e.g., Pd / H2). 1 was introduced with the appropriate carboxylic acid or amine under various urea-forming conditions to give BB4. After removal of the amine protecting group (PG) under appropriate conditions, this amine was coupled with a carboxylic acid or acid chloride to give heterocyclic compound BB5. [Example]

[0348] Example 1 Synthesis of 8-bromo-5-methylquinoline (1A): To a stirred solution of 2-bromo-5-methylaniline (1200 g, 6.45 mol) in nitrobenzene (660 mL) and 75% H2SO4 (3.6 L), glycerol (1180 g, 6.45 mol) was added at room temperature and then slowly heated to 150 °C for 3 h. The mixture was cooled to room temperature and poured into ice water while maintaining the temperature below 10 °C. The pH was adjusted to approximately 10 with aqueous 10 N NaOH, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a material that was dissolved in DCM / hexane (5:1) and stirred for 30 min. The solid was filtered off, and the filtrate was evaporated under reduced pressure to give 1A. [ka]

[0349] Synthesis of 8-bromo-5-(bromomethyl)quinoline (1B): To a stirred solution of compound 1A (500 g, 2.25 mol) in benzene (7.5 L) was added NBS (481 g, 2.7 mol) at room temperature. The reaction mixture was heated to 80° C. under a tungsten lamp for 12 hours. The reaction was cooled to room temperature, water was added, and extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The material was triturated with 20% ethyl acetate in hexane at room temperature. The material was filtered, washed with hexane, and dried under reduced pressure to give 1B.

[0350] Synthesis of (S)-methyl 3-(8-bromoquinolin-5-yl)-2-((diphenylmethylene)amino)propanoate (1C): To a stirred solution of 1B (392 g, 1.3 mol) in DCM (9 L) was added (-)-cinchonidine (35 g, 0.12 mol) at room temperature. The reaction mixture was cooled to 10°C, and KOH (2.4 L, 50% aq) was added, followed by methyl 2-((diphenylmethylene)amino)acetate (300 g, 1.2 mol). The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with water and stirred for 15 min. DCM was added, and the organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. This material was purified by filtration through a 100-200 mesh filtration filter. Purification by silica gel column chromatography eluting with 10-15% ethyl acetate in hexane gave compound 1C.

[0351] Synthesis of methyl (S)-2-amino-3-(8-bromoquinolin-5-yl)propanoate (1D): To a stirred solution of 1C (400 g, 845 mmol) in methanol (2 L) was added HCl in 1,4-dioxane (2.8 L, 4N) while maintaining the temperature below 5° C. The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure, dissolved in water, and washed with ethyl acetate. The aqueous layer was adjusted to approximately pH 8 using saturated NaHCO3 and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a 70:30 mixture of racemic 1D. A suspension of this material in MTBE was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, the solid was filtered off, and the filtrate was evaporated under reduced pressure to give a solid that was again stirred with MTBE at room temperature. The solid was filtered off, and the filtrate was evaporated under reduced pressure to give 1D. This material was dissolved in ethyl acetate and cooled to 0° C., after which 4N HCl was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and triturated with MTBE to give 1D.

[0352] Synthesis of (S)-methyl 2-amino-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)propanoate (1E): To a microwave vial was added 1D (50 mg, 0.145 mmol), (2-chloro-4-cyanophenyl)boronic acid (45 mg, 0.246 mmol), Pd(PPh3)4 (8 mg, 0.007 mmol), and aq Na2CO3 (0.217 mL, 2 M) in DME (2 mL). The reaction mixture was stirred at 120 °C for 20 min. EA and water were added to the reaction mixture. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The material was purified by silica gel chromatography using 0-30% MeOH in EA to give the title compound.

[0353] Synthesis of (S)-methyl 3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2-fluoro-6-methylbenzamido)propanoate (1F): To a stirred solution of 1E (29 mg, 0.08 mmol) in THF (2 mL) was added 2-fluoro-6-methylbenzoyl chloride (21 mg, 0.12 mmol) and DIEA (0.07 mL, 0.4 mmol). The reaction mixture was stirred for 1 h, then diluted with DCM and concentrated. The material was purified on silica gel eluting with MeOH (0-30%) in DCM to give the title compound.

[0354] Synthesis of (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2-fluoro-6-methylbenzamido)propanoic acid (1): To a stirred solution of 1F (35 mg, 0.07 mmol) in THF (3 mL) was added aqueous LiOH (0.35 mL, 0.035 mmol). The reaction mixture was stirred for 1 hour and then concentrated under reduced pressure. The material was purified by reverse-phase HPLC to give the title compound. MS (m / z) 488.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J= 8.4Hz, 1H),8.84 (dd, J = 4.2, 1.6 Hz, 1H), 8.64 (dd, J = 8.7, 1.7 Hz, 1H),8.16 (d,J =1.7 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.68 - 7.60 (m, 3H), 7.55 (d, J = 7.9Hz, 1H), 7.26 (d, J =6.1Hz, 1H), 6.99 (d, J = 6.7 Hz, 2H), 4.82 (t, J = 9.9Hz, 1H), 3.39 (d, J = 12.9Hz, 1H), 2.65 (s, 1H), 2.31 (s, 1H), 2.07 (s, 1H),1.96 (s, 3H). Example 2 [ka]

[0355] Synthesis of (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2-chloro-6-fluorobenzamido)propanoic acid (2): The title compound was prepared according to the method proposed for the synthesis of compounds 1F and 1, starting with 2-chloro-6-fluorobenzoyl chloride and 1E. MS (m / z) 508.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.27 (d, J= 8.3Hz, 1H),8.84 (dd, J = 4.1, 1.6 Hz, 1H), 8.65 (dd, J = 8.6, 1.7 Hz, 1H),8.16(dd, J =1.7, 0.4 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.68 - 7.60 (m, 3H), 7.54 (d, J =7.9 Hz, 1H), 7.42 (td, J = 8.3, 6.1Hz,1H), 7.30 - 7.19 (m, 2H), 4.82 (s, 1H),3.77 (d, J = 14.7 Hz, 1H), 3.38 (dd,J =14.6, 10.6 Hz, 1H). Example 3

[0356] Synthesis of (S)-methyl 3-(8-bromoquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (3A): The title compound was prepared according to the method presented for the synthesis of compound 1F, starting with 2,6-difluorobenzoyl chloride and 1D.

[0357] Synthesis of (S)-methyl 3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (3B): The title compound was prepared starting with 3A according to the method presented for the synthesis of compound 1E. [ka]

[0358] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2- Synthesis of (2,6-difluorobenzamido)propanoic acid (3): The title compound was prepared starting with 3B according to the method presented for the synthesis of compound 1F. MS (m / z) 492.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.25 (d, J = 8.1Hz,1H), 8.84(dd, J = 4.1, 1.6 Hz, 1H), 8.64 (dd, J = 8.8, 1.7 Hz, 1H), 8.15 (d,J= 1.7 Hz,1H), 7.90 (dd, J = 8.0, 1.7 Hz, 1H), 7.66 - 7.61 (m, 3H), 7.57 (d, J =7.9 Hz,1H), 7.53 - 7.41(m, 1H), 7.10 (t, J = 8.0 Hz, 2H), 4.77 (s, 1H), 3.76(s, 1H),3.41(s, 1H). Example 4 [ka]

[0359] Synthesis of methyl (S)-3-(8-bromoquinolin-5-yl)-2-(2,6-dichlorobenzamido)propanoate (4A): The title compound was prepared according to the method presented for the synthesis of compound 3A, starting with 2,6-dichlorobenzoyl chloride and 1D.

[0360] Synthesis of (S)-(5-(2-(2,6-dichlorobenzamido)-3-methoxy-3-oxopropyl)quinolin-8-yl)boronic acid (4B): To a stirred solution of 4A (0.61 g, 1.4 mmol) in dioxane was added bis(pinacolato)diboron (0.42 g, 1.6 mmol), followed by KOAc (0.4 g, 4.1 mmol), Pd(dppf)Cl (0.03 g, 0.03 mmol) and cataCXium A (0.04 g, 0.08 mmol). The reaction vessel was flushed with nitrogen and then heated to 100° C. for 4 h. EA was added, followed by filtration through Celite and concentration under reduced pressure to give the title compound, which was used without further purification.

[0361] Synthesis of (S)-methyl 3-(8-(2,6-dichloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-dichlorobenzamido)propanoate (4C): To a stirred solution of 4B (0.08 g, 0.017 mmol) in DME was added 4-bromo-3,5-dichlorobenzonitrile (0.08 g, 0.034 mmol), XPhos Pd G3 (0.014 g, 0.0017 mmol), and aq. K3PO4 (0.6 mL, 1 M). The reaction was degassed with nitrogen and heated at 90 °C for 30 min. The reaction mixture was concentrated under reduced pressure to provide the title compound, which was used without further purification.

[0362] Synthesis of (S)-3-(8-(2,6-dichloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-dichlorobenzamido)propanoic acid (4): The title compound was synthesized by the following reaction: Prepared according to the method proposed for the synthesis of compound 1, starting with 4C. MS (m / z) 558.0 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 9.28 (d, J = 8.4Hz, 1H),8.82 (dd, J = 4.2, 1.6 Hz,1H), 8.65 (dd, J = 8.7, 1.6 Hz, 1H), 8.25 -8.15 (m,2H), 7.74 - 7.62 (m, 2H), 7.60 (d, J = 7.3 Hz, 1H), 7.45 - 7.32 (m, 3H), 4.83(ddd, J = 11.8,8.6,3.7 Hz, 1H), 3.78 (dd, J = 14.5, 3.8 Hz, 1H), 3.38 (dd, J= 14.5, 11.0Hz,1H) . Example 5

[0363] Synthesis of (S)-(5-(2-(2,6-difluorobenzamido)-3-methoxy-3-oxopropyl)quinolin-8-yl)boronic acid (5A): The title compound was prepared according to the method presented for the synthesis of compound 4B in Example 4, starting with 3A.

[0364] Synthesis of (S)-methyl 3-(8-(4,5-dichloro-2-methoxyphenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (5B): To a microwave vial was added 5A (145 mg, 0.234 mmol), 1-bromo-4,5-dichloro-2-methoxybenzene (50 mg, 0.195 mmol), Pd(PPh) (11 mg, 0.01 mmol), and aq NaCO (0.293 mL, 2 M) in DME (2 mL). The reaction mixture was stirred at 120 °C for 30 min. EA and water were added to the reaction mixture. The organic layer was washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the title compound.

[0365] Synthesis of (S)-3-(8-(4,5-dichloro-2-methoxyphenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoic acid (5): The title compound was prepared starting with 5B according to the method presented for the synthesis of compound 1. MS (m / z) 530.7 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.27 (d, J =8.1Hz, 1H),8.86 (dd, J = 4.3, 1.6 Hz, 1H), 8.73 - 8.61 (m, 1H), 7.66 (dd, J = 8.6, 4.3 Hz,1H), 7.60(q,J = 7.4 Hz, 2H), 7.52 - 7.43 (m, 1H), 7.40 (d, J = 8.7Hz, 2H),7.16 - 7.05(m, 2H), 4.78 - 4.70 (m, 1H), 3.74 (dd, J = 14.5, 4.4 Hz, 1H), 3.64(s, 3H),3.39(dd, J = 14.6, 10.1 Hz, 1H), 1.05 (s, 1H). [ka] Example 6 [ka]

[0366] Synthesis of 2-bromo-5-fluoro-1-methoxy-3-(trifluoromethyl)benzene (6A): To a stirred solution of 2-bromo-5-fluoro-3-(trifluoromethyl)phenol (0.21 g, 0.64 mmol) in DMF, KCO (133 mg, 0.96 mmol) and iodomethane (0.105 g, 0.74 mmol) were added. The reaction mixture was stirred at room temperature. EA and water were added to the reaction mixture. The organic layer was washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure, and purified by silica gel chromatography using hexane / EA as the eluent.

[0367] Synthesis of methyl (2S)-2-(2,6-difluorobenzamido)-3-(8-(4-fluoro-2-methoxy-6-(trifluoromethyl)phenyl)quinolin-5-yl)propanoate (6B): The title compound was prepared starting from 5A and 6A according to the method presented for the synthesis of compound 5B.

[0368] Synthesis of (2S)-2-(2,6-difluorobenzamido)-3-(8-(4-fluoro-2-methoxy-6-(trifluoromethyl)phenyl)quinolin-5-yl)propanoic acid (6): The title compound was prepared starting with 6B according to the method proposed for the synthesis of compound 1. MS (m / z) 549.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.28 (dd,J =12.4, 8.1Hz, 1H), 8.81 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (d, J = 8.7 Hz, 1H),7.67- 7.56 (m,2H), 7.49 (dqd, J = 8.2, 6.6, 1.6 Hz, 2H), 7.41 - 7.34 (m, 1H),7.29(dd, J =9.1, 2.5 Hz, 1H), 7.11 (ddd, J = 8.3, 7.4, 3.8 Hz, 2H), 4.84 -4.75 (m,1H),3.76 (dd, J = 31.6, 4.3 Hz, 1H), 3.59 (d, J = 5.7 Hz, 3H), 3.42(ddd, J =21.3,14.6, 10.4 Hz, 1H). Examples 7 and 8 [ka]

[0369] Preparation of (S)-2-(2,6-difluorobenzamido)-3-((R)-8-(4-fluoro-2-methoxy-6-(trifluoromethyl)phenyl)quinolin-5-yl)propanoic acid (7): 6 was separated into its two diastereomeric atropisomers by supercritical fluid chromatography using an AD-H 5 μm 21×250 mm column with 25% EtOH / TFA cosolvent at a flow rate of 50 mL / min. The title compound was identified as the first eluting peak. MS (m / z) 549.1 [M+H] + . 1H NMR (400 MHz, Methanol-d4)δ 9.36 (dd, J = 8.7, 1.6 Hz, 1H), 8.95 (dd, J = 5.0, 1.5 Hz, 1H),8.00(dd, J =8.7, 5.0 Hz, 1H), 7.89 (d, J = 7.4 Hz, 1H), 7.78 (dd, J = 7.4, 0.9 Hz, 1H),7.45 (tt, J = 8.4, 6.4 Hz, 1H), 7.32 (s, 1H), 7.30 (s, 1H), 7.02 - 6.95 (m,2H), 5.12 (dd, J = 9.8, 5.2 Hz, 1H), 4.03 (dd, J = 14.4, 5.2 Hz, 1H),3.71-3.63 (m, 4H).

[0370] Preparation of (S)-2-(2,6-difluorobenzamido)-3-((S)-8-(4-fluoro-2-methoxy-6-(trifluoromethyl)phenyl)quinolin-5-yl)propanoic acid (8): 6 was separated into its two diastereomeric atropisomers by supercritical fluid chromatography using an AD-H 5 μm 21×250 mm column with 25% EtOH / TFA cosolvent at a flow rate of 50 mL / min. The title compound was identified as the second eluting peak. MS (m / z) 549.1 [M+H] + . 1H NMR (400 MHz, Methanol-d4) δ 9.35 (dd, J = 8.7, 1.5 Hz, 1H), 8.95 (dd, J = 5.0, 1.5 Hz, 1H), 7.99(dd, J =8.6, 5.0 Hz, 1H), 7.86 (d, J = 7.4 Hz, 1H), 7.77 (d, J = 7.4 Hz,1H),7.45 (tt,J = 8.6, 6.4 Hz, 1H), 7.32 (s, 1H), 7.29 (s, 1H), 7.03 - 6.96 (m,2H),5.14(dd, J = 9.9, 5.0 Hz, 1H), 4.04 (dd, J = 14.6, 5.1 Hz, 1H), 3.69 - 3.61 (m, 4H). Example 9 [ka]

[0371] Synthesis of (S)-methyl 2-(2,6-difluorobenzamido)-3-(8-(3-methoxynaphthalen-2-yl)quinolin-5-yl)propanoate (9A): The title compound was prepared starting from 2-bromo-3-methoxynaphthalene and 5A according to the method presented for the synthesis of compound 5B.

[0372] Synthesis of (S)-2-(2,6-difluorobenzamido)-3-(8-(3-methoxynaphthalen-2-yl)quinolin-5-yl)propanoic acid (9): The title compound was synthesized by the following reaction: Prepared according to the method proposed for the synthesis of 1, starting with 9A. MS (m / z) 513.0 [M+H] + . 1H NMR(400 MHz, DMSO-d6) δ 9.30 (d, J = 8.2 Hz, 1H), 8.86(d,J = 4.8 Hz, 2H), 7.95 -7.83 (m, 2H), 7.81 - 7.64 (m, 3H), 7.55 - 7.43 (m,3H),7.38 (ddd, J = 8.1,6.9, 1.2 Hz, 1H), 7.17 - 7.08 (m, 2H), 4.80 (ddd, J = 10.1,8.1, 4.4 Hz,1H),3.80 (dd, J = 14.6, 4.5 Hz, 1H), 3.71 (s, 3H), 3.45 (dd, J =14.6, 10.1 Hz, 1H). Example 10 [ka]

[0373] Synthesis of 1-bromo-2-(cyclopropylmethoxy)-4,5-difluorobenzene (10A): To a stirred solution of 2-bromo-4,5-difluorophenol (1.2 g, 5.5 mmol) in MeCN, KCO (2.3 g, 16.4 mmol) and (bromomethyl)cyclopropane (0.82 g, 6.0 mmol) were added. The reaction mixture was stirred at 70 °C for 2 h. EA and water were added to the reaction mixture. The organic layer was washed with brine, dried over anhydrous NaSO, concentrated under reduced pressure, and purified by silica gel chromatography using hexane / EA as the eluent.

[0374] Synthesis of (S)-methyl 3-(8-(2-(cyclopropylmethoxy)-4,5-difluorophenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (10B): The title compound was prepared starting from 10A and 5A according to the method presented for the synthesis of compound 5B.

[0375] Synthesis of (S)-3-(8-(2-(cyclopropylmethoxy)-4,5-difluorophenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoic acid (10): The title compound was prepared according to the method proposed for the synthesis of compound 1, starting with 10B. MS (m / z) 538.6 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.81(s,1H),9.28 (d, J =8.1 Hz, 1H), 8.89 (d, J = 4.1 Hz, 1H), 8.69 (s, 2H), 7.66 (d,J =7.3 Hz, 2H),7.60 (d, J = 7.4 Hz, 1H), 7.55 - 7.45 (m, 1H), 7.37 - 7.21 (m,2H), 7.16 - 7.08(m, 2H), 4.76 (td, J = 10.3, 9.2, 4.2 Hz, 1H), 3.78 - 3.74 (m,2H), 3.41(dd, J= 14.6, 10.0 Hz, 1H), 3.10 (p, J = 4.8 Hz, 2H), 0.81 (d, J =4.8 Hz, 1H), 0.24(dt, J = 9.0, 2.9 Hz, 2H), -0.01 - -0.05 (m, 2H). Example 11

[0376] Synthesis of (S)-methyl 2-(2,6-difluorobenzamido)-3-(8-(3,5,6-trimethylpyridin-2-yl)quinolin-5-yl)propanoate (11A): The title compound was prepared according to the method presented for the synthesis of compound 4C in Example 4, starting with 2-bromo-3,5,6-trimethylpyridine and 5A. [ka]

[0377] Synthesis of (S)-2-(2,6-difluorobenzamido)-3-(8-(3,5,6-trimethylpyridin-2-yl)quinolin-5-yl)propanoic acid (11): The title compound was prepared starting with 11A according to the method presented for the synthesis of compound 1. MS (m / z) 476.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.33 (d, J= 8.3Hz, 1H),8.89 (dd, J = 4.2, 1.6 Hz, 1H), 8.78 - 8.72 (m, 1H), 8.36 (s,1H), 7.92(d, J =7.5 Hz, 1H), 7.78 - 7.69 (m, 2H), 7.49 (tt, J = 8.5, 6.6 Hz,1H), 7.11(dd, J =8.4, 7.6 Hz, 2H), 4.84 - 4.74 (m, 1H), 3.85 (dd, J = 14.3,4.2 Hz, 1H),3.43(dd, J = 14.4, 10.4 Hz, 1H), 2.64 (s, 3H), 2.46 (s, 3H), 2.05(s, 3H). Example 12 [ka]

[0378] Synthesis of (S)-methyl 2-(2,6-difluorobenzamido)-3-(8-(5,6-dimethyl-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoate (12A): The title compound was prepared using Pd XPhos G4, starting from 2-bromo-5,6-dimethyl-3-(trifluoromethyl)pyridine and 5A, according to the method presented for the synthesis of compound 4C in Example 4.

[0379] Synthesis of (S)-2-(2,6-difluorobenzamido)-3-(8-(5,6-dimethyl-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoic acid (12): The title compound was prepared starting with 12A according to the method presented for the synthesis of compound 1. MS (m / z) 530.1 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 9.28 (d, J = 8.1 Hz,1H), 8.77 (dd, J = 4.1, 1.6 Hz,1H), 8.62 (dd, J = 8.7, 1.6 Hz, 1H),8.02 (s,1H), 7.62 - 7.54 (m, 3H), 7.52 -7.43 (m, 1H), 7.11 (dd, J = 8.5, 7.5Hz, 2H),4.74 (td, J = 9.0, 4.3 Hz, 1H),3.75 (m, 1H), 3.40 (m, 1H), 2.50 (s,3H), 2.41(s, 3H). Example 13 [ka]

[0380] Synthesis of (S)-methyl 2-(2,6-difluorobenzamido)-3-(8-(4-methoxy-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoate (13A): The title compound was prepared according to the method presented for the synthesis of compound 4C in Example 4, starting from 3-bromo-4-methoxy-1-methylpyridin-2(1H)-one and 5A.

[0381] Synthesis of (S)-2-(2,6-difluorobenzamido)-3-(8-(4-methoxy-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (13): The title compound was prepared starting with 13A according to the method presented for the synthesis of compound 1. MS (m / z) 464.1 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 9.32 (d, J = 7.9 Hz, 1H), 9.08 - 8.98 (m, 1H), 8.96(d, J = 4.6 Hz, 1H), 7.95(d,J = 7.7 Hz, 1H), 7.91 - 7.83 (m, 1H), 7.75 - 7.65(m, 2H), 7.50 (tt, J =8.4, 6.5Hz, 1H), 7.16 - 7.08 (m, 2H), 6.49 (dd, J =7.7, 3.5 Hz, 1H), 4.84 -4.72 (m,1H), 3.85 - 3.75 (m, 1H), 3.68 (d, J = 7.5Hz, 3H), 3.55 - 3.40 (m, 4H). Example 14 [ka]

[0382] Synthesis of (S)-methyl 2-(2,6-difluorobenzamido)-3-(1-methyl-2-oxo-1,2-dihydro-[3,8'-biquinolin]-5'-yl)propanoate (14A): The title compound was prepared according to the method presented for the synthesis of compound 4C in Example 4, starting from 3-bromo-1-methylquinolin-2(1H)-one and 5A.

[0383] Synthesis of (S)-2-(2,6-difluorobenzamido)-3-(1-methyl-2-oxo-1,2-dihydro-[3,8'-biquinoline]-5'-yl)propanoic acid (14): The title compound was prepared starting with 14A according to the method presented for the synthesis of compound 1. MS (m / z) 514.1 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 9.30 (d, J = 8.1 Hz,1H),8.88 (d, J = 4.3 Hz, 1H),8.77 (s, 1H), 7.98 (s, 1H), 7.78 (dd, J = 7.8,1.5 Hz,1H), 7.74 (d, J = 7.3Hz, 1H), 7.70 - 7.56 (m, 3H), 7.49 (tt, J = 8.4,6.5 Hz, 1H), 7.35 - 7.27 (m,1H), 7.18 - 7.08 (m, 2H), 4.75 (td, J = 9.5, 4.5Hz,1H), 3.77 (dd, J = 14.5,4.5 Hz, 1H), 3.68 (s, 3H), 3.44 (dd, J = 14.5, 9.9 Hz,1H). Example 15

[0384] Synthesis of (S)-methyl 2-(2,6-difluorobenzamido)-3-(5'-fluoro-[8,8'-biquinolin]-5-yl)propanoate (15A): The title compound was prepared starting from (5-fluoroquinolin-8-yl)boronic acid and 3A according to the method presented for the synthesis of compound 3B.

[0385] Synthesis of (S)-2-(2,6-difluorobenzamido)-3-(5'-fluoro-[8,8'-biquinolin]-5-yl)propanoic acid (15): The title compound was prepared starting with 15A according to the method presented for the synthesis of compound 1. MS (m / z) 502.9 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 9.32 (d, J = 8.1 Hz,1H),8.74 (dd, J = 4.2, 1.8 Hz,1H), 8.70 (s, 1H), 8.56 (d, J = 8.7 Hz, 1H),7.77 -7.43 (m, 8H), 7.19 - 7.05(m, 2H), 4.79 (m, 1H), 3.77 - 3.65 (m, J = 1H),3.56 -3.40 (m, 1H). [ka] Example 16 [ka]

[0386] Synthesis of (S)-methyl 3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(3-(difluoromethoxy)-2,6-difluorobenzamido)propanoate (16A): To a stirred solution of 1E (0.15 g, 0.41 mmol) in DCM was added 3-(difluoromethoxy)-2,6-difluorobenzoic acid (0.11 g, 0.49 mmol), HATU (0.187 g, 0.49 mmol), and TEA (0.36 mL, 2.1 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and used without further purification.

[0387] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2- Synthesis of (3-(difluoromethoxy)-2,6-difluorobenzamido)propanoic acid (16): The title compound was prepared starting with 16A according to the method presented for the synthesis of compound 1. MS (m / z) 559.9 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 8.16 (m,J = 8.4 Hz,3H), 7.67 (d, J = 8.5 Hz, 2H),7.56 - 7.21 (m, 6H), 4.75 (ddd, J =11.7, 8.4,3.7 Hz, 1H), 3.10 (m, 2H) 2.99(dd, J = 14.3, 11.3 Hz, 1H). Example 17 [ka]

[0388] Synthesis of (S)-2-(6-chloro-2,3-difluorobenzamido)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)propanoic acid (17): The title compound was prepared according to the method proposed for the synthesis of compounds 1F and 1, starting with 6-chloro-2,3-difluorobenzoyl chloride and 1E. MS (m / z) 559.9 [M+H] +. 1HNMR (400 MHz, DMSO-d6) δ 9.37 (d, J = 8.4 Hz,1H),8.84 (dd, J = 4.1, 1.6 Hz,1H), 8.64 (dd, J = 8.6, 1.6 Hz, 1H), 8.16 (dd, J=1.6, 0.4 Hz, 1H), 7.91 (d, J= 7.8 Hz, 1H), 7.67 - 7.64 (m, 1H), 7.63 (s,2H),7.55 (d, J = 7.9 Hz, 1H),7.33 (td, J = 8.7, 3.8 Hz, 1H), 4.83 (s, 1H), 3.84-3.74 (m, 1H), 3.38 (dd, J= 14.6, 10.6 Hz, 1H). Example 18 [ka]

[0389] Synthesis of (S)-2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)quinolin-5-yl)propanoic acid (18): The title compound was prepared according to the method proposed for the synthesis of compounds 3B and 3, starting with (4-(ethoxymethyl)-2,6-dimethoxyphenyl)boronic acid and 3A. MS (m / z) 551.1 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 9.30(d, J = 8.1 Hz, 1H), 9.10 - 8.69(m, 2H), 7.96 - 7.30 (m, 4H), 7.11 (t, J = 8.0Hz,2H), 6.75 (d, J = 3.4 Hz,2H), 4.85 - 4.74 (m, 1H), 4.53 (s, 2H), 3.86 - 3.66(m, 1H), 3.64 - 3.53 (m,8H), 3.45 (dd, J = 14.7, 10.1 Hz, 1H), 1.21 (t, J = 7.0Hz, 3H). Example 19 [ka]

[0390] Synthesis of (S)-3-(8-(2,6-dichloro-4-fluorophenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoic acid (19): The title compound was prepared according to the method proposed for the synthesis of compounds 5B and 5, starting with 2-bromo-1,3-dichloro-5-fluorobenzene and 5A. MS (m / z) 518.9 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 9.26(d, J =8.1 Hz, 1H), 8.82 (dd, J =4.1, 1.6 Hz, 1H), 8.68 - 8.58 (m, 1H), 7.70 -7.59 (m,3H), 7.57 (d, J = 7.3Hz, 1H), 7.47 (tt, J = 8.5, 6.5 Hz, 1H), 7.15 -7.03 (m,2H), 4.78 (ddd, J =10.2, 8.1, 4.4 Hz, 1H), 3.76 (dd, J = 14.5, 4.4 Hz, 1H), 3.41(dd, J = 14.6,10.3 Hz, 1H). Example 20 [ka]

[0391] Synthesis of (S)-3-(8-(3,5-dichloropyridin-4-yl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoic acid (20): The title compound was prepared according to the method proposed for the synthesis of compounds 5B and 5, starting with 4-bromo-3,5-dichloropyridine and 5A. MS (m / z) 501.9 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.27 (d, J = 8.2 Hz, 1H), 8.83 (dd, J = 4.1, 1.6 Hz,1H), 8.75 (d, J = 2.4 Hz, 2H), 8.66 (dd, J = 8.7, 1.7 Hz, 1H), 7.69 - 7.60 (m, 3H),7.47 (tt, J=8.5, 6.5 Hz, 1H), 7.09 (dd, J = 8.4, 7.5 Hz, 2H), 4.80 (ddd, J =10.4, 8.2,4.4 Hz, 1H), 3.78 (dd, J = 14.5, 4.4 Hz, 1H), 3.43 (dd, J = 14.6,10.4 Hz, 1H). Example 21

[0392] Synthesis of (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-methoxybenzamido)propanoic acid (21): The title compound was prepared according to the method proposed for the synthesis of compounds 16A and 16, starting with 2,6-difluoro-4-methoxybenzoic acid and 1E. MS (m / z) 523.2 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.62 (s,1H),8.30 (s, 1H), 8.15 - 7.98(m, 4H), 7.11 (d, J = 6.7 Hz, 3H), 6.82 (d, J =9.1 Hz,2H), 6.67 (s, 2H), 4 .47(s, 2H), 3.62 (s, 6H), 3.53 (q, J = 7.0Hz, 2H), 3.18 (dd, J = 124.4, 13.3Hz,2H), 1.28 (s, 3H), 1.19 (t, J = 7.0 Hz,3H). [ka] Example 22

[0393] Synthesis of (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-dichloro-4-fluorobenzamido)propanoic acid (22): The title compound was prepared according to the method presented for the synthesis of compounds 3A, 3B, and 3, starting with 2,6-dichloro-4-fluorobenzoyl chloride and 1D. MS (m / z) 541.9 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 9.26 (d, J = 8.5 Hz,1H),8.83 (dd, J = 4.1, 1.6 Hz,1H), 8.65 (dd, J = 8.7, 1.7 Hz, 1H), 8.15 (dd, J = 1.6, 0.4 Hz,1H),7.94 -7.87 (m, 1H), 7.69 - 7.58 (m, 3H), 7.50 (d, J = 8.6 Hz, 3H), 4.84(s, 1H),3.76(dd, J = 14.5, 4.1 Hz, 1H), 3.37 (s, 1H). [ka] Example 23 [ka]

[0394] Synthesis of (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2-fluoro-6-methoxybenzamido)propanoic acid (23): The title compound was prepared according to the method proposed for the synthesis of compounds 1F and 1, starting with 2-fluoro-6-methoxybenzoyl chloride and 1E. MS (m / z) 504.2 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 8.92 (d, J = 8.1 Hz,1H),8.84 (dd, J = 4.1, 1.6 Hz,1H), 8.64 (dd, J = 8.7, 1.7 Hz, 1H), 8.16 (dd, J=1.6, 0.4 Hz, 1H), 7.90 (dd,J = 7.9, 1.7 Hz, 1H), 7.68 - 7.64 (m, 2H), 7.58(d, J = 7.6 Hz, 1H), 7.35 (td,J = 8.4,6.8 Hz, 1H), 6.84 (d, J = 8.5 Hz, 1H),6.78 (t, J = 8.6 Hz, 1H), 4.80- 4.68 (m, 1H), 3.69 - 3.65 (m, 1H), 3.63 (s, 3H), 3.50 - 3.40 (m, 1H). Example 24 [ka]

[0395] Synthesis of methyl 2,6-difluoro-4-(2-oxopropyl)benzoate (24A): To a stirred solution of methyl 4-bromo-2,6-difluorobenzoate (0.15 g, 0.41 mmol) in 1,4-dioxane was added acetone (1.8 mL), Pd(OAc) (18 mg, 0.081 mmol), CsCO (1.05 g, 3.2 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (93.98 mg, 0.16 mmol). The mixture was flushed with N for 5 min and then 100 mL of HCl was added. C. for 2.5 h. The reaction mixture was filtered through Celite, rinsed with EA, and purified by silica gel chromatography using EA in hexane as eluent to give the title compound.

[0396] Synthesis of methyl 2,6-difluoro-4-(2-hydroxypropyl)benzoate (24B): To a stirred solution of 24A (306.4 mg, 1.34 mmol) in MeOH was added ammonium acetate (1.04 g, 13.43 mmol). NaBH4 (83.81 mg, 2.22 mmol) was then added slowly to prevent a large exotherm. The reaction mixture was stirred at room temperature for 2 hours, after which NaOH (1 M) and DCM were added. The organic layer was washed with brine, dried, and concentrated under reduced pressure. The material was purified by silica gel chromatography using EA and hexanes as eluents to give the title compound.

[0397] Synthesis of 2,6-difluoro-4-(2-hydroxypropyl)benzoic acid (24C): To a stirred solution of 24B (87.3 mg, 0.38 mmol) in THF was added LiOH (79.56 mg, 1.9 mmol). The reaction mixture was stirred at room temperature for 3 hours, and then HCl (1 M) and EA were added. The organic layer was washed with brine, dried, and concentrated under reduced pressure to give the title compound, which was used without further purification.

[0398] (2S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(2-hydroxypropyl)benzamido)propanoic acid (24): The title compound was prepared according to the method proposed for the synthesis of compounds 16A and 16, starting with 1E and 24C. MS (m / z) 550.2 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 9.18 (d, J = 8.1 Hz, 1H), 8.84(dd, J =4.2, 1.6 Hz, 1H), 8.64(dd, J = 8.6, 1.6 Hz, 1H), 8.16 (d, J = 1.6 Hz,1H), 7.90(dd, J = 7.9, 1.6 Hz,1H), 7.68 - 7.59 (m, 3H), 7.57 (d, J = 7.9 Hz,1H), 6.94 (d, J = 8.8 Hz, 2H),4.80 - 4.69 (m, 1H), 3.80 (pd, J = 8.9, 7.6, 3.0 Hz, 2H), 3.40 (s, 1H), 2.62(d, J = 6.2 Hz, 2H), 1.02 (d, J = 6.1 Hz, 3H). Example 25

[0399] Synthesis of (S)-tert-butyl 4-((3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-1-methoxy-1-oxopropan-2-yl)carbamoyl)-3,5-difluorobenzoate (25A): The title compound was prepared according to the method proposed for the synthesis of compound 16A, starting with 4-(tert-butoxycarbonyl)-2,6-difluorobenzoic acid and 1E.

[0400] Synthesis of (S)-4-((3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-1-methoxy-1-oxopropan-2-yl)carbamoyl)-3,5-difluorobenzoic acid (25B): To a stirred solution of 25A (150 mg, 0.25 mmol) in DCM was added TFA (1.5 mL). The reaction mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, and then purified by silica gel chromatography using DCM and MeOH as eluents to give the title compound. [ka]

[0401] (S)-4-((1-carboxy-2-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)ethyl)carbamoyl)-3,5-difluorobenzoic acid (25): The title compound was prepared according to the method proposed for the synthesis of compound 1, starting with 25B. MS (m / z) 535.8 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 9.40 (d, J = 8.2 Hz, 1H), 8.84 (dd, J = 4.1, 1.6 Hz, 1H), 8.64 (dd, J = 8.7, 1.7 Hz, 1H), 8.16 (d, J = 1.6 Hz,1H), 7.95 - 7.86 (m, 1H), 7.64(t, J = 4.3 Hz, 1H), 7.61 (d, J = 5.1 Hz,1H),7.57 (dd, J = 7.7, 6.0 Hz, 2H),4.80 (t, J = 11.5 Hz, 1H), 3.79 (s, 1H),3.41 (s, 1H). Example 26 [ka]

[0402] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(phenylcarbamoyl)benzamido)propanoic acid (26): The title compound was prepared according to the method proposed for the synthesis of compounds 16A and 16, starting with 25B and aniline. MS (m / z) 611.2 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.41 (d, J = 8.3 Hz, 1H), 8.88 - 8.80 (m, 1H), 8.65 (d, J = 8.7 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.76 -7.61 (m, 7H), 7.57 (d, J = 7.9 Hz, 1H), 7.42 -7.29 (m, 2H), 7.12 (t, J = 7.4Hz,1H), 4.81 (s, 1H), 3.76 (s, 1H), 3.25 - 3.17(m, 1H). Example 27 [ka]

[0403] Synthesis of (R)-2,6-difluoro-4-((1-phenylethyl)carbamoyl)methyl benzoate (27A): To a stirred solution of 3,5-difluoro-4-(methoxycarbonyl)benzoic acid (20 mg, 0.093 mmol) in DMF was added (R)-1-phenylethan-1-amine (13.46 mg, 0.11 mmol), HATU (42 mg, 0.11 mmol), and TEA (0.06 mL, 0.463 mmol). The reaction was stirred at room temperature for 1 hour, concentrated under reduced pressure, and then purified by silica gel chromatography using DCM / MeOH as the eluent.

[0404] Synthesis of (R)-2,6-difluoro-4-((1-phenylethyl)carbamoyl)benzoic acid (27B): To a stirred solution of 27A (29.5 mg, 0.09 mmol) in THF was added aqueous LiOH (0.46 mL, 1 M). The mixture was stirred at room temperature for 3 hours, concentrated under reduced pressure, and then purified by silica gel chromatography using DCM / MeOH as the eluent.

[0405] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(((R)-1-phenylethyl)carbamoyl)benzamido)propanoic acid (27): The title compound was prepared according to the method proposed for the synthesis of compounds 16A and 16, starting with 27B. MS (m / z) 639.2 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 9.35 (d, J = 8.3 Hz, 1H), 8.98 (d, J = 7.9 Hz, 1H), 8.84 (dd, J= 4.1, 1.6 Hz, 1H), 8.64 (d, J = 7.7 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H),7.90(d,J = 7.7 Hz, 1H), 7.66 - 7.53 (m, 6H), 7.32 (dt, J = 15.1, 7.5 Hz, 4H),7.21(t, J = 7.1 Hz, 1H), 5.11 (t, J = 7.3 Hz, 1H), 4.80 (s, 1H), 3.50-3.40 (m, 1H),1.45 (d, J = 7.0 Hz, 3H). Example 28 [ka]

[0406] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((2,2,2-trifluoroethyl)carbamoyl)benzamido)propanoic acid (28): The title compound was prepared according to the method proposed for the synthesis of compounds 16A and 16, starting with 25B. MS (m / z) 616.9 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 9.38 (d, J = 8.3 Hz, 1H), 9.29(t, J = 6.4 Hz, 1H), 8.84(dd, J= 4.2, 1.6 Hz, 1H), 8.68 - 8.60 (m, 1H), 8.16(d, J = 1.6 Hz, 1H), 7.90(d, J =8.1 Hz, 1H), 7.64 (d, J = 4.6 Hz, 1H), 7.62 -7.58 (m, 3H), 7.57 (d, J = 7.9Hz, 1H), 4.80 (s, 1H), 4.09 (dd, J = 9.8, 6.4 Hz,1H), 3.75-3.60 (m, 1H). Example 29

[0407] Synthesis of (S)-ethyl 3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-dichloro-4-iodobenzamido)propanoate (29A): The title compound was prepared according to the method presented for the synthesis of compound 16A, starting with 2,6-dichloro-4-iodobenzoic acid and 1E.

[0408] (S)-Methyl 3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-dichloro-4-(3-hydroxy-3-methylbut-1-yn-1-yl)benzamide)propanoate (29B) Synthesis: To a stirred solution of 29A (60 mg, 0.09 mmol) in THF, 2-methylbut-3-yn-2-ol (0.02 ml, 0.27 mmol), <CuI (3.44 mg, 0.02 mmol), PdCl2(PPh3)2 (12.71 mg, 0.02 mmol), and DIEA (0.08 ml, 0.45 mmol) were added. The reaction mixture was stirred at 60 °C for 1 h, then concentrated under reduced pressure and used without further purification.

[0409] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-dichloro-4-(3-hydroxy-3-methylbut-1-yn-1-yl)benzamide)propanoic acid (29): The title compound was prepared starting from 29B according to the method presented for the synthesis of compound 1. MS (m / z) 606.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 9.30 (d, J = 7.9 Hz, 1H), 8.83 (dd, J = 4.1, 1.6 Hz, 1H), 8.64 (dd, J = 8.6, 1.7 Hz, 1H), 8.18 - 8.13 (m, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.68 - 7.57 (m, 2H), 7.61 - 7.48 (m, 1H), 7.43 (s, 1H), 7.41 - 7.30 (m, 3H), 4.85 (s, 1H), 3.76 (dd, J = 14.4, 4.2 Hz, 1H), 3.39 (t, J = 12.4 Hz, 1H), 1.43 (d, J = 3.7 Hz, 6H).

Chemical Structure

[0410] Synthesis of methyl quinoline-5-carboxylate (30A): To a stirred solution of 3-nitrobenzoic acid (244.0 g, 1.46 mol) in conc. H2SO4 (750 mL) was added glycerol (1.17 L, 15.33 mol) and 3-aminobenzoic acid (500.0 g, 3.65 mol). The resulting reaction mixture was heated to 150 °C for 7 h. The reaction mixture was then cooled to 0 °C and treated with methanol (5.0 L), and the resulting reaction mixture was heated to reflux for 12 h. The reaction mixture was cooled to 0 °C and quenched with ice water and neutralized with solid Na2CO3. The aqueous material was extracted with EA (4 L × 2), and the organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The material was purified by column chromatography using EA / petroleum ether to give 30A.

[0411] Synthesis of 5-(methoxycarbonyl)quinoline 1-oxide (30C): m-CPBA (604.8 g, 2.19 mol) was added to a solution of compound 30A (205.0 g, 1.095 mol) in chloroform (4.1 L) at 0° C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 6 hours. The reaction mixture was cooled to 0° C. and quenched with saturated NaHCO solution and extracted with DCM. The organic layer was separated, dried over NaSO, and concentrated under reduced pressure. The compound was purified by column chromatography using 5% MeOH / DCM as the eluent to give 30C. [ka]

[0412] Synthesis of 5-(methoxycarbonyl)-3-nitroquinoline 1-oxide (30D): t-BuONO (708.1 mL, 5.9 mol) was added to a solution of compound 30C (120.0 g, 0.59 mol) in acetonitrile (6.0 L) at room temperature, and the resulting reaction mixture was heated to 100° C. in an autoclave for 8 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The compound was washed with EA to give compound 30D.

[0413] Synthesis of methyl 3-aminoquinoline-5-carboxylate (30E): Fe powder (39.38 g, 0.705 mol) and conc. HCl (50.0 mL) were added to a solution of compound 30D (25.0 g, 0.1 mol) in a mixture of ethanol (500 mL) and water (500 mL) at 70 °C, and the resulting reaction mixture was stirred for 18 h. The reaction mixture was cooled to room temperature, filtered through Celite, concentrated under reduced pressure, and extracted with DCM. The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The compound was purified by column chromatography using 50% EA in pet ether as the eluent to give 30E.

[0414] Synthesis of methyl 3-fluoroquinoline-5-carboxylate (30F): Sodium nitrite A solution of compound 30E (13.64 g, 0.197 mol) in water (60.0 mL) was added to a solution of compound 30E (20.0 g, 0.0989 mol) in 50% HBF (200 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 h, then filtered under reduced pressure. The filtered compound was added to chlorobenzene, and the reaction mixture was refluxed at 125 °C for 2 h. The chlorobenzene was removed by distillation to give a material that was dissolved in DCM and water. The organic layer was washed with water and brine, dried over NaSO, and concentrated under reduced pressure. The compound was purified by column chromatography using 4-5% EA in petroleum ether as the eluent to give 30F.

[0415] Synthesis of methyl 8-bromo-3-fluoroquinoline-5-carboxylate (30G): NBS (41.89 g, 0.243 mol) was added to a stirred solution of 30F (25.0 g, 0.121 mol) in HSO (500.0 mL) at 0° C., and the resulting reaction mixture was allowed to warm to room temperature and stirred for 24 hours. The reaction mixture was poured onto crushed ice, and the resulting solid was filtered and dried under reduced pressure to give compound 30G.

[0416] Synthesis of (8-bromo-3-fluoroquinolin-5-yl)methanol (31H): To a stirred solution of 30G (26.0 g, 0.091 mol) in THF (260 mL) was slowly added 2 M LiBH4 in THF (137 mL, 0.274 mol) at 0 °C. The reaction mixture was heated at 40 °C for 2 h, then cooled to 0 °C, quenched with ice water, and stirred for 30 min. The reaction mixture was acidified with aq. 2 N HCl (pH 4-5) and heated to 40 °C for 2 h. The reaction mixture was cooled to room temperature and made basic (pH 8-9) with saturated NaHCO3 solution and extracted with DCM (250 mL × 2). The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The compound was washed with pentane to give 31H.

[0417] Synthesis of 8-bromo-5-(bromomethyl)-3-fluoroquinoline (30I): PBr (48.5 g, 0.179 mol) was added to a stirred solution of 31H (23.0 g, 0.0897 mol) in DCM (230 mL) at 0° C., and the mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was concentrated, cooled to 0° C., and basified (pH 8-9) with saturated NaCO solution to give a solid, which was collected by filtration and dried under reduced pressure to give 30I.

[0418] Synthesis of (S)-methyl 3-(8-bromo-3-fluoroquinolin-5-yl)-2-((diphenylmethylene)amino)propanoate (30J): To a stirred solution of methyl 2-((diphenylmethylene)amino)acetate (16.6 g, 0.0655 mol) in DCM (500 mL) was added (−)-cinchonidine (1.93 g, 0.0065 mol) at room temperature. The reaction mixture was cooled to 0° C. KOH solution (50%) (133 mL) and 30I (23.0 g, 0.0721) were added, and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with water (200 mL) and stirred for 15 min. After washing with water and EA, the combined organic layers were dried over anhydrous NaSO, filtered through Celite, washed with EA, and concentrated under reduced pressure to give 30J.

[0419] Synthesis of free base (S)-methyl 2-amino-3-(8-bromo-3-fluoroquinolin-5-yl)propanoate (30K): 4 M HCl in 1,4-dioxane (720 mL) was added to a stirred solution of 30J (60 g, 0.1221 mol) in methanol (420 mL) at 0 °C. The reaction mixture was stirred at room temperature for 36 h. The reaction mixture was concentrated under reduced pressure, dissolved in water (100 mL), and washed with EA (100 mL × 2 L). The aqueous layer was separated and made basic (pH ∼ 8) using sat. Na2CO3 and extracted with DCM (500 mL × 5). The combined organic layers were dried over anhydrous Na2SO4. and concentrated under reduced pressure to give 30K.

[0420] Chiral purification of (S)-methyl 2-amino-3-(8-bromo-3-fluoroquinolin-5-yl)propanoate hydrochloride (30K): 30K was enriched to the desired enantiomer by supercritical fluid chromatography using a Chiralpak IC (30 x 250 mm), 5 μm column, at a flow rate of 100 mL / min using a 50% (0.5% TEA in IPA) cosolvent.

[0421] Synthesis of methyl (S)-2-amino-3-(8-bromo-3-fluoroquinolin-5-yl)propanoate hydrochloride (30K): The free amine was dissolved in DCM (300 mL) and treated with 4 M HCl in 1,4-dioxane (100 mL) at 0° C., and the reaction mixture was stirred at room temperature for 30 minutes, then concentrated under reduced pressure to give 30K as its HCl salt.

[0422] Synthesis of methyl (S)-3-(8-bromo-3-fluoroquinolin-5-yl)-2-(2,6-dichlorobenzamido)propanoate (30L): The title compound was prepared according to the method presented for the synthesis of compound 1F, starting with 30K and 2,6-dichlorobenzoyl chloride.

[0423] Synthesis of (S)-3-(8-(2-chloro-4-cyanophenyl)-3-fluoroquinolin-5-yl)-2-(2,6-dichlorobenzamido)propanoic acid (30): The title compound was prepared according to the method proposed for the synthesis of compounds 3B and 3, starting with 30L. MS (m / z) 542.0 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 9.24 (d, J = 8.4 Hz, 1H), 8.90(d, J = 2.7 Hz, 1H), 8.46 (d, J= 10.3 Hz, 1H), 8.16 (dd, J = 1.6, 0.4Hz, 1H),7.92 (d, J = 7.9 Hz, 1H), 7.73(d, J = 7.4 Hz, 1H), 7.62 (d, J = 7.3 Hz,1H),7.53 (d, J = 7.9 Hz, 1H), 7.43 -7.24 (m, 3H), 4.87 (s, 1H), 3.69 (dd, J =14.6,4.2 Hz, 1H), 3.45 - 3.35 (m,1H). Example 31

[0424] Synthesis of 5-bromo-8-iodo-2-methylquinoline (31A): To a stirred solution of 2-iodo-5-bromoaniline (5 g, 17 mmol) in nitrobenzene (1.7 mL) and 75% H2SO4 (15 mL) was added but-2-enal (2.35 g, 34 mmol) at room temperature and then slowly heated to 150 °C for 3 h. Caution: Highly exothermic reaction. The mixture was cooled to room temperature and poured into ice water while maintaining the temperature below 10 °C. The pH was adjusted to approximately 12 with solid KOH, and the resulting material was collected. This material was washed three times with water, then taken up in ethyl acetate and filtered. The organic solution was concentrated and purified by flash chromatography eluting with a linear gradient of 5 to 100% DCM / hexane to give 31A. [ka]

[0425] Synthesis of 5-bromo-8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinoline (31B): To a stirred solution of compound 31A (850 mg, 2.44 mmol) and (4-(ethoxymethyl)-2,6-dimethoxyphenyl)boronic acid (586 mg, 2.44 mmol) in 1,2-dimethoxyethane (12 mL) was added 2 M sodium carbonate in water (2.44 mL, 4.9 mmol), and the reaction was degassed with dry nitrogen. To this was added tetrakis(triphenylphosphine)palladium(0) (141 mg, 0.12 mmol), the reaction was sealed, and it was heated to 80° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and brine. It was then dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash chromatography eluting with a linear gradient of 5-50% ethyl acetate / hexanes to provide 31B.

[0426] 2-((tert-butoxycarbonyl)amino)-3-(8-(4-(ethoxymethyl) Synthesis of methyl 2-((tert-butoxycarbonyl)-2,6-dimethoxyphenyl)-2-methylquinolin-5-yl)acrylate (31C): To a stirred solution of 31B (190 mg, 0.46 mmol) in DMF (4.7 mL) was added palladium(II) acetate, and the reaction was degassed with nitrogen for 30 minutes. To this was added methyl 2-((tert-butoxycarbonyl)amino)acrylate (230 mg, 1.1 mmol), tetrabutylammonium chloride (152 mg, 0.55 mmol), and trimethylamine (0.074 mL, 0.53 mmol), and the reaction was sealed and heated to 90° C. for 3 hours. It was cooled to room temperature, diluted with ethyl acetate, and washed with 10% citric acid, saturated sodium bicarbonate, and saturated sodium chloride. It was dried over anhydrous sodium sulfate, filtered, and concentrated. This was purified by flash chromatography eluting with a linear gradient of 5-100% ethyl acetate / hexane to give compound 31C.

[0427] Synthesis of methyl 2-((tert-butoxycarbonyl)amino)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinolin-5-yl)propanoate (31D): To a stirred solution of 31C (150 mg, 0.28 mmol) and tosylhydrazide (781 mg, 4 mmol) in THF (3 mL) was added sodium acetate (609 mg, 4 mmol) in water (3 mL) dropwise at 60° C., and the reaction was then heated to reflux overnight. It was partitioned between ethyl acetate and water, and the aqueous layer was then extracted twice with ethyl acetate. The combined organics were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to these conditions two more times to give 31D.

[0428] Synthesis of methyl 2-amino-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinolin-5-yl)propanoate dihydrochloride (31E): To a stirred solution of compound 31D (150 mg, 0.28 mmol) in ethyl acetate (2 mL) was added 4 M hydrogen chloride in dioxane (0.7 mL, 1.8 mmol) and the reaction was stirred at room temperature overnight. It was diluted with EA and the resulting solid was collected by trituration to give 31E.

[0429] Synthesis of methyl 2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinolin-5-yl)propanoate (31F): The title compound was prepared according to the method presented for the synthesis of compound 1F, starting with 31E and 2,6-difluorobenzoyl chloride.

[0430] Synthesis of 2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinolin-5-yl)propanoic acid (31G): Synthesized via sodium hydroxide method to give 31G.

[0431] Synthesis of (S)-2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinolin-5-yl)propanoic acid (31): 2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinolin-5-yl)propanoic acid (31G) was separated into its two enantiomers by supercritical fluid chromatography on an IC SFC column using 20% ​​MeOH / DEA co-solvent to give the desired enantiomer 31H as the second eluting peak. MS (m / z) 565.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 8.56 (d, J = 8.7 Hz, 1H), 7.51 -7.41 (m, 1H), 7.38 (d, J = 7.4Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 7.26 (d, J = 7.3 Hz, 1H), 7.15 -7.05(m,2H), 6.68 (s, 2H), 4.50 (s, 2H), 4.40 (s, 1H), 3.68 - 3.49 (m, 9H), 3.42-3.34(m, 1H), 2.45 (s, 3H), 1.20 (t, J = 7.0 Hz, 3H). Example 32 [ka]

[0432] Synthesis of (8-bromo-3-fluoroquinolin-5-yl)methanol (32A): A flask containing methyl 8-bromo-3-fluoroquinoline-5-carboxylate (1.06 g, 3.73 mmol) in THF (19 mL) was flushed with N, then LiBH (813 mg, 37.3 mmol) was added in one portion. After stirring at room temperature for 1 hour, the reaction mixture was cooled to 0° C., and water (6 mL) was added, followed by the dropwise addition of 1 M HCl (84 mL). The reaction mixture was heated at 40° C. for 2.5 hours, then cooled to room temperature, and then diluted with water and EA. The aqueous material was extracted, and the organic layer was dried over anhydrous MgSO and concentrated under reduced pressure. The material was purified by silica gel chromatography using 0-100% EA in hexanes to provide the title compound.

[0433] Synthesis of 8-bromo-5-(bromomethyl)-3-fluoroquinoline (32B): Dissolve triphenylphosphine (1.12 g, 4.27 mmol) and CBr (1.42 g, 4.27 mmol) in 32A (729 mg, 2.85 mmol) in DCM (5.7 mL). and this was stirred at room temperature for 20 minutes. The reaction mixture was then subjected to silica gel chromatography using 0-40% EA in hexane to give the title compound.

[0434] Synthesis of (S)-tert-butyl 3-(8-bromo-3-fluoroquinolin-5-yl)-2-((diphenylmethylene)amino)propanoate (32C): To a stirred solution of tert-butyl 2-((diphenylmethylene)amino)acetate (270 mg, 0.914 mmol) in DCM (7 mL) was added (−)-cinchonidine (27 mg, 0.091 mmol). The mixture was cooled to 0° C. using an ice bath, and then 50% aqueous KOH (1.8 mL) was added, followed by 32B (321 mg, 1.01 mmol). The reaction was stirred in the ice bath as it slowly warmed to room temperature. After 3.5 h, the reaction was diluted with water and DCM, and the aqueous material was extracted. The organic layer was dried over MgSO and concentrated under reduced pressure. This material was purified by silica gel chromatography using 0-30% EA in hexanes to give the title compound.

[0435] Synthesis of (S)-tert-butyl 3-(8-(2,6-dichloro-4-fluorophenyl)-3-fluoroquinolin-5-yl)-2-((diphenylmethylene)amino)propanoate (32D): 32C (65 mg, 0.122 mmol), (2,6-dichloro-4-fluorophenyl)boronic acid (51 mg, 0.244 mmol), KPO (91 mg, 0.426 mmol), SPhos Pd G (95 mg, 0.122 mmol) were dissolved in toluene (2.4 mL) and heated to 100 °C for 3 h. After cooling to room temperature, the reaction mixture was diluted with EA and filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using 0 to 50% EA in hexane to give the title compound.

[0436] Synthesis of tert-butyl (S)-2-amino-3-(8-(2,6-dichloro-4-fluorophenyl)-3-fluoroquinolin-5-yl)propanoate (32E): 2 M HCl (0.43 mmol, 0.21 mL) was added to a stirred solution of 32D (88.2 mg, 0.14 mmol) in THF (0.84 mL). After stirring at room temperature for 2 h, saturated NaHCO and EA were added. The aqueous material was extracted, and the organic layer was dried over MgSO and concentrated under reduced pressure. This material was purified by silica gel chromatography using 0-90% EA in hexanes with 1% TEA to provide the title compound.

[0437] Synthesis of (S)-tert-butyl 3-(8-(2,6-dichloro-4-fluorophenyl)-3-fluoroquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (32F): To a stirred solution of 32E (36.6 mg, 0.081 mmol) in DCM (0.54 mL) was added TEA (23 μL, 0.161 mmol). The reaction was cooled to 0° C., and then 2,6-difluorobenzoyl chloride (15 μL, 0.121 mmol) was added dropwise. After stirring at room temperature for 1.25 h, water and DCM were added. The aqueous layer was extracted, and the organic layer was dried over MgSO and concentrated under reduced pressure. This material was purified by silica gel chromatography using 0-40% EA in hexanes to provide the title compound.

[0438] Synthesis of (S)-3-(8-(2,6-dichloro-4-fluorophenyl)-3-fluoroquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoic acid (32): TFA (0.12 mL, 1.61 mmol) was added to a stirred solution of 32F (47.9 mg, 0.081 mmol) in DCM (0.40 mL). After stirring at room temperature for 3 hours, additional TFA (0.06 mL, 0.81 mmol) was added. The reaction was stirred at room temperature for 3 hours. The mixture was stirred at rt for an additional 1 h and then concentrated under reduced pressure. This material was purified by prep HPLC using 0-100% MeCN in water with 1% TFA to give the title compound. MS (m / z) 537.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 9.27 (d, J = 8.2 Hz, 1H), 8.90 (d, J = 2.7 Hz,1H), 8.45 (dd, J = 10.5, 2.8 Hz, 1H),7.70(d, J = 7.4 Hz, 1H), 7.65 (d, J =8.6 Hz, 2H), 7.59 (d, J = 7.3 Hz, 1H), 7.48(ddd, J = 8.5, 6.5, 1.9 Hz, 1H),7.15 - 7.05 (m, 2H), 4.82 (ddd, J = 10.2, 8.1,4.5 Hz,1H), 3.78-3.55 (m, 1H),3.43 (dd, J = 14.7, 10.3 Hz, 1H). Example 33 [ka]

[0439] Synthesis of (S)-methyl 2-(4-acetyl-2,6-difluorobenzamido)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)propanoate (33A): The title compound was prepared according to the method presented for the synthesis of compound 16A, starting with 1E and 4-acetyl-2,6-difluorobenzoic acid.

[0440] (2S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(1-hydroxyethyl)benzamido)propanoic acid (33): The title compound was prepared according to the method proposed for the synthesis of compounds 24B and 16, starting with 33A. MS (m / z) 563.2 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 9.19 (d, J = 8.2 Hz, 1H), 8.83 (dd, J = 4.2, 1.6 Hz, 1H), 8.63 (dd, J = 8.7, 1.6 Hz, 1H), 8.16 (dd, J = 1.6,0.4 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H),7.73 - 7.50 (m, 4H), 7.03 (d, J = 8.8 Hz, 2H), 4.71 (d, J = 6.5 Hz, 1H), 1.27(d, J = 6.5 Hz,3H) . Example 34

[0441] Synthesis of 8-bromo-7-fluoro-5-methylquinoline (34A): The title compound was prepared starting from 2-bromo-3-fluoro-5-methylaniline according to the method presented for the synthesis of compound 1A in Example 1. MS (m / z) 240.0 [M+H ] + .

[0442] Synthesis of 8-bromo-5-(bromomethyl)-7-fluoroquinoline 34B: The title compound was prepared starting with 34A according to the method presented for the synthesis of compound 1B in Example 1. MS (m / z) 317.9 [M+H] + .

[0443] Synthesis of 8-bromo-7-fluoro-5-(((2S,5S)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)methyl)quinoline (34C): A solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (0.365 mL, 2.04 mmol) in THF (10 mL) was cooled to −78 °C under a positive nitrogen pressure with stirring. This mixture was treated dropwise with n-BuLi (0.98 mL, 1.6 M, 1.57 mmol). A solution of 34B (497 mg, 1.57 mmol) was then added as a 1.0 M THF solution. After 30 min, the reaction mixture was removed from the cooling bath, quenched with a saturated aqueous solution of NH4Cl, and allowed to warm to room temperature with vigorous stirring. The resulting mixture was extracted twice with EA, and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0–20% EA in hexanes to give the title compound. MS (m / z) 422.1 [M+H] + .

[0444] Synthesis of (S)-methyl 2-amino-3-(8-bromo-7-fluoroquinolin-5-yl)propanoate dihydrochloride (34D): To a stirred solution of 34C (380 mg, 0.9 mmol) in THF (3.6 mL) was added 2 M aqueous hydrochloric acid (2.7 mL, 5.4 mmol). After 3 h, the reaction mixture was concentrated under reduced pressure to give the title compound (as a mixture with valine methyl ester hydrochloride), which was carried forward without further purification. MS (m / z) 327.0 [M+H] + . [ka]

[0445] Synthesis of (S)-methyl 3-(8-bromo-7-fluoroquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (34E): The title compound was prepared starting with 34 according to the method presented for the synthesis of compound 1F in Example 1. MS (m / z) 467.0 [M+H] + .

[0446] Synthesis of (2S)-3-(8-(2-chloro-4-cyanophenyl)-7-fluoroquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoic acid (34): The title compound was prepared according to the method proposed for the synthesis of compounds 3B and 3, starting with 34E. MS (m / z) 510.1 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 9.27 (dd, J = 8.3, 1.3Hz,1H), 8.87 (dt, J = 3.9, 1.8Hz, 1H), 8.67 (dd, J = 8.6, 1.6 Hz, 1H), 8.24(t, J =1.9 Hz, 1H), 7.95 (ddd, J= 7.9, 4.2, 1.7 Hz, 1H), 7.67 - 7.57 (m, 3H),7.49(ttd, J = 8.7, 6.6, 2.3 Hz,1H), 7.16 - 7.08 (m, 2H), 4.82 (dddd, J = 10.8,8.4,4.2, 2.2 Hz, 1H), 3.85(ddd, J = 18.1, 14.5, 4.1 Hz, 1H), 3.42 (ddd, J = 19.5, 14.6, 10.8 Hz, 1H). Example 35 [ka]

[0447] Synthesis of (S)-(5-(2-(2,6-dichlorobenzamido)-3-methoxy-3-oxopropyl)-3-fluoroquinolin-8-yl)boronic acid (35A): The title compound was prepared according to the method presented for the synthesis of compound 5A, starting with 30L.

[0448] Synthesis of (S)-2-(2,6-dichlorobenzamido)-3-(3-fluoro-8-(4-(trifluoromethyl)isoquinolin-3-yl)quinolin-5-yl)propanoic acid (35): The title compound was prepared according to the method proposed for the synthesis of compounds 4C and 4, starting with 35A and 3-bromo-4-(trifluoromethyl)isoquinoline (71B). MS (m / z) 601.9 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.60 (d, J = 3.4 Hz,1H), 9.29 (dd, J = 14.2, 8.4 Hz, 1H),8.81 (dd, J = 3.4, 2.8 Hz, 1H), 8.46(ddd,J = 10.1, 6.9, 2.8 Hz, 1H), 8.38(dd, J = 8.2, 1.1 Hz, 1H), 8.18 (d, J =8.6 Hz,1H), 8.10 - 8.01 (m, 1H), 7.94- 7.85 (m, 1H), 7.74 (d, J = 7.4 Hz, 1H),7.69(dd, J = 7.3, 1.9 Hz, 1H), 7.45- 7.35 (m, 3H), 4.85 (dtd, J = 23.5, 9.2,4.5Hz, 1H), 3.69 (dt, J = 14.4, 4.4Hz, 1H), 3.44 (dd, J = 14.6, 10.1 Hz, 1H). Example 36

[0449] Synthesis of (S)-methyl 3-(8-bromo-3-iodoquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (36A): A solution of 3A (300 mg, 0.67 mmol) in AcOH (2.5 mL) was treated with N-iodosuccinimide (300 mg, 1.34 mmol) and stirred at 70 °C for 24 h. A second portion of N-iodosuccinimide (300 mg, 1.34 mmol) was added, and stirring was continued at 70 °C for an additional 24 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in DCM and washed with saturated aqueous NaHCO3, and the aqueous material was back-extracted twice with DCM. The combined organic layers were adsorbed onto silica gel for purification by silica gel chromatography using 0-100% EA in hexanes to give the title compound. MS (m / z) 575.0 [M+H]+.

[0450] Synthesis of (S)-methyl 3-(8-bromo-3-cyanoquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (36B): A suspension of 36A (50 mg, 0.087 mmol) and cuprous cyanide (12 mg, 0.130 mmol) in DMF (1.5 mL) was stirred at 135 °C for 30 min under microwave irradiation. The reaction mixture was then cooled to room temperature, diluted with EA and saturated aqueous NaCl, and filtered through Celite. The phases were separated, and the aqueous layer was extracted twice more with EA. The combined organic layers were concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography using 0-40% EA in hexane to give the title compound. MS (m / z) 474.0 [M+H]+. [ka]

[0451] Synthesis of (S)-3-(3-cyano-8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoic acid (36): The title compound was prepared according to the method proposed for the synthesis of compound 18, starting with 36B. MS (m / z) 576.2 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 9.27 (d, J = 8.1 Hz, 1H), 9.21(d, J = 2.1 Hz, 1H), 9.02 (d, J= 2.0 Hz, 1H), 7.69 (d, J = 7.4 Hz, 1H), 7.63 (d, J = 7.4 Hz, 1H), 7.49 (tt, J= 8.4, 6.6 Hz, 1H), 7.15-7.08 (m, 2H), 6.71 (q, J = 1.3 Hz, 2H), 4.82 (ddd, J= 10.0, 8.2, 4.5 Hz,1H),4.52 (s, 2H), 3.77 - 3.70 (m, 1H), 3.61 - 3.45 (m,9H), 1.21 (t, J = 7.0 Hz,3H). Example 37

[0452] Synthesis of (S)-methyl 3-(8-bromo-3-(trifluoromethyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (37A): A vial was charged with 36A (50 mg, 0.087 mmol) and (1,10-phenanthroline)(trifluoromethyl)copper(I) (98 mg, 0.313 mmol), sealed with a septum cap, and purged with nitrogen for 15 min. DMF (1 mL, previously degassed with nitrogen for 15 min) was added, and the mixture was vigorously stirred at 50 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with EA, and filtered through Celite. The filtrate was washed with saturated aqueous NaHCO3, and the aqueous layer was back-extracted twice with EA. The combined organic layers were adsorbed onto silica gel for silica gel chromatography using 0-50% EA in hexane to give the title compound. MS (m / z) 517.1 [M+H]+. [ka]

[0453] Synthesis of (S)-2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-3-(trifluoromethyl)quinolin-5-yl)propanoic acid (37): The title compound was prepared according to the method proposed for the synthesis of compound 18, starting with 37A. MS (m / z) 619.2 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 9.31 (d, J = 8.0 Hz, 1H), 9.08 -9.06(m, 1H), 8.97 (dd, J =2.3, 1.1 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.63 (d,J =7.3 Hz, 1H), 7.50 (tt,J = 8.5, 6.6 Hz, 1H), 7.15 - 7.08 (m, 2H), 6.72 (q, J = 1.3 Hz, 2H), 4.78 (ddd,J = 9.7, 8.0, 4.6 Hz, 1H), 4.53 (s, 2H), 3.77 (dd, J = 14.8, 4.6 Hz, 1H), 3.61- 3.43 (m, 9H), 1.22 (t, J = 7.0 Hz, 3H). Example 38

[0454] Synthesis of 4-((2-bromo-5-methylphenyl)amino)-1,1,1-trifluorobut-3-en-2-one (38A): To a stirred solution of 2-bromo-5-methylaniline (2.149 g, 12 mmol) and 4-(tert-butylamino)-1,1,1-trifluorobut-3-en-2-one (2.05 g, 10.5 mmol) in glacial acetic acid (4 mL) was added TFA (4 mL) and the reaction was heated to 75° C. for 16 hours. It was cooled to room temperature, poured into water, and the solid was collected by filtration to give 38A.

[0455] Synthesis of 8-bromo-5-methyl-2-(trifluoromethyl)quinoline (38B): To a stirred suspension of compound 38A (2.81 g, 9.1 mmol) in heptane (9 mL) was added POCl (0.855 mL, 9.12 mmol), and the reaction was heated to 100 °C overnight. It was poured into a solution of 2 M sodium carbonate in water. It was extracted twice with ethyl acetate, and the combined organics were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. It was purified by flash chromatography eluting with a linear gradient of 1 to 20% ethyl acetate / hexane to give 38B.

[0456] Synthesis of 8-bromo-5-(bromomethyl)-2-(trifluoromethyl)quinoline (38C): To a stirred solution of 38B (1.32 g, 4.6 mmol) in benzene (10 mL) was added N-bromosuccinimide (0.97 g, 5.5 mmol), and the reaction was heated to reflux under a tungsten work lamp for 16 h. It was cooled to room temperature, filtered, and concentrated. The residue was dissolved in ethyl acetate and washed twice with water and once with saturated sodium chloride solution. This was purified by flash chromatography eluting with a linear gradient of 5–70% DCM / hexane to give compound 38C. [ka]

[0457] Synthesis of tert-butyl 3-(8-bromo-2-(trifluoromethyl)quinolin-5-yl)-2-((diphenylmethylene)amino)propanoate (38D): A stirred solution of tert-butyl 2-((diphenylmethylene)amino)acetate (260 mg, 0.88 mmol) in tetrahydrofuran (3 mL) was cooled to −78° C. under dry nitrogen. 1 M lithium hexamethyldisilazide in THF (0.968 mL, 0.968 mmol) was added dropwise, and the reaction was stirred at this temperature for 15 minutes. To this was added a solution of 38C (357 mg, 0.97 mmol) in THF (2 mL), and the reaction was allowed to warm to room temperature and stirred for 16 hours. It was quenched by the addition of saturated ammonium chloride, and it was partitioned between water and ethyl acetate. The aqueous material was extracted with ethyl acetate, and the combined organics were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated, which was purified by flash chromatography eluting with a linear gradient of 5-50% ethyl acetate / hexane to give compound 38D.

[0458] 2-amino-3-(8-bromo-2-(trifluoromethyl)quinolin-5-yl)propanol Synthesis of tert-butyl propanoate (38E): To a stirred solution of compound 38D (335 mg, 0.57 mmol) in tetrahydrofuran (6 mL) was added 0.5 M citric acid in water (5.7 mL, 2.87 mmol), and the reaction was stirred at room temperature for 1 hour. It was diluted with water and washed once with diethyl ether. The aqueous material was treated with 1 M sodium hydroxide in water until a pH of approximately 8 was reached, and it was extracted twice with diethyl ether. The combined extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 38E.

[0459] Synthesis of tert-butyl 3-(8-bromo-2-(trifluoromethyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (38F): The title compound was prepared according to the method presented for the synthesis of compound 1F, starting with 38E and 2,6-difluorobenzoyl chloride.

[0460] Synthesis of tert-butyl 2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-(trifluoromethyl)quinolin-5-yl)propanoate (38G): To a solution of 38F (187 mg, 0.33 mmol) and (4-(ethoxymethyl)-2,6-dimethoxyphenyl)boronic acid (104 mg, 0.44 mmol) in 1,2-dimethoxyethane (3 mL) was added 2 M aqueous sodium carbonate in water (0.5 mL, 0.67 mmol) and the reaction was degassed with nitrogen. To this was added XPhos Pd G3 (14 mg, 0.017 mmol), the reaction was sealed, and it was heated to 85° C. for 1 hour. This was cooled to room temperature and purified by flash chromatography eluting with a linear gradient of 1-10% MeOH / DCM to afford 38G.

[0461] Synthesis of 2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-(trifluoromethyl)quinolin-5-yl)propanoic acid (38): To a solution of 38G (214 mg, 0.32 mmol) in DCM (1 mL) was added TFA (723 mg, 6 mmol) and the reaction was stirred at room temperature for 4 hours. It was concentrated and purified by preparative HPLC to give 38. MS (m / z) 619.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 9.30 (d, J = 8.1 Hz, 1H), 8.85 (dd, J = 8.9, 0.8 Hz, 1H), 7.95(d, J = 8.8 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.61 (d, J = 7.3 Hz, 1H), 7.48(tt, J = 8.4, 6.5 Hz, 1H), 7.11 (dd, J = 8.5, 7.5 Hz, 2H), 6.72 (q, J = 1.3 Hz,2H), 4.77 (ddd, J = 10.1, 8.0, 4.5 Hz, 1H), 4.52 (d, J =0.7Hz, 2H), 3.76 (dd,J = 14.7, 4.5 Hz, 1H), 3.64 - 3.50 (m, 8H), 3.44 (dd, J=14.8, 10.1 Hz, 1H),1.20 (t, J = 7.0 Hz, 3H). Example 39 [ka]

[0462] Synthesis of 8-bromo-6-fluoro-5-methylquinoline (39A). The title compound was prepared using 2-bromo-4-fluoro-5-methylaniline according to the method described for the synthesis of compound 1A in Example 1. MS (m / z) 240.0 [M+H]+.

[0463] Synthesis of 8-bromo-5-(bromomethyl)-6-fluoroquinoline (39B): The title compound was prepared using 39A according to the method presented for the synthesis of compound 1B in Example 1. MS (m / z) 317.9 [M+H]+.

[0464] Synthesis of 8-bromo-6-fluoro-5-(((2S,5S)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)methyl)quinoline (39C): The title compound was prepared using 39B according to the method presented for the synthesis of compound 34C4. MS (m / z) 422.1 [M+H]+.

[0465] Synthesis of methyl (S)-2-amino-3-(8-bromo-6-fluoroquinolin-5-yl)propanoate (39D): The title compound was prepared using 39C according to the method proposed for the synthesis of compound 34. MS (m / z) 327.0 [M+H]+.

[0466] Synthesis of (S)-methyl 3-(8-bromo-6-fluoroquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (39E): The title compound was prepared using 39D according to the method presented for the synthesis of compound 16A in Example 16. MS (m / z) 467.0 [M+H]+.

[0467] Synthesis of (S)-2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-6-fluoroquinolin-5-yl)propanoic acid (39): The title compound was prepared using 39E according to the method proposed for the synthesis of compound 18. MS (m / z) 569.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 9.30 (d, J = 8.3 Hz, 1H), 8.83 -8.70(m, 2H), 7.68 (dd, J =8.8, 4.3 Hz, 1H), 7.55 - 7.44 (m, 2H), 7.11 (dd, J =8.5,7.6 Hz, 2H), 6.75 (s,2H), 4.77 (td, J = 8.5, 6.2 Hz, 1H), 4.54 (s, 2H),3.70 -3.50 (m, 11H), 1.22(t, J = 7.0 Hz, 3H). Example 40 [ka]

[0468] (S)-2-(2,6-Difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-7-fluoroquinolin-5-yl)propanoic acid (40): The title compound was prepared using 34E according to the method proposed for the synthesis of compound 18. MS (m / z) 569.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 9.32 (d, J = 8.1 Hz, 1H), 8.83 (dd,J = 4.3, 1.5 Hz, 1H), 8.70(d, J = 5.0 Hz, 1H), 7.64 (dd,J = 8.0, 3.9 Hz, 1H),7.56 - 7.46 (m, 2H), 7.18- 7.10 (m, 2H), 6.75 (d, J = 1.7Hz, 2H), 4.80 (ddd, J= 10.6, 8.1, 4.1 Hz,1H), 4.54 (s, 2H), 3.80 (dd, J = 14.6,4.1 Hz, 1H), 3.62 -3.55 (m, 8H), 3.43(dd, J = 14.8, 10.5 Hz, 1H), 1.22 (t, J = 7.0 Hz, 3H). Example 41

[0469] Synthesis of 2,6-difluoro-4-((phenoxycarbonyl)amino)benzoic acid (41A): To a stirred solution of 4-amino-2,6-difluorobenzoic acid (504 mg, 2.16 mmol) in DCM was added phenyl chloroformate (0.41 mL, 3.24 mmol) and pyridine (0.87 mL, 10.81 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by reverse-phase preparative chromatography using aqueous 0.1% TFA / MeCN as the eluent.

[0470] Synthesis of (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((phenoxycarbonyl)amino)benzamido)propanoic acid (41): The title compound was prepared according to the method proposed for the synthesis of compounds 16A and 16, starting with 41A and 1E. MS (m / z) 686.5 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 10.76 (s, 1H), 9.18 (d, J = 8.0 Hz,1H),8.81 (s, 1H), 7.85 - 7.37 (m, 6H), 7.32 - 7.13 (m, 5H), 6.72 (s, 2H), 4.74(s,1H), 4.52 (s, 2H), 3.85-3.75 (m, 1H), 3.60 - 3.51 (m, 8H), 1.20 (t, J = 7.0Hz, 3H). [ka] Example 42 and Example 43 [ka]

[0471] Synthesis of (S)-methyl 3-(8-bromoquinolin-5-yl)-2-(4-cyano-2,6-difluorobenzamido)propanoate (42A): To a stirred solution of 4-cyano-2,6-difluorobenzoic acid (0.12 g, 0.65 mmol) in DCM, 1D (0.2 g, 0.65 mmol), HATU (0.25 g, 0.65 mmol), and TEA (1 mL) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography using EA in hexane as the eluent.

[0472] (S)-2-(4-Cyano-2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)quinolin-5-yl)propanoic acid (42): To a microwave vial was added 42A (0.24 g, 0.5 mmol), (4-(ethoxymethyl)-2,6-dimethoxyphenyl)boronic acid (200 mg, 0.5 mmol), XPhos Pd G3 (0.043 g, 0.05 mmol), and K3PO4 (0.21 g, 0.15 mmol) in dioxane (2 mL). The reaction mixture was stirred at 120 °C for 30 min. EA and water were added to the reaction mixture. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The mixture was purified by silica gel chromatography using MeOH and DCM as eluents to give both 42 and 43. MS(m / z)576.2 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 8.72 (dd, J = 4.1, 1.6Hz,1H), 8.60 (s, 1H), 8.15 (s,1H), 7.72 (s, 1H), 7.57 (d, J = 8.1 Hz, 2H),7.53 -7.46 (m, 2H), 7.36 (d, J =7.3 Hz, 1H), 6.68 (d, J = 2.3 Hz, 2H), 4.61 (s, 1H), 4.50 (s, 2H), 3.68 (dd, J= 14.0, 4.7 Hz,1H),3.56 (d, J = 7.0 Hz, 1H), 3.52 (d, J = 7.1 Hz, 6H), 3.44 -3.33 (m, 1H),1.20 (t,J =7.0 Hz, 3H).

[0473] (S)-2-(4-carbamoyl-2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)quinolin-5-yl)propanoic acid (43). MS (m / z) 595.5 [M+H] +. 1HNMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 9.48(d, J =8.0 Hz, 1H), 8.74 (dd, J =4.1, 1.7 Hz, 1H), 8.53 (dd, J = 8.7, 1.7 Hz,1H), 8.01- 7.73 (m, 2H), 7.53 (dd,J = 8.6, 4.1 Hz, 1H), 7.48 (d, J = 7.4 Hz,1H), 7.38 (d, J = 7.3 Hz, 1H), 6.76- 6.63 (m, 2H), 4.75 (td, J = 8.8, 4.4 Hz,1H),4.50 (s, 2H), 3.91 - 3.61 (m,1H), 3.55 (t, J = 7.0 Hz, 2H), 3.53 (s, 3H),3.46 -3.22 (m, 4H), 1.20 (t, J =7.0 Hz, 3H). Example 44

[0474] Synthesis of methyl (S)-2-amino-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)quinolin-5-yl)propanoate (44A): The title compound was prepared according to the method presented for the synthesis of compound 1E, starting with (4-(ethoxymethyl)-2,6-dimethoxyphenyl)boronic acid.

[0475] (S)-2-(4-amino-2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)quinolin-5-yl)propanoic acid (44): The title compound was prepared according to the method proposed for the synthesis of compounds 16A and 16, starting with 44A and 4-amino-2,6-difluorobenzoic acid. MS (m / z) 567.6 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 8.84 (s, 2H), 8.67 (d, J=7.9 Hz, 1H), 7.64 (t, J =37.5 Hz, 3H), 6.74 (d, J = 2.2 Hz, 2H), 6.11 (d, J =10.7 Hz, 2H),4.75 - 4.62(m, 1H), 4.53 (s, 2H), 3.81 - 3.65 (m, 1H), 3.58 (d, J = 7.0 Hz, 2H),3.55 (d,J = 6.1 Hz, 7H), 1.20 (t, J = 7.0 Hz, 3H). [ka] Example 45 [ka]

[0476] Synthesis of methyl 2,6-difluoro-4-(methylsulfonamido)benzoate (45A): To a stirred solution of methyl 4-amino-2,6-difluorobenzoate (500 mg, 0.3 mmol) in DCM was added methylsulfonyl chloride (0.31 mL, 0.4 mmol), and pyridine (1.08 mL, 1.3 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with EA, washed with 1M HCl, bicarbonate, brine, and dried, filtered, and concentrated. The material was recrystallized from EA / hexane to give the title compound.

[0477] Synthesis of 2,6-difluoro-4-(methylsulfonamido)benzoic acid (45B): To a stirred solution of 45A (534 mg, 0.2 mmol) in THF was added aqueous LiOH (5 mL, 2 M). The mixture was stirred at room temperature for 2 days, diluted with water, and acidified with 1 M HCl. The material was extracted with DCM, dried, filtered, and concentrated under reduced pressure. The material was purified by silica gel chromatography using EA / hexane as the eluent to provide the title compound.

[0478] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(methylsulfonamido)benzamido)propanoic acid (45): The title compound was prepared according to the method proposed for the synthesis of compounds 16A and 16, starting with 45B. MS (m / z) 585.1 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 10.46 (s, 1H), 9.15 (d, J = 8.1Hz, 1H), 8.85 (dd, J = 4.1, 1.6Hz, 1H), 8.65 (dd, J = 8.7, 1.7 Hz, 1H), 8.17 (dd, J = 1.6, 0.4 Hz, 1H), 7.92(dd, J = 7.9, 1.6Hz,1H), 7.70 - 7.55 (m, 4H), 6.83 (d, J = 9.3 Hz, 2H), 4.83- 4.68 (m, 1H), 3.87-3.66 (m, 1H), 3.51 - 3.33 (m, 1H), 3.14 (s, 3H). Example 46 [ka]

[0479] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(phenylsulfonamido)benzamido)propanoic acid (46): The title compound was prepared according to the method proposed for the synthesis of compounds 45A, 45B, and 45, starting with phenylsulfonyl chloride. MS (m / z) 647.1 [M+H] . 1H NMR (400MHz, DMSO-d6) δ 11.09 (s, 1H), 9.12 (d, J = 8.1 Hz, 1H), 8.84 (dd,J= 4.2, 1.6Hz, 1H), 8.63 - 8.60 (m, 1H), 8.17 (d, J = 1.7 Hz, 1H), 7.92 (dd, J = 7.9, 1.7Hz, 1H), 7.89 - 7.82 (m, 2H), 7.73 - 7.53 (m, 7H), 6.75 (d, J =9.2Hz, 2H), 4.75 - 4.65 (m, 1H), 3.82 - 3.65 (m, 1H), 3.47 - 3.27 (m, 1H). Example 47 [ka]

[0480] Synthesis of (S)-methyl 3-(8-bromoquinolin-5-yl)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)propanoate (47A): The title compound was prepared according to the method presented for the synthesis of compound 16 in Example 16, starting with 2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzoic acid.

[0481] Synthesis of (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)propanoic acid (47): The title compound was prepared starting with 47A according to the method presented for the synthesis of compounds 3B and 3. MS (m / z) 742.4 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 9.11 (d, J=8.1 Hz, 1H), 8.81 (dd, J =4.1, 1.6 Hz, 1H), 8.59 (dd, J = 8.6, 1.7 Hz,1H),8.33 (d, J = 5.3 Hz, 1H),8.14 (d, J = 1.6 Hz, 1H), 8.09 - 8.03 (m, 2H), 8.01 -7.94 (m, 2H), 7.89 (dd, J= 7.9, 1.6 Hz, 1H), 7.72 (dt, J = 5.4, 1.8 Hz, 1H),7.64 - 7.51 (m, 5H),6.78(d, J = 9.2 Hz, 2H), 4.83 - 4.59 (m, 1H), 3.71 (s,1H), 3.34 (s, 1H). Example 48

[0482] Synthesis of 2,6-difluoro-4-((methylsulfonyl)methyl)benzoic acid (48A): To a stirred solution of methyl 4-(bromomethyl)-2,6-difluorobenzoate (125 mg, 0.47 mmol) in DMF was added sodium methyl sulfinate (96.28 mg, 0.94 mmol). This was heated to 65° C. and stirred for 1 hour. EA and water were added. The combined organics were washed with brine, dried, and concentrated. This material was then converted to the title compound according to the method described for the synthesis of compound 1G. [ka]

[0483] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((methylsulfonyl)methyl)benzamido)propanoic acid (48): The title compound was prepared according to the method proposed for the synthesis of compounds 16A and 16, starting with 48A. MS (m / z) 584.2 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (d, J = 8.2 Hz, 1H), 8.84(dd, J = 4.2, 1.6 Hz, 1H), 8.65 (dd,J = 8.7,1.6 Hz, 1H), 8.15 (d, J = 1.6 Hz,1H), 7.90 (dd, J = 7.9, 1.7 Hz, 1H),7.68 -7.53 (m, 4H), 7.16 (d, J = 8.1 Hz, 2H), 4.84 - 4.73 (m, 1H), 4.55 (s,2H), 3.77(s,1H), 3.40 (s, 1H), 2.93 (s, 3H). Example 49 [ka]

[0484] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((phenylsulfonyl)methyl)benzamido)propanoic acid (49): The title compound was prepared starting with sodium phenylsulfinate according to the method proposed for the synthesis of compound 48A in Example 48, followed by 49A according to the method proposed for 16 and 16C. MS (m / z) 646.3 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 9.28 (d, J = 8.2 Hz, 1H), 8.83(dd, J =4.1, 1.6 Hz, 1H), 8.64(dd, J = 8.7, 1.7 Hz, 1H), 8.15 (d, J = 1.6 Hz,1H), 7.90(dd, J = 7.9, 1.7 Hz,1H), 7.81 - 7.69 (m, 3H), 7.69 - 7.50 (m, 6H),6.88 (d, J =8.1 Hz, 2H), 4.82 -4.73 (m, 1H), 4.77 (s, 2H), 3.76 (s, 1H), 3.40(s, 1H). Example 50 [ka]

[0485] (S)-2-(2,6-Difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)quinolin-5-yl)propanoic acid (50): The title compound was prepared according to the method proposed for the synthesis of compounds 3B and 3, starting with 47A and (4-(ethoxymethyl)-2,6-dimethoxyphenyl)boronic acid. MS (m / z) 802.4 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 11.24 (s, 1H), 9.16 (d, J = 8.0Hz, 1H), 8.83 (s, 2H), 8.35 (d,J = 5.3 Hz, 1H), 8.12 - 8.04 (m, 2H), 8.03 - 7.95(m,2H), 7.82 - 7.43 (m, 5H),6.81 (d, J = 9.0 Hz, 2H), 6.74 (s, 2H), 4.72 (q, J=8.3 Hz, 1H), 4.54 (s, 2H),3.73 (dd, J = 13.3, 3.5 Hz, 1H), 3.59 (d, J = 7.0Hz, 1H), 3.54 (d, J = 2.0 Hz,6H), 3.43 (s, 1H), 1.22 (t, J = 7.0 Hz, 3H). Example 51 [ka]

[0486] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((methylsulfonyl)methyl)benzamido)propanoic acid (51): The title compound was prepared according to the method proposed for the synthesis of compounds 3B and 3, starting with 47A and (2,3-dihydrobenzo[b][1,4]dioxin-5-yl)boronic acid. MS (m / z) 741.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 9.12 (d, J = 8.1 Hz, 1H), 8.87 (s, 1H), 8.71 (s,1H), 8.38 - 8.26(m,1H), 8.10 - 8.02 (m, 2H), 8.02 - 7.93 (m, 2H), 7.78 - 7.47(m, 5H), 6.90 (d,J =9.3 Hz, 2H), 6.79 (t, J = 8.8 Hz, 2H), 4.67 (s, 1H), 4.20(s, 2H), 4.05 (s,2H),3.71 (d, J = 14.0 Hz, 1H), 3.42 - 3.27 (m, 1H). Example 52 [ka]

[0487] (S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(thiophen-3-yl)quinolin-5-yl)propanoic acid (52): The title compound was prepared according to the method proposed for the synthesis of compounds 3B and 3, starting with 47A and thiophen-3-ylboronic acid. MS (m / z) 689.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 11.23 (s, 1H), 9.11 (d, J = 8.1 Hz, 1H), 8.97 (dd, J = 4.1, 1.7Hz, 1H), 8.60 (dd, J = 8.6, 1.7Hz,1H), 8.37 - 8.32 (m, 1H), 8.09 - 8.04 (m,3H), 8.01 - 7.96 (m, 2H), 7.86 (d,J =7.5 Hz, 1H), 7.74 (dt, J = 5.4, 1.8 Hz,1H), 7.69 - 7.59 (m, 4H), 7.51 (d, J =7.5Hz, 1H), 6.81 (d, J = 9.1 Hz, 2H),4.66 (ddd, J = 10.1, 8.1, 4.4 Hz, 1H), 3.69(dd, J = 14.3, 4.4 Hz, 1H), 3.31(dd, J = 14.5, 10.1 Hz, 1H). Example 53

[0488] Synthesis of (S)-3-(8-boronoquinolin-5-yl)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)propanoic acid (53A): The title compound was prepared starting from 47A according to the method presented for the synthesis of compound 4B. [ka]

[0489] (S)-3-(8-(2-chloro-4-(cyanomethyl)phenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)propanoic acid (53): The title compound was prepared according to the method proposed for the synthesis of compounds 5B and 5, starting with 53A and 2-(4-bromo-3-chlorophenyl)acetonitrile. MS (m / z) 756.1 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 11.19 (s, 1H), 9.10 (d, J = 8.1Hz, 1H),8.81 (dd, J = 4.1, 1.6Hz, 1H), 8.58 (dd, J = 8.7, 1.7 Hz, 1H), 8.33(dt, J =5.3, 0.6 Hz, 1H), 8.09 -8.02 (m, 2H), 8.01 - 7.94 (m, 2H), 7.72 (dt, J = 5.4, 1.8 Hz, 1H), 7.62 - 7.49(m, 5H), 7.43 - 7.32 (m, 2H), 6.79 (d, J = 9.1 Hz, 2H), 4.67 (d, J =11.2Hz,1H), 4.14 (s, 2H), 3.36 (s, 2H). Example 54 [ka]

[0490] (S)-3-(8-(2-chloro-4-cyclopropylphenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)propanoic acid (54). The title compound was prepared by the procedure of compound 3. Prepared according to the methods proposed for the synthesis of B and 3, starting with 47A and (2-chloro-4-cyclopropylphenyl)boronic acid. MS (m / z) 757.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 11.23 (s, 1H), 9.12 (d, J = 8.1 Hz, 1H), 8.82 (d, J = 4.3 Hz, 1H), 8.61 (d, J = 8.7 Hz, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.13 - 8.05 (m, 2H), 8.03 - 7.95 (m, 2H), 7.74 (dt, J = 5.3, 1.8 Hz, 1H), 7.66 - 7.52(m, 4H), 7.25(d, J = 1.8 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.11 (dd, J = 8.1, 1.8 Hz,1H),6.80(d, J = 9.1 Hz, 2H), 4.76 - 4.64 (m, 1H), 3.82 - 3.62 (m, 1H), 3.45 -3.25(m,1H), 2.02 (tt, J = 8.4, 5.1 Hz, 1H), 1.07 - 0.99 (m, 2H), 0.84 - 0.73(m,2H). Example 55 [ka]

[0491] (S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(3,5-dimethylsiloxazol-4-yl)quinolin-5-yl)propanoic acid (55): The title compound was prepared according to the method proposed for the synthesis of compounds 3B and 3, starting with 47A and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole. MS (m / z) 702.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 11.19 (s, 1H), 9.07 (d, J = 8.2Hz, 1H), 8.88 (dd, J = 4.1, 1.6Hz, 1H), 8.58(dd, J = 8.7, 1.6 Hz, 1H), 8.33(d, J = 5.3 Hz, 1H), 8.05 (s,1H), 8.01 - 7.93(m, 2H), 7.72 (dt, J = 5.4, 1.8Hz, 1H), 7.65 - 7.57 (m, 3H),7.52 (d, J = 7.4Hz, 1H), 6.77 (d, J = 9.1 Hz,2H), 4.69 (s, 1H), 3.75-3.60 (m,1 H), 3.30 (dd, J= 14.4, 10.6 Hz, 1H), 2.22(s, 3H), 2.01 (s, 3H). Example 56

[0492] (S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(pyrimidin-4-yl)quinolin-5-yl)propanoic acid (56): The title compound was prepared according to the method proposed for the synthesis of compounds 5B and 5, starting with 53A and 4-bromopyrimidine. MS (m / z) 685.4 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 11.21 (s, 1H), 9.30 (d, J = 1.4 Hz, 1H), 9.11 (d, J = 8.2 Hz,1H), 8.99 (dd, J = 4.2, 1.6 Hz, 1H), 8.86 (d,J= 5.4 Hz, 1H), 8.67 (dd, J =8.7, 1.7 Hz, 1H), 8.42 - 8.25 (m, 2H), 8.19 (d, J=7.5 Hz, 1H), 8.10 - 8.00(m, 2H), 8.01 - 7.92 (m, 2H), 7.74 - 7.70 (m, 1H),7.71- 7.66 (m, 1H), 7.63(d, J = 7.6 Hz, 1H), 7.59 (d, J = 1.5 Hz, 1H), 6.78(d, J =9.1 Hz, 2H), 4.68(ddd, J = 10.3, 8.2, 4.4 Hz, 1H), 3.81 - 3.65 (m, 1H),3.34 ( d, J = 7.0 Hz, 1H). [ka] Example 57 [ka]

[0493] (S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(5-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoic acid (57): The title compound was prepared according to the method proposed for the synthesis of compounds 5B and 5, starting with 53A and 2-bromo-5-(trifluoromethyl)pyridine. MS (m / z) 752.4 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 11.21 (s, 1H), 9.20 - 9.05 (m,2H), 8.98 (dd, J = 4.2, 1.6Hz,1H), 8.69 (dd, J = 8.7, 1.7 Hz, 1H), 8.38 - 8.23(m, 3H), 8.11 (d, J = 7.5Hz, 1H),8.09 - 8.02 (m, 2H), 8.00 - 7.90 (m, 2H),7.76 - 7.65 (m, 2H), 7.63 (d, J =7.5Hz, 1H), 7.58 (d, J = 1.7 Hz, 1H), 6.78(d, J = 9.1 Hz, 2H), 4.78 - 4.62(m,1H), 3.74 (dd, J = 14.5, 4.4 Hz, 1H), 3.36(dd, J = 14.5, 10.2 Hz, 1H). Example 58 [ka]

[0494] (S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(pyrimidin-2-yl)quinolin-5-yl)propanoic acid (58): The title compound was prepared according to the method proposed for the synthesis of compounds 5B and 5, starting with 53A and 2-bromopyrimidine. MS (m / z) 685.4 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 11.22 (s, 1H), 9.29 (d, J = 4.9 Hz, 1H), 9.23 (d, J = 8.7 Hz,1H), 9.15 - 9.02 (m, 3H), 8.76 (s, 1H),8.33(dd, J = 5.3, 0.6 Hz, 1H), 8.10 -8.00 (m, 2H), 8.00 - 7.92 (m, 2H), 7.86(d, J= 7.7 Hz, 1H), 7.71 (dt, J = 5.3,1.8 Hz, 1H), 7.67 (t, J = 4.9 Hz, 1H), 7.58(p, J = 0.7 Hz, 1H), 6.76 (d, J =9.1 Hz, 2H), 4.77 (ddd, J = 10.4, 8.3, 4.4 Hz,1H),3.92 - 3.79 (m, 1H), 3.47(dd, J = 14.6, 10.4 Hz, 1H). Example 59

[0495] (S)-3-(8-(2-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)propanoic acid (59): The title compound was prepared according to the method proposed for the synthesis of compounds 5B and 5, starting with 53A and 2-bromobenzonitrile. MS (m / z) 708.2 [M+H]. 1H NMR (400 MHz,DMSO-d6) δ 11.22 (d, J = 15.6 Hz, 1H), 9.23- 9.03(m, 1H), 8.90 - 8.77 (m,1H), 8.77 - 8.47 (m, 1H), 8.33 (dd, J = 5.3, 2.2Hz,1H), 8.18 - 7.82 (m, 5H),7.82 - 7.15 (m, 7H), 6.89 - 6.72 (m, 2H), 4.78 -4.36 (m, 1H), 3.72 (d, J =10.6 Hz, 1H), 3.30 (m, 1H). [ka] Example 60 [ka]

[0496] (S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(3-fluoro-2-methoxyphenyl)quinolin-5-yl)propanoic acid (60): The title compound was prepared according to the method proposed for the synthesis of compounds 3B and 3, starting from 47A and (3-fluoro-2-methoxyphenyl)boronic acid. MS (m / z) 731.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 11.20 (s, 1H), 9.11 (d, J = 8.1 Hz, 1H), 8.85 (dd, J = 4.1,1.6Hz,1H), 8.61 (d, J = 8.6 Hz, 1H), 8.37 - 8.29 (m, 1H), 8.11 - 8.02 (m,2H),8.02 -7.93 (m, 2H), 7.72 (dt, J = 5.3, 1.8 Hz, 1H), 7.65 - 7.50 (m, 4H), 7.31(ddd, J=11.8, 8.2, 1.6 Hz, 1H), 7.15 (td, J = 8.0, 5.1 Hz, 1H), 7.06 - 7.01(m, 1H),6.79 (d, J = 9.1 Hz, 2H), 4.74 - 4.62 (m, 1H), 3.71 (dd, J = 14.4, 4.4Hz, 1H),3.48(d, J = 1.4 Hz, 3H), 3.38 - 3.28 (m, 1H). Example 61 [ka]

[0497] (S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(4-fluoro-2-(methylsulfonyl)phenyl)quinolin-5-yl)propanoic acid (61): The title compound was prepared according to the method proposed for the synthesis of compounds 3B and 3, starting with 47A and (4-fluoro-2-(methylsulfonyl)phenyl)boronic acid. MS (m / z) 779.3 [M+H]+. 1H NMR (400MHz, DMSO-d6) (50:50 mixture of diastereomers) δ 11.21 (s, 1H), 9.12 (dd, J = 8.1, 3.4 Hz,1H), 8.80 (td, J = 3.8, 3.3, 1.5 Hz, 1H),8.60(t, J = 7.4 Hz, 1H), 8.33 (d, J= 5.3 Hz, 1H), 8.10 - 8.02 (m, 2H), 8.01 - 7.94(m,2H), 7.87 (ddd, J = 8.9,2.8, 1.2 Hz, 1H), 7.73 (dd, J = 5.3, 1.7Hz, 1H),7.68 - 7.57 (m, 3H), 7.61 -7.48 (m, 2H), 7.41 - 7.32 (m, 1H), 6.79 (dd, J = 9.1, 1.9 Hz, 2H), 4.76 - 4.61(m, 1H), 3.77 (dd, J = 14.3, 4.0 Hz, 0.5H), 3.62 (dd, J=14.7, 5.1 Hz, 0.5H),3.44 (dd, J = 14.6, 9.6 Hz, 0.5H), 3.27 (dd, J = 14.5,10.5Hz, 0.5H), 2.85 (s,1.5H), 2.80 (s, 1.5H). Example 62

[0498] (S)-3-(8-(chroman-8-yl)quinolin-5-yl)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)propanoic acid (62): The title compound was prepared according to the method proposed for the synthesis of compounds 3B and 3, starting with 47A and chroman-8-ylboronic acid. MS (m / z) 739.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 11.22 (s, 1H), 9.12 (d, J = 8.1 Hz, 1H), 8.88 (s, 1H), 8.33(dt, J = 5.4, 0.6 Hz, 1H), 8.10 - 8.01(m,2H), 8.01 - 7.90 (m, 2H), 7.72 (dt,J = 5.4, 1.8 Hz, 1H), 7.59 (q, J = 1.1Hz,3H), 7.14 (d, J = 7.8 Hz, 1H), 7.01(d, J = 7.3 Hz, 1H), 6.91 (t, J = 7.4Hz,1H), 6.86 - 6.64 (m, 2H), 4.75 - 4.57 (m, 1H), 3.97 - 3.85 (m, 2H), 3.72 (d,J =14.3 Hz, 1H), 3.43 - 3.27 (m, 1H),2.82 (t, J = 6.5 Hz, 2H), 1.87 (t, J =5.6Hz, 3H). [ka] Example 63 [ka]

[0499] (S)-2-(2,6-Difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(o-tolyl)quinolin-5-yl)propanoic acid (63): The title compound was prepared according to the method proposed for the synthesis of compounds 3B and 3, starting with 47A and o-tolylboronic acid. MS (m / z) 697.2 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 11.20 (s, 1H), 9.09 (d, J = 8.2Hz, 1H),8.81 (dd, J = 4.2, 1.6Hz, 1H), 8.62 (d, J = 8.7 Hz, 1H), 8.36 - 8.28(m, 1H),8.11 - 8.01 (m, 2H),7.97 (d, J = 8.4 Hz, 2H), 7.72 (dt, J = 5.4, 1.8Hz, 1H),7.65 - 7.55 (m, 2H),7.55 - 7.41 (m, 2H), 7.34 - 7.17 (m, 3H), 7.13 (d,J = 7.0 Hz, 1H), 6.78 (d, J= 9.5 Hz, 2H), 4.70 (s, 1H), 3.72 (dd, J = 14.4, 4.4 Hz, 1H),3.32 (dd, J =14.4, 10.3 Hz, 1H), 1.87 (s, 3H). Example 64 [ka]

[0500] (2S)-2-(2,6-Difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(2-methoxy-6-methylphenyl)quinolin-5-yl)propanoic acid (64): The title compound was prepared according to the method proposed for the synthesis of compounds 3B and 3, starting with 47A and (2-methoxy-6-methylphenyl)boronic acid. MS (m / z) 727.5 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 13.03 (s, 1H), 11.20 (s, 1H),9.08 (d, J= 8.2 Hz, 1H), 8.73(d, J = 42.8 Hz, 2H), 8.33 (d, J = 5.3 Hz, 1H),8.13 - 7.89(m, 4H), 7.72 (dt,J = 5.3, 1.7 Hz, 1H), 7.69 - 7.37 (m, 4H), 7.28(t, J = 7.9Hz, 1H), 6.90 (t, J= 8.9 Hz, 2H), 6.83 - 6.71 (m, 2H), 4.79 - 4.66(m, 1H), 3.77(d, J = 14.2 Hz,1H), 3.49 (s, 3H), 3.28 (dd, J = 14.4, 10.6 Hz,1H), 1.74 (s,3H). Example 65 [ka]

[0501] (S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(2-(trifluoromethyl)phenyl)quinolin-5-yl)propanoic acid (65): The title compound was prepared by the reaction of compound 3B with Prepared according to the method proposed for the synthesis of 47A and 3, starting with 47A and (2-(trifluoromethyl)phenyl)boronic acid. MS (m / z) 751.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.20 (d, J = 2.3 Hz, 1H), 9.10 (dd, J = 8.2, 6.2 Hz, 1H), 8.77(dt, J = 4.0, 1.9 Hz, 1H), 8.59 (d, J = 8.5 Hz, 1H), 8.33 (d, J = 5.3 Hz, 1H),8.10 - 8.02 (m, 2H), 8.01 - 7.93 (m, 2H), 7.82 (dt, J = 7.9, 1.9 Hz, 1H), 7.75-7.54(m, 6H), 7.51 (d, J = 1.9 Hz, 2H), 7.32 (dd, J = 7.7, 4.4 Hz, 1H), 6.78(dd, J =9.0, 3.5 Hz, 2H), 4.69 (ddd, J = 10.2, 8.1, 4.6 Hz, 1H), 3.71 (ddd, J= 29.9,14.4,4.4 Hz, 1H), 3.34 (ddd, J = 25.9, 14.5, 10.2 Hz, 1H). Example 66 [ka]

[0502] (S)-3-(8-(4-chloroisoquinolin-3-yl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoic acid (66): The title compound was prepared according to the method proposed for the synthesis of compounds 5B and 5, starting with 5A and 3-bromo-4-chloroisoquinoline. MS (m / z) 514.1 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (d, J = 8.1 Hz, 1H), 8.88(d, J = 4.3 Hz, 1H), 8.77 (s,1H), 7.98 (s, 1H), 7.78 (dd, J = 7.8, 1.5 Hz, 1H),7.74 (d, J = 7.3 Hz, 1H),7.70 - 7.56 (m, 3H),7.49 (tt, J = 8.4, 6.5 Hz, 1H),7.35 - 7.27 (m, 1H), 7.18- 7.08 (m, 2H), 4.75(td, J = 9.5, 4.5 Hz, 1H), 3.77(dd, J = 14.5, 4.5 Hz,1H), 3.68 (s, 3H), 3.44(dd, J = 14.5, 9.9 Hz, 1H). Example 67 [ka]

[0503] (S)-2-(2,6-Difluorobenzamido)-3-(4-methoxy-1-methyl-2-oxo-1,2-dihydro-[3,8'-biquinolin]-5'-yl)propanoic acid (67): The title compound was prepared according to the method proposed for the synthesis of compounds 11A and 11, starting with 5A and 3-bromo-4-methoxy-1-methylquinolin-2(1H)-one. MS (m / z) 518.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.41 (d, J = 0.8 Hz, 1H), 9.31 (d, J = 8.1 Hz, 1H),8.81 (dd, J =4.2, 1.6 Hz, 1H), 8.72(dd, J = 8.7, 1.7 Hz, 1H), 8.38 - 8.29 (m, 1H), 8.24(dq, J = 8.5, 0.9 Hz, 1H),8.02 (ddd, J = 8.4, 6.9, 1.3 Hz, 1H), 7.87 (ddd, J =8.1, 7.0, 1.1 Hz, 1H), 7.78 (d,J= 7.3 Hz, 1H), 7.72 - 7.64 (m, 2H), 7.48 (tt,J = 8.5, 6.6 Hz, 1H), 7.16 -7.07 (m, 2H), 4.80 (ddd, J = 10.1, 8.1, 4.4 Hz,1H), 3.81 (dd, J = 14.5, 4.4 Hz, 1H), 3.46 (dd, J = 14.5, 10.1 Hz, 1H). Example 68 [ka]

[0504] (S)-2-(2,6-Dichlorobenzamido)-3-(8-(6-methyl-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoic acid (68): The title compound was prepared according to the method proposed for the synthesis of compounds 4C and 4, starting with 4B and 2-chloro-6-methyl-3-(trifluoromethyl)pyridine. MS (m / z) 549.5 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 9.31 (d, J = 8.3 Hz, 1H), 8.81 (dd, J = 4.2, 1.6 Hz, 1H), 8.69 (dd, J = 8.7, 1.7 Hz, 1H), 8.20 (d, J = 8.3 Hz, 1H). 7.70 - 7.52 (m, 4H), 7.48- 7.35 (m, 3H), 4.84 (td, J = 9.3, 4.3 Hz, 1H),3.75 (dd,J = 14.6, 4.4 Hz,1H), 3.44 (dd, J = 14.6, 10.1 Hz, 1H), 2.58 (s, 3H). Example 69 [ka]

[0505] (S)-2-(2,6-dichlorobenzamido)-3-(8-(6-methoxy-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoic acid (69): The title compound was prepared according to the method proposed for the synthesis of compounds 4C and 4, starting with 4B and 2-chloro-6-methoxy-3-(trifluoromethyl)pyridine. MS (m / z) 565.9 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 9.28 (s, 1H), 8.83 (dd, J = 4.2, 1.6 Hz, 1H), 8.68 (dd, J =8.7, 1.7 Hz, 1H), 8.16 (d, J = 8.9 Hz, 1H), 7.70 - 7.58 (m, 3H), 7.47 - 7.34(m, 3H), 7.06 (dt, J = 8.7, 0.8 Hz, 1H), 4.86(m,1H), 3.81 (s, 3H), 3.78 (m,1H), 3.43 (m, 1H). Example 70 [ka]

[0506] (S)-2-(2,6-Difluorobenzamido)-3-(8-(5-methoxy-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)quinolin-5-yl)propanoic acid (70): The title compound was prepared according to the method proposed for the synthesis of compounds 11A and 11, starting with 5A and 4-chloro-5-methoxy-2-methylpyridazin-3(2H)-one. MS (m / z) 495.1 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (d, J = 7.6 Hz, 1H), 8.88 (d, J = 4.4 Hz, 1H), 8.75 (d, J = 8.6 Hz, 1H), 8.27 (s, 1H), 7.77 - 7.65 (m, 1H), 7.59 (d, J = 7.8 Hz, 2H), 7.48 (tt,J = 8.5,6.6Hz, 1H), 7.12 (dd, J = 8.4, 7.6 Hz, 2H), 4.74 (s, 1H), 3.86 - 3.63(m, 7H), 3.43(q,J = 13.6 Hz, 1H). Example 71 [ka]

[0507] Synthesis of 4-(trifluoromethyl)isoquinolin-3-amine (71A): To a stirred solution of 3-aminoisoquinoline (150 mg, 1.04 mmol) in MeCN, 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (412.1 mg, 1.25 mmol) and tris(trimethylsilyl)silyl chloride (0.35 ml, 1.25 mmol) were added. The mixture was heated to 80° C. for 1 hour. The reaction mixture was filtered through Celite, rinsed with EA, and purified by silica gel chromatography using EA in hexane as the eluent to give the title compound.

[0508] Synthesis of 3-bromo-4-(trifluoromethyl)isoquinoline (71B): To a stirred solution of 71A (91 mg, 0.43 mmol) in HBr (6.9 mL) was added Br (0.13 mL, 2.57 mmol). The reaction mixture was maintained at 0 °C for 10 min, at which point NaNO (147.96 mg, 2.14 mmol) was added as a pre-prepared solution in water (5 mL). The reaction mixture was stirred at 0 °C for 30 min and then allowed to warm to room temperature for 60 min. The reaction was quenched with sodium bicarbonate, extracted with DCM, concentrated, and purified by silica gel chromatography eluting with Hex / EA to provide the title compound.

[0509] (S)-2-(2,6-Difluorobenzamido)-3-(8-(4-(trifluoromethyl)isoquinolin-3-yl)quinolin-5-yl)propanoic acid (71): The title compound was prepared according to the method proposed for the synthesis of compounds 5B and 5, starting with 4B and 71B. MS (m / z) 552.2 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 9.60 (d, J = 3.3 Hz, 1H), 9.29(t, J = 7.6 Hz, 1H), 8.75 (dt, J= 3.9, 1.8 Hz, 1H), 8.65(ddd, J = 8.7, 5.6,1.7 Hz, 1H), 8.38 (d, J = 8.2 Hz,1H), 8.18 (d, J = 8.7 Hz,1H), 8.05 (ddd, J =8.6, 6.9, 1.4 Hz, 1H), 7.90 (t, J= 7.6 Hz, 1H), 7.70 (dd, J= 7.3, 4.7 Hz, 1H),7.66 - 7.58 (m, 2H), 7.55 - 7.41(m, 1H), 7.12 (q, J = 8.2 Hz, 2H),4.77 (dtd, J= 18.5, 8.8, 4.4 Hz, 1H), 3.77(ddd, J = 25.7, 14.5, 4.5 Hz, 1H),3.49 - 3.34(m, 1H). Example 72 [ka]

[0510] (S)-3-(8-(6-amino-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)-2-(2,6-dichlorobenzamido)propanoic acid (72): The title compound was prepared according to the method proposed for the synthesis of compounds 4C and 4, starting with 4B and 6-chloro-5-(trifluoromethyl)pyridin-2-amine. MS (m / z) 550.4 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 9.33 (d, J = 8.3 Hz, 1H), 8.89 (dd, J = 4.1, 1.6 Hz, 1H), 8.70 (dd, J = 8.7, 1.6 Hz, 1H), 7.97 (d, J = 9.1 Hz, 1H), 7.74 - 7.63 (m, 3H), 7.49- 7.36 (m, 3H), 6.81 (d, J = 9.1 Hz, 1H), 4.80(td, J = 9.2, 4.4 Hz, 1H), 3.74(dd, J = 14.5, 4.4 Hz, 1H), 3.43 (dd, J = 14.6,9.9Hz, 1H). Example 73 [ka]

[0511] (S)-2-(2,6-Dichlorobenzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (73): The title compound was prepared according to the method proposed for the synthesis of compounds 11A and 11, starting with 4B and 3-iodo-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one. MS (m / z) 578.1 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 13.00 (s, 1H), 9.27 (dd, J = 27.2, 8.3Hz, 1H), 8.83 (dt, J =4.2, 2.0 Hz, 1H), 8.69 (d, J = 8.6 Hz, 1H), 7.72 - 7.59 (m,2H),7.49 - 7.31(m, 4H), 6.55 (d, J = 4.7 Hz, 1H), 4.90 - 4.71 (m, 1H), 3.73(td, J= 14.4, 4.0Hz, 1H), 3.47 (d, J = 4.2 Hz, 3H), 3.38 (ddd, J = 24.5, 14.7,10.5Hz, 1H),2.52 (m, 3H). Example 74

[0512] Synthesis of tert-butyl 4-bromo-2,6-difluorobenzoate (74A): To a stirred solution of 4-bromo-2,6-difluorobenzoic acid (5 g, 21.1 mmol) in DCM (50 mL) and tert-butyl alcohol (50 mL) was added di-tert-butyl dicarbonate (9.2 g, 42.2 mol), followed by 4-dimethylaminopyridine (0.8 g, 6.3 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate (100 mL), and washed with 10% aqueous citric acid solution (100 mL). The organic layer was washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the material. The material was suspended in hexane, the solid was filtered off, and the filtrate was evaporated under reduced pressure to give compound 74A. MS(m / z)236.6 [M+H-C4H8] + . 1 H NMR(400MHz, DMSO-d6)δ 7.69 - 7.56 (m, 2H), 1.50 (s, 9H).

[0513] Synthesis of tert-butyl (R)-2,6-difluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoate (74B): To a stirred suspension of tert-butyl 4-bromo-2,6-difluorobenzoate (74A) (250 mg, 0.55 mmol), (R)-1,1,1-trifluorobutan-2-amine (85 mg, 0.67 mmol), and cesium carbonate (904 mg, 2.8 mmol) in toluene (5 mL) was added XPhos Pd G3 (42 mg, 0.06 mmol). The reaction mixture was sparged with nitrogen and then heated to 90° C. for 12 hours. The mixture was cooled to room temperature and diluted with ethyl acetate (50 mL). The resulting suspension was filtered through a pad of Celite, and the filtrate was evaporated under reduced pressure to provide compound 74B. MS(m / z)284.1 [M+H-C4H8] + . [ka]

[0514] Synthesis of (R)-2,6-difluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoic acid (74C): To a stirred solution of (R)-2,6-difluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoate tert-butyl (74B) (188 mg, 0.55 mmol) in DCM (1 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure to give the material, which was purified by silica gel column chromatography and eluted with ethyl acetate in hexane to give compound 74C. MS (m / z) 338.1 [M+H] + .

[0515] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)propanoic acid (74): The title compound was prepared according to the method proposed for the synthesis of compounds 16A and 16, starting with 74C. MS (m / z) 617.2 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 8.87 - 8.77 (m, 2H), 8.64 (dd, J = 8.7, 1.7 Hz, 1H), 8.15 (dd, J = 1.7, 0.4 Hz, 1H), 7.90 (dd, J = 7.9, 1.7 Hz,1H), 7.73 - 7.44(m, 4H), 6.76(d, J = 9.4 Hz, 1H), 6.43 (d, J = 11.6 Hz, 2H),4.68 (s, 1H), 4.29(d, J = 10.2Hz, 1H), 3.73 (s, 1H), 3.49 - 3.33 (m, 1H), 1.75(ddt, J = 10.1,7.5, 3.8 Hz,1H), 1.51 (ddt, J = 17.6, 14.4, 7.3Hz, 1H), 0.90(t, J = 7.3 Hz,3H). Example 75 [ka]

[0516] Synthesis of (R)-2,6-difluoro-4-(2-(trifluoromethyl)piperidin-1-yl)benzoic acid (75A): To a 150 mL pressure vessel equipped with a stir bar was added methyl 4-bromo-2,6-difluorobenzoate (700 mg, 1.8 mmol), RuPhos (169 mg, 0.36 mmol), tBuBrettPhos Pd G3 (155 mg, 0.18 mmol), Cs2CO3 (2.95 g, 9.1 mmol), (R)-2-(trifluoromethyl)piperidine (416 mg, 2.7 mmol), and toluene (18 mL). The reaction vessel was then sealed and heated at 90 °C overnight. The reaction mixture was cooled to room temperature and filtered through a pad of Celite, rinsed with EA, and the filtrate was evaporated to dryness under reduced pressure. This material was purified by silica gel chromatography using EA in hexane as the eluent. To this material was added THF (6 mL) and aqueous LiOH (6.2 mL, 1.0 M). The reaction mixture was stirred at 60° C. for 20 hours. The reaction mixture was cooled to room temperature and acidified with 1.0 M HCl, then diluted with EA. The organic layers were combined and dried over Na2SO4. The solvent was removed under reduced pressure to provide 75A.

[0517] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((R)-2-(trifluoromethyl)piperidin-1-yl)benzamido)propanoic acid (75): The title compound was prepared according to the method proposed for the synthesis of compounds 16A and 16, starting with 75A. MS (m / z) 645.2 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 8.90 (d, J = 8.1 Hz, 1H), 8.83 (dd, J = 4.2, 1.6 Hz, 1H), 8.64 (dd, J = 8.6, 1.7 Hz, 1H), 8.15 (dd, J = 1.7, 0.4 Hz, 1H), 7.90 (dd, J = 1.7, 0.4 Hz, 1H). = 7.9,1.7 Hz, 1H), 7.67 - 7.52 (m, 4H), 6.72 (d, J =12.0 Hz, 2H), 4.93 (d, J =9.0Hz, 1H), 4.70 (dt, J = 9.7, 4.9 Hz, 1H), 3.74 (s,1H), 3.59 (d, J = 12.9Hz,1H), 3.41 (s, 1H), 2.99 (t, J = 12.2 Hz, 1H), 1.94(d, J = 14.4 Hz, 1H), 1.85 -1.67 (m, 2H), 1.67 - 1.42 (m, 3H). Example 76

[0518] Synthesis of (R)-2,6-difluoro-4-(2-(trifluoromethyl)pyrrolidin-1-yl)benzoic acid (76A): The title compound was prepared starting with (R)-2-(trifluoromethyl)pyrrolidine according to the method presented for the synthesis of compound 75A.

[0519] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((R)-2-(trifluoromethyl)pyrrolidin-1-yl)benzamido)propanoic acid (76): The title compound was prepared according to the method proposed for the synthesis of compounds 16A and 16, starting with 76A. MS (m / z) 629.5 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 8.88 (d, J = 8.2 Hz, 1H), 8.83 (dd, J = 4.1, 1.6 Hz, 1H), 8.65(dd, J = 8.7, 1.7 Hz, 1H),8.15 (dd, J = 1.7, 0.4 Hz, 1H), 7.96 -7.83 (m, 1H),7.66 - 7.58 (m, 3H), 7.56(dt, J = 7.9, 0.6 Hz, 1H), 6.48 (d, J =11.5 Hz, 2H),4.82 - 4.63 (m, 2H), 3.72 (d, J = 13.0 Hz, 1H), 3.56 (t, J = 8.5Hz,1H), 3.41(s, 1H), 3.15 (q, J = 8.7 Hz, 1H), 2.16 - 1.91 (m, 4H). [ka] Example 77 [ka]

[0520] Synthesis of (R)-2,6-difluoro-4-(2-(trifluoromethyl)piperazin-1-yl)benzoic acid (77A): The title compound was prepared starting with (R)-2-(trifluoromethyl)piperazine according to the method presented for the synthesis of compound 75A.

[0521] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((R)-2-(trifluoromethyl)piperazin-1-yl)benzamido)propanoic acid (77): The title compound was prepared according to the method proposed for the synthesis of compounds 16A and 16, starting with 77A. MS (m / z) 644.1 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 8.94 (d, J = 8.1 Hz, 1H), 8.83 (dd, J = 4.1, 1.6 Hz, 1H), 8.63 (dd, J = 8.7, 1.7 Hz, 1H), 8.15 (dd, J = 1.6, 0.4 Hz, 1H), 7.90 (dd, J = 1.6, 0.4 Hz, 1H). = 7.9,1.6 Hz, 1H), 7.67 - 7.57 (m, 3H), 7.58 - 7.53(m, 1H), 6.79 (d, J = 11.5Hz,2H), 4.71 (td, J = 9.2, 8.2, 4.3 Hz, 1H), 4.26(br, 1H), 4.05 (d, J = 13.2 Hz,1H), 3.84 (d, J = 10.9 Hz, 1H), 3.75 (s, 1H), 3.42 (s, 1H), 3.29 (d, J=10.7Hz, 1H), 3.12 - 2.96 (m, 3H). Example 78 [ka]

[0522] Synthesis of 2,6-difluoro-4-(2-(trifluoromethyl)azetidin-1-yl)benzoic acid (78A): The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with 2-(trifluoromethyl)azetidine hydrochloride.

[0523] (2S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(2-(trifluoromethyl)azetidin-1-yl)benzamido)propanoic acid (78): The title compound was prepared according to the method proposed for the synthesis of compounds 16A and 16, starting with 78A. MS (m / z) 617.1 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 8.93 (dd, J = 8.1, 3.2 Hz, 1H), 8.87 -8.77 (m, 1H), 8.64 (dd,J = 8.7, 1.7 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H),7.90 (dd, J = 7.9, 1.6 Hz,1H),7.67 - 7.50 (m, 4H), 6.24 (d, J = 9.9 Hz, 2H),4.91 (q, J = 6.3 Hz, 1H),4.71(d, J = 9.6 Hz, 1H), 4.16 - 3.97 (m, 1H), 3.84 -3.62 (m, 2H), 3.40 (s,1H),2.68 - 2.53 (m, 1H), 2.37 (ddd, J = 11.7, 5.6, 2.6Hz, 1H). Example 79 [ka]

[0524] Synthesis of 2,6-difluoro-4-morpholinobenzoic acid (79A): The title compound was prepared starting with morpholine according to the method presented for the synthesis of compound 75A.

[0525] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-morpholinobenzamido)propanoic acid (79): The title compound was prepared according to the method proposed for the synthesis of compounds 16A and 16, starting with 79A. MS (m / z) 577.3 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 8.87 (d, J = 8.0 Hz, 1H), 8.83 (dd, J = 4.1, 1.6 Hz, 1H), 8.64 (dd, J = 8.7, 1.7 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.96 - 7.84 (m, 1H), 7.67-7.58 (m, 3H), 7.56 (d, J = 7.9 Hz,1H), 6.61 (d, J = 11.8 Hz, 2H), 4.69 (q, J=5.9, 4.3 Hz, 1H), 3.74 (s, 1H),3.70 - 3.61 (m, 4H), 3.42 (s, 1H), 3.22 -3.12 (m, 4H). Example 80 [ka]

[0526] Synthesis of 4-(1,1-dioxidethiomorpholino)-2,6-difluorobenzoic acid (80A): The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with thiomorpholine 1,1-dioxide.

[0527] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(4-(1,1-dioxidothiomorpholino)-2,6-difluorobenzamido)propanoic acid (80): The title compound was prepared according to the method proposed for the synthesis of compounds 16A and 16, starting with 80A. MS (m / z) 625.5 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 8.90 (d, J = 8.1 Hz, 1H), 8.84(dd, J =4.1, 1.6 Hz, 1H), 8.64(dd, J = 8.6, 1.7 Hz, 1H), 8.15 (dd, J = 1.7,0.4 Hz, 1H),7.90 (dd, J = 7.9,1.7 Hz, 1H), 7.67 - 7.58 (m, 3H), 7.56 (dd, J = 7.9, 0.4 Hz, 1H), 6.76 (d, J =11.7 Hz,2H),4.78 - 4.64 (m, 1H), 3.85 (s, 4H), 3.75 (s, 1H), 3.42 (s, 1H),3.06 (s, 4H). Example 81

[0528] Synthesis of 2,6-difluoro-4-morpholinobenzoic acid (81A): The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with 3-(trifluoromethyl)morpholine hydrochloride. [ka]

[0529] 2,6-Difluoro-4-(3-(trifluoromethyl)morpholino)benzoic acid (81): The title compound was prepared according to the method presented for the synthesis of compounds 16A and 16. Prepared starting with 81A. MS (m / z) 645.1 [M+H]+. 1H NMR(400MHz, DMSO-d6) δ 8.96 (dd, J =8.0, 2.7 Hz, 1H), 8.84 (dd, J = 4.1, 1.6 Hz,1H),8.65 (dd, J = 8.7, 1.7 Hz,1H), 8.16 (dd, J = 1.6, 0.4 Hz, 1H), 7.90 (dd, J=7.9, 1.6 Hz, 1H), 7.68 - 7.59(m, 3H), 7.57 (dt, J = 7.9, 0.6 Hz, 1H), 6.74(d,J = 11.7 Hz, 2H), 4.89 (dd, J= 8.7, 3.6 Hz, 1H), 4.71 (d, J = 6.2 Hz, 1H),4.14 (d, J = 12.7 Hz, 1H),3.93(dd, J = 11.5, 3.8 Hz, 1H), 3.72 (d, J = 13.0Hz, 2H), 3.59 - 3.45 (m, 1H),3.40(d, J = 12.7 Hz, 2H), 3.21 (t, J = 12.2 Hz,1H). Examples 82 and 83 [ka]

[0530] Preparation of (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)propanoic acid (82): 81 was separated into its two stereoisomers using 25% MeOH / DEA cosolvent in a Chiralpak AD-H column at a flow rate of 50 mL / min. Separation was performed by supercritical fluid chromatography using a 5um 21 x 250mm column. The title compound was identified as the first eluting peak. MS (m / z) 645.1 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 8.78 (dd, J = 4.2, 1.6 Hz, 1H), 8.74 (s,1H),8.14(dd, J = 1.6, 0.4 Hz, 1H), 8.0-8.4 (br, 1H), 7.88 (dd, J = 7.9, 1.7Hz,1H),7.61 - 7.49 (m, 4H), 6.74 (d, J = 11.9 Hz, 2H), 4.88 (d, J = 9.0 Hz, 1H),4.43(s,1H), 4.14 (d, J = 12.7 Hz, 1H), 3.93 (dd, J = 11.5, 3.7 Hz, 1H), 3.72 (d, J=12.6 Hz, 2H), 3.60 - 3.48 (m, 1H), 3.41 (d, J = 12.9 Hz, 1H), 3.21 (t, J =13.1Hz, 2H).

[0531] Preparation of (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((S)-3-(trifluoromethyl)morpholino)benzamido)propanoic acid (83): 81 was separated into its two stereoisomers using 25% EtOH / TFA cosolvent in a Chiralpak AD-H column at a flow rate of 50 mL / min. Separation was performed by supercritical fluid chromatography using a 5 μm 21×250 mm column. The title compound was identified as the second eluting peak. MS (m / z) 645.1 [M+H] + . 1H NMR (400 MHz,DMSO-d6) δ 8.77 (dd, J = 4.1, 1.5 Hz,2H),8.13 (dd, J = 1.7, 0.4 Hz, 1H), 8.08(s, 1H), 7.88 (dd, J = 7.9, 1.7 Hz,1H), 7.65 - 7.42 (m, 4H),6.74 (d, J = 11.9Hz, 2H), 4.88 (dt, J = 9.4, 4.7 Hz,1H), 4.40 (d, J = 6.6 Hz, 1H), 4.14 (d, J =12.7 Hz, 1H), 3.93 (dd, J = 11.5, 3.7 Hz, 1H), 3.71 (d, J=13.0 Hz, 2H), 3.60 -3.46 (m, 1H), 3.41 (d, J = 13.0 Hz, 2H), 3.23 (d, J = 11.8Hz, 1H). Example 84 [ka]

[0532] Synthesis of (S)-2,6-difluoro-4-(2-methylmorpholino)benzoic acid (84A): The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with (S)-2-methylmorpholine.

[0533] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((S)-2-methylmorpholino)benzamido)propanoic acid (84): The title compound was prepared according to the method proposed for the synthesis of compounds 16A and 16, starting with 84A. MS (m / z) 591.8 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 8.88 (d, J = 8.1 Hz, 1H), 8.85(dd, J = 4.2, 1.5 Hz, 1H), 8.65(d, J = 8.6 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H),7.91 (dd, J = 7.9, 1.6 Hz, 1H),7.69 - 7.55 (m, 4H), 6.62 (d, J = 11.9 Hz, 2H), 4.71 (t, J = 11.2 Hz, 1H), 3.87(dd, J =11.2,3.4 Hz, 1H), 3.71 (d, J = 12.4 Hz, 2H), 3.66 - 3.50 (m, 3H),3.44 (s, 1H), 2.70(td,J = 11.8, 3.6 Hz, 1H), 2.38 (dd, J = 12.3, 10.4 Hz,1H), 1.13 (d, J = 6.2Hz, 3H) . Example 85

[0534] Synthesis of (S)-2,6-difluoro-4-(2-methylmorpholino)benzoic acid (85A): The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with (S)-2-(trifluoromethyl)morpholine.

[0535] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((S)-2-(trifluoromethyl)morpholino)benzamido)propanoic acid (85): The title compound was prepared according to the method proposed for the synthesis of compounds 16A and 16, starting with 85A. MS (m / z) 645.1 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 8.93 (d, J = 8.1 Hz, 1H), 8.83(dd, J =4.1, 1.6 Hz, 1H), 8.64(dd, J = 8.7, 1.7 Hz, 1H), 8.16 (d, J = 1.6 Hz,1H), 7.90(dd, J = 7.9, 1.7 Hz,1H), 7.67 - 7.57 (m, 3H), 7.56 (d, J = 7.9 Hz,1H), 6.75(d, J = 11.6 Hz, 2H),4.77 - 4.66 (m, 1H), 4.29 (dq, J = 6.7, 3.3 Hz,1H), 4.03 (dd, J = 10.9, 3.3Hz, 1H),3.86 (d, J = 12.2 Hz, 1H), 3.75 (m, 1H),3.69 (t, J = 10.4 Hz, 2H),3.41 (s, 1H), 2.92 - 2.72 (m, 2H). [ka] Example 86 [ka]

[0536] Synthesis of (R)-2,6-difluoro-4-((2,2,2-trifluoro-1-phenylethyl)amino)benzoic acid (86A): The title compound was prepared starting with (R)-2,2,2-trifluoro-1-phenylethan-1-amine according to the method presented for the synthesis of compound 75A.

[0537] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(((R)-2,2,2-trifluoro-1-phenylethyl)amino)benzamido)propanoic acid (86): The title compound was prepared according to the method proposed for the synthesis of compounds 16A and 16, starting with 86A. MS (m / z) 665.2 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 8.85 - 8.77 (m, 2H), 8.61 (dd, J = 8.8, 1.7 Hz, 1H), 8.15 (dd, J =1.6, 0.4 Hz, 1H), 7.89 (dd, J = 7.9, 1.6 Hz,1H), 7.66 -7.48 (m, 7H), 7.46 -7.32 (m, 3H), 6.53 (d, J = 11.6 Hz, 2H), 5.67(q, J = 8.7Hz, 1H), 4.64 (d, J =11.6 Hz, 1H), 3.71 (s, 1H), 3.37 (s, 1H). Example 87 [ka]

[0538] Synthesis of (R)-2,6-difluoro-4-(methyl(1,1,1-trifluoropropan-2-yl)amino)benzoic acid (87A): The title compound was prepared starting from (R)-1,1,1-trifluoro-N-methylpropan-2-amine according to the method presented for the synthesis of compound 75A.

[0539] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(methyl((R)-1,1,1-trifluoropropan-2-yl)amino)benzamido)propanoic acid (87): The title compound was prepared according to the method proposed for the synthesis of compounds 16A and 16, starting with 87A. MS (m / z) 617.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 8.92 - 8.81 (m, 2H), 8.65 (dd, J =8.7,1.7 Hz, 1H), 8.16 (dd,J = 1.7, 0.4 Hz, 1H), 7.90 (dd, J = 7.9, 1.6 Hz,1H),7.68 - 7.53 (m, 4H), 6.63(d, J = 12.0 Hz, 2H), 4.93 (p, J = 7.4 Hz, 1H), 4.70(s, 1H), 3.74 (s, 1H),3.41 (s, 1H), 2.83 - 2.77 (m, 3H), 1.36 (d, J = 6.8 Hz, 3H). Example 88 [ka]

[0540] Synthesis of 2,6-difluoro-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)amino)benzoic acid (88A): The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with 1,1,1,3,3,3-hexafluoropropan-2-amine.

[0541] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)amino)benzamido)propanoic acid (88). The title compound was prepared from compounds 16A and 16B. Prepared according to the method proposed for the synthesis of 16 and 17, starting with 88A. MS (m / z) 657.1 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J = 8.0 Hz, 1H), 8.83 (dd, J = 4.1, 1.6 Hz, 1H), 8.66 -8.59 (m, 1H), 8.15 (d, J = 1.7 Hz, 1H), 7.90 (dd, J = 7.8, 1.6 Hz, 1H), 7.67 -7.53 (m, 5H), 6.69 (d, J = 11.1 Hz, 2H), 5.93 (s,1H),4.70 (s, 1H), 3.62 (s,1H), 3.40 (s, 1H). Example 89 [ka]

[0542] Synthesis of 4-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)-2,6-difluorobenzoic acid (89A): The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with 1-cyclopropyl-2,2,2-trifluoroethan-1-amine.

[0543] (2S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(4-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)-2,6-difluorobenzamido)propanoic acid (89): The title compound was prepared according to the method proposed for the synthesis of compounds 16A and 16, starting with 89A. MS (m / z) 629.2 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 8.86 - 8.75 (m, 2H), 8.63 (dd, J = 8.7, 1.6 Hz, 1H), 8.15 (dd, J =1.7, 0.4 Hz, 1H), 7.90 (dd, J = 7.9, 1.6 Hz,1H), 7.67 -7.53 (m, 4H), 6.93 (d,J = 9.5 Hz, 1H), 6.40 (d, J = 11.8 Hz, 2H),4.67 (s, 1H),3.91 (q, J = 8.1 Hz,1H), 3.72 (s, 1H), 3.40 (s, 1H), 1.08 - 0.96(m, 1H), 0.60 (dq, J = 8.5, 4.1,3.3 Hz, 1H), 0.49 (dd, J = 11.1, 5.8 Hz, 2H), 0.34 - 0.23 (m, 1H). Example 90 [ka]

[0544] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2- Preparation of (2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)propanoic acid (90): 89 was separated into its two stereoisomers by supercritical fluid chromatography using an IE 5 μm 21×250 mm column with 30% EtOH / TFA cosolvent at a flow rate of 45 mL / min. The title compound was identified as the first eluting peak. MS (m / z) 629.2 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 8.86 - 8.75 (m, 2H), 8.66 - 8.59 (m, 1H), 8.15 (dd, J = 1.7, 0.4 Hz,1H),7.90(dd, J = 7.9, 1.7 Hz, 1H), 7.67 - 7.49 (m, 4H), 6.92 (d, J = 9.5 Hz,1H),6.40(d, J = 11.8 Hz, 2H), 4.67 (s, 1H), 3.91 (d, J = 7.8 Hz, 1H), 3.72(s, 1H), 3.39(s,1H), 1.08 - 1.00 (m, 1H), 0.66 - 0.56 (m, 1H), 0.53 - 0.42(m, 2H), 0.33 -0.26(m, 1H). Example 91 [ka]

[0545] Synthesis of (S)-methyl 3-(8-bromoquinolin-5-yl)-2-(tritylamino)propanoate (91A): To a stirred solution of 1D (15 g, 43.4 mmol) in DCM was added TEA (15.12 mL, 108.5 mmol) and trityl chloride (12.7 g, 45.57 mmol). The reaction mixture was stirred for 2 hours, then filtered through Celite and washed three times with EA. The filtrate was concentrated and purified by silica gel chromatography eluting with EA / hexane to give the title compound.

[0546] Synthesis of (S)-(5-(3-methoxy-3-oxo-2-(tritylamino)propyl)quinolin-8-yl)boronic acid (91B): The title compound was synthesized as described for the synthesis of compound 4B. This was prepared according to the method presented in

[2002] , starting with 91A.

[0547] Synthesis of (S)-methyl 3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)-2-(tritylamino)propanoate (91C): The title compound was prepared according to the method presented for the synthesis of compound 11A, starting with 91B and 3-iodo-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one.

[0548] Synthesis of (S)-methyl 2-amino-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoate (91D): To a stirred solution of 91C (0.3 g, 0.46 mmol) in DCM was added triethylsilane (0.064 g, 0.49 mmol) and TFA (0.18 mL, 2.0 mmol). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to provide the material, which was used without further purification.

[0549] (S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (91): The title compound was prepared according to the method proposed for the synthesis of compound 74, starting with 91D. MS (m / z) 671.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.84 - 8.70 (m, 2H), 8.62 (s,1H), 7.55 (s, 2H), 7.42 (s, 1H), 6.75(dd, J = 9.4, 5.5 Hz, 1H), 6.54 (s, 1H), 6.42 (dd, J = 11.4, 4.2 Hz, 2H), 4.66(s,1H),4.29 (s, 1H), 3.66 (d, J = 13.6 Hz, 1H), 3.59 - 3.21 (m, 5H), 2.51 (s,2H),1.79- 1.70 (m, 1H), 1.51 (ddd, J = 13.7, 10.4, 7.1 Hz, 1H), 0.91 (t, J =7.3 Hz, 3H). Example 92

[0550] Synthesis of 2-chloro-4-methoxy-3-(trifluoromethyl)pyridine (92A): To a stirred solution of 2,4-dichloro-3-(trifluoromethyl)pyridine (157.5 mg, 0.729 mmol) in methanol at 0° C. was added powdered sodium methoxide (118.19 mg, 2.188 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography using EA in hexane as the eluent to give the title compound.

[0551] Synthesis of methyl (S)-2-amino-3-(8-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoate (92B): The title compound was prepared starting with 92A according to the method presented for the synthesis of compounds 91C and 91D.

[0552] (S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoic acid (92): The title compound was prepared according to the method proposed for the synthesis of compound 74, starting with 92B. MS (m / z) 657.8 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 8.80 (d, J = 8.9 Hz, 2H), 8.73(d, J =5.9 Hz, 1H), 8.62 (t, J= 7.9 Hz, 1H), 7.60 (t, J = 6.8 Hz, 3H), 7.44(d, J = 6.0Hz, 1H), 6.76 (t, J =8.2 Hz, 1H), 6.45 (dd, J = 11.7, 7.2 Hz, 2H),4.68 (d, J =19.6 Hz, 1H), 4.30(s, 1H), 4.07 (s, 3H), 3.74 (d, J = 15.1Hz,1H), 3.69 - 3.64 (m, 1H), 1.77 (s,1H), 1.53 (s, 1H), 0.93 (t, J = 7.4 Hz, 3H). [ka] Example 93 [ka]

[0553] Synthesis of (R)-2,6-difluoro-4-(3-(trifluoromethyl)morpholino)benzoic acid (93A): The title compound was prepared according to the method presented for the synthesis of compound 75A, starting with (R)-3-(trifluoromethyl)morpholine.

[0554] (S)-2-(2,6-Difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoic acid (93): The title compound was prepared according to the method proposed for the synthesis of compounds 16A and 16, starting with 92B and 93A. MS (m / z) 685.9 [M+H]. 1H NMR (500 MHz, DMSO-d6) δ 8.95 (dd, J = 11.7, 8.0 Hz, 1H), 8.80 (d, J = 3.7 Hz, 1H), 8.74 (d,J = 6.0 Hz, 1H), 8.63 (t, J =8.7Hz, 1H), 7.61 (dd, J = 13.0, 5.4 Hz, 3H),7.46 (d, J = 6.1 Hz, 1H), 6.76 (t,J =11.2 Hz, 2H), 4.91 (d, J = 9.3 Hz, 1H),4.77 - 4.64 (m, 1H), 4.19 - 4.13 (m,1H),4.08 (s, 3H), 3.95 (d, J = 11.7 Hz,1H), 3.80 - 3.66 (m, 2H), 3.55 (t, J =11.8Hz, 1H), 3.51 - 3.36 (m, 2H), 3.23(t, J = 12.5 Hz, 1H). Example 94 [ka]

[0555] Synthesis of methyl (S)-3-(8-bromoquinolin-5-yl)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)propanoate (94A): The title compound was prepared according to the method presented for the synthesis of compound 16A in Example 16, starting with 93A.

[0556] Synthesis of (5-((S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-methoxy-3-oxopropyl)quinolin-8-yl)boronic acid (94B): The title compound was prepared starting with 94A according to the method presented for the synthesis of compound 4B.

[0557] (S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(5,6-dimethyl-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoic acid (94): The title compound was prepared according to the method proposed for the synthesis of compounds 11A and 11, starting with 94B and 2-chloro-5,6-dimethyl-3-(trifluoromethyl)pyridine. MS (m / z) 683.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 8.96 (d, J = 8.0 Hz, 1H), 8.77 (dd, J = 4.0, 1.5 Hz, 1H), 8.67- 8.59 (m, 1H), 8.03 (s, 1H), 7.68 - 7.47 (m, 3H), 6.74 (d, J = 11.7 Hz, 2H),4.95 - 4.84 (m, 1H), 4.72 - 4.61 (m, 1H), 4.14 (d, J =12.8Hz, 1H), 3.98 -3.86 (m, 1H), 3.72 (d, J = 13.1 Hz, 2H), 3.58 - 3.30 (m,3H),3.21 (s, 1H),2.50 (s, 3H), 2.41 (s, 3H). Example 95 [ka]

[0558] (S)-2-(2,6-Difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1,4,6-trimethyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (95): The title compound was prepared according to the method proposed for the synthesis of compounds 11A and 11, starting with 94B and 3-chloro-1,4,6-trimethylpyridin-2(1H)-one. MS (m / z) 645.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 8.99 - 8.81 (m, 3H), 7.76 (s,1H), 7.65(dd, J = 13.5, 7.3 Hz,1H), 7.53 (t, J = 8.1 Hz, 1H), 6.72 (dd, J =11.5, 2.7 Hz, 2H), 6.20 (s, 1H),4.88 (d, J = 9.4 Hz, 1H), 4.74 - 4.69 (m, 1H),4.14 (d, J= 12.7 Hz, 1H), 3.93(dd, J = 11.5, 3.8 Hz, 1H), 3.79 (s, 1H), 3.70(t, J= 9.9Hz, 1H), 3.51 (d, J= 10.7 Hz, 2H), 3.46 - 3.34 (m, 4H), 3.21 (t, J= 12.3 Hz, 1H), 2.40 (s, 3H),1.73 (d, J = 10.6 Hz, 3H). Example 96 [ka]

[0559] (S)-2-(2,6-Difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (96): The title compound was prepared according to the method proposed for the synthesis of compounds 11A and 11, starting with 94B and 3-iodo-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one. MS (m / z) 699.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 8.96 (dd, J = 7.9, 4.2 Hz, 1H),8.86 -8.79 (m, 1H), 8.67 (s,1H), 7.60 (dt, J = 25.1, 8.5 Hz, 2H), 7.48 - 7.39(m, 1H),6.74 (dd, J = 11.6,4.3 Hz, 2H), 6.54 (s, 1H), 4.90 (dd, J = 8.7, 3.6Hz, 1H),4.72 - 4.63 (m, 1H),4.14 (d, J = 12.7 Hz, 1H), 3.93 (dd, J = 11.5, 3.8 Hz,1H), 3.75 - 3.62 (m,2H), 3.60 -3.32 (m, 6H), 3.23 (d, J = 12.4 Hz, 1H), 2.52 (s, 3H). Example 97 [ka]

[0560] (S)-2-(2,6-Difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(4,5-dimethylpyrimidin-2-yl)quinolin-5-yl)propanoic acid (97): The title compound was prepared according to the method proposed for the synthesis of compounds 11A and 11, starting with 94B and 2-chloro-4,5-dimethylpyrimidine. MS (m / z) 617.0 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 9.37 (s, 1H), 9.31 (s, 1H), 8.94 (d, J = 8.3 Hz, 1H), 8.78 (s, 2H), 8.11 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 6.77 (dd, J = 37.8, 12.3 Hz, 2H),4.97 - 4.75 (m, 2H), 4.16(dd,J = 12.9, 8.0 Hz, 1H), 3.91 (ddd, J = 25.2,12.9, 4.2 Hz, 2H), 3.72 (d, J =13.1Hz, 1H), 3.59-3.53 (m, 2H),3.41-3.36 (m,1H), 3.22 (dd, J = 14.4, 11.1 Hz,1H), 2.66 (s, 3H), 2.39 (s, 3H). Example 98

[0561] (S)-2-(2,6-Difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (98): The title compound was prepared according to the method proposed for the synthesis of compounds 11A and 11, starting with 94B and 3-bromo-1-methyl-5-(trifluoromethyl)pyridin-2(1H)-one. MS (m / z) 685.2 [M+H]+. 1H NMR (400 MHz,DMSO-d6) δ 12.96 (s, 1H), 8.96 (d, J = 8.0Hz, 1H),8.89 (d, J = 4.2 Hz, 1H),8.71 (d, J = 8.6 Hz, 1H), 8.50 (s, 1H), 7.73- 7.64 (m,3H), 7.61 (d, J = 7.3Hz, 1H), 6.76 (d, J = 11.8 Hz, 2H), 4.91 (d, J= 9.7 Hz, 1H), 4.68 (s, 1H),4.16 (d, J = 12.7 Hz, 1H),3.95 (d, J = 11.4 Hz,1H), 3.73 (d, J = 13.4 Hz,2H), 3.57 (s, 4H), 3.44 (dd, J = 14.0, 9.3 Hz, 2H), 3.24 (t, J = 12.5 Hz, 1H). [ka] Example 99 [ka]

[0562] (S)-2-(2,6-Difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(4-methoxy-6-methylpyrimidin-2-yl)quinolin-5-yl)propanoic acid (99): The title compound was prepared according to the method proposed for the synthesis of compounds 11A and 11, starting with 94B and 2-chloro-4-methoxy-6-methylpyrimidine. MS (m / z) 632.2 [M+H]. 1H NMR (400MHz, DMSO-d6) δ 9.49 (d, J = 4.9 Hz, 1H), 9.39(d, J =8.7 Hz, 1H), 9.04 (d, J= 7.5 Hz, 1H), 8.95 (d, J = 8.4 Hz, 1H), 8.18(dd, J =8.7, 5.0 Hz, 1H), 8.00(d, J = 7.8 Hz, 1H), 7.10 (s, 1H), 6.72 (d, J =12.2 Hz,2H), 4.94 - 4.78 (m,2H), 4.15 (s, 4H), 4.00 - 3.84 (m, 2H), 3.74 (t, J= 16.0Hz, 1H), 3.65 - 3.46(m, 2H), 3.39 (d, J = 12.8 Hz, 1H), 3.21 (t, J = 12.5 Hz, 1H), 2.70 (s, 3H). Example 100 [ka]

[0563] Synthesis of methyl (S)-2-amino-3-(8-(4-chloro-1,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoate (100A): The title compound was prepared according to the method proposed for the synthesis of compounds 91C and 91D, starting with 4-chloro-3-iodo-1,6-dimethylpyridin-2(1H)-one.

[0564] (S)-3-(8-(4-chloro-1,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)propanoic acid (100): The title compound was prepared according to the method proposed for the synthesis of compound 93, starting with 100A. MS (m / z) 665.7 [M+H]+. 1H NMR (400 MHz,DMSO-d6) δ 8.98 (d, J = 7.9 Hz, 1H), 8.87(d, J =4.3 Hz, 1H), 8.73 (s, 1H),7.67 (d, J = 9.1 Hz, 1H), 7.63 (dd, J = 7.6,4.2 Hz,1H), 7.54 (d, J = 7.3 Hz,1H), 6.76 (dd, J = 11.7, 3.9 Hz, 2H), 6.49 (d,J = 2.8Hz, 1H), 4.91 (dd, J =8.9, 3.6 Hz, 1H), 4.70 (dd, J = 12.5, 7.4 Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H),3.97 - 3.93 (m, 2H), 3.73 (dd, J = 12.0, 8.5 Hz, 2H), 3.52 (d, J = 22.8 Hz,1H), 3.45 (d,...

Claims

1. Formula (J): 【Chemical 310】 or a pharmaceutically acceptable salt thereof, wherein: L is selected from a bond, —O—, —O—C(O)—*, —NH—, —C(O)—N(H)—*, and —N(H)—C(O)—*; where * indicates the point of attachment of L to R 1 ; R 1 is selected from A 1 , A 2 , A 3 , and A 4 ; A 1 is a 5- to 10-membered heteroaryl containing 1 to 5 heteroatoms independently selected from S, N, and O; wherein A 1 optionally contains 1 to 3 C(O); and A 1 is optionally substituted with 1 to 6 R a ; A 2 is C 6-10 aryl optionally substituted with 1 to 6 R a ; A 3 is C 5-10 cycloalkyl or 5- to 14-membered heterocyclyl; where A 3 is optionally substituted with 1 to 4 groups independently selected from oxo and R a ; and A 4 is —NR a1 R a2 ; wherein each R a is independently selected from halo, cyano, hydroxyl, —NR a1 R a2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxyl, C 1-6 haloalkyl, C 1-6 haloalkoxyl, —S(O) m —C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 6-membered heterocyclyl, C 6-10 aryl, 5- to 6-membered heteroaryl, —O—C 3-8 cycloalkyl, —O—(3- to 6-membered heterocyclyl), —O—C 1-4 alkylene-C 3-8 cycloalkyl, and —O-phenyl; wherein each of R a 's C 3-8 cycloalkyl, 3- to 6-membered heterocyclyl, C 6-10 aryl, 5- to 6-membered heteroaryl, —O—C 3-8 cycloalkyl, —O—(3- to 6-membered heterocyclyl), —O—C 1-4 alkylene-C 3-8 cycloalkyl, and —O-phenyl is independently optionally substituted with 1 to 3 groups independently selected from halo, cyano, hydroxyl, —NR a1 R a2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, and C 1-6 haloalkoxyl; and wherein each of R a 's C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxyl, C 1-6 haloalkyl, C 1-6 haloalkoxyl, and —S(O) m —C 1-6 alkyl is optionally substituted with 1 to 3 R a3 , wherein each R a3 is independently selected from halo, cyano, hydroxyl, —NR a1 R a2 , C 1-6 alkoxyl, C 3-8 cycloalkyl, and 3- to 6-membered heterocyclyl; wherein each of the C 3-8 cycloalkyl and 3- to 6-membered heterocyclyl of R a3 is optionally substituted with 1 to 3 R a4 ; and each R a4 is independently selected from halo, cyano, hydroxyl, —NR a1 R a2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, C 3-8 cycloalkyl, and 3- to 6-membered heterocyclyl; R 2 , R 3 , R 4 , R 5 , and R 6 are each independently H, halo, cyano, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxyl, C 1-8 haloalkyl, C 1-8 haloalkoxyl, —NR b1 R b2 , —R b3 S(O) m R b4 , —S(O) m R b4 , —NR b1 S(O) n R b4 , —COOR b1 , —CONR b1 R b2 , —NR b1 COOR b2 , —NR b1 COR b4 , —R b3 NR b1 R b2 , —S(O) n NR b1 R b2 is selected from C 3-12 cycloalkyl, C 6-10 aryl, 5- to 6-membered heteroaryl, and 3- to 12-membered heterocyclyl; wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxyl, C 1-8 haloalkyl, and C 1-8 haloalkoxyl of R 2 , R 3 , R 4 , R 5 , and R 6 is optionally substituted with 1 to 2 R c ; and wherein each R c is independently selected from azido, oxo, cyano, halo, hydroxyl, —NR a1 R a2 , C 1-4 alkoxyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl; and wherein each of the C 3-8 cycloalkyl, C 6-10 aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl of R c is halo, cyano, hydroxyl, —NR a1 R a2 is optionally substituted with 1 to 3 groups independently selected from C 1-4 alkyl, C 1-6 haloalkyl, C 1-4 alkoxyl, and C 3-6 cycloalkyl; wherein each of the C 6-10 aryl and 5- to 6-membered heteroaryl of R 2 , R 3 , R 4 , R 5 , and R 6 is independently optionally substituted with 1 to 5 R b ; and wherein each of the C 3-12 cycloalkyl and 3- to 12-membered heterocyclyl of R 2 , R 3 , R 4 , R 5 , and R 6 is independently optionally substituted with 1 to 6 groups independently selected from ═CR b1 R b2 and R b ; wherein each R b is independently selected from azido, cyano, halo, hydroxyl, —NR a1 R a2 , C 1-6 alkyl, C 1-8 haloalkyl, C 1-6 alkoxyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl; and wherein each of the C 3-6 cycloalkyl, C 6-10 aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl of R b is independently optionally substituted with 1 to 3 groups independently selected from halo, cyano, hydroxyl, —NR a1 R a2 , C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxyl; wherein each of R b1 and R b2 is independently selected from H, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 6-membered heteroaryl, and 3- to 8-membered heterocyclyl; wherein each of the C 3-8 cycloalkyl, C 6-10 aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl of R b1 and R b2 is independently optionally substituted with 1 to 3 groups independently selected from halo, cyano, hydroxyl, —NR a1 R a2 , C 1-8 alkyl, C 1-8 haloalkyl, C 1-6 alkoxyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl; and wherein each of the C 1-8 alkyl and C 1-8 haloalkyl of R b1 and R b2 is optionally substituted with 1 to 2 R b5 ; wherein R b3 is C 1-4 alkylene; wherein R b4 is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl; and wherein each of the C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 6-membered heteroaryl, and the 4- to 6-membered heterocyclyl of R b4 is optionally substituted with 1 to 3 R b6 ; wherein each R b5 is independently selected from cyano, hydroxyl, C 1-4 alkoxyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl; and each of the C 1-4 alkoxyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl of R b5 is optionally substituted with 1 to 3 groups independently selected from halo, cyano, hydroxyl, —NR a1 R a2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyl, and phenyl; and wherein each R b6 is independently selected from halo, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyl, C 3-6 cycloalkyl, phenyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; wherein each of the C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl of R b6 is independently optionally substituted with 1 to 3 groups independently selected from halo, cyano, —NR a1 R a2 , C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxyl; or R 2 and R 3 , R 3 and R 4 , or R 5 and R 6 , together with the atoms to which they are attached, form a C 6-10 aryl, a 5- to 6-membered heteroaryl, a C 3-6 cycloalkyl, or a 5- to 6-membered heterocyclyl; wherein each of the C 6-10 aryl, the 5- to 6-membered heteroaryl, the C 3-6 cycloalkyl, and the 5- to 6-membered heterocyclyl is independently halo, cyano, —NR a1 R a2 , C 1-6 alkyl, C 1-6 alkoxyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3- to 6-membered heterocyclyl, C 6-10 aryl, 5- to 6-membered heteroaryl, C 1-4 alkylene-C 3-8 cycloalkyl, C 1-4 alkylene-C 6-10 aryl, and C 1-4 optionally substituted with 1 to 3 groups independently selected from alkylene-(5- to 6-membered heteroaryl); each of R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is independently selected from H, halo, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxyl, C 1-6 haloalkyl, C 1-6 haloalkoxyl, and —NR a1 R a2 ; R 13 is selected from H, C 1-4 alkyl, and C 1-4 haloalkyl; and R 15 is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, and -L 1 -R 16 ; wherein L 1 is —C 1-4 alkylene-; and wherein R 16 is selected from C 6-10 aryl, and 5- to 10-membered heteroaryl; wherein each of the C 6-10 aryl and 5- to 10-membered heteroaryl of R 15 and R 16 is optionally substituted with 1 to 4 groups independently selected from halo, hydroxyl, —COOR b7 , NR a1 R a2 , —S(O) 2 R a5 , C 1-4 alkyl, C 1-4 alkoxyl, C 1-4 haloalkyl, C 1-4 haloalkoxyl, and —C 1-4 alkylene-NR a1 R a2 ; each of R a1 and R a2 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; R a5 is C 1-6 alkyl; R b7 is independently selected from H and C 1-6 alkyl; m is selected from 0, 1, and 2; and n is selected from 1 and 2; The compound or a pharmaceutically acceptable salt thereof.

2. The compound represented by formula (Ja): 【Chemical 311】 where: Y 1 , Y 2 , Y 3 , and Y 4 are independently selected from CR y and N; wherein each R y is independently selected from H and R a ; and R z is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and 3- to 6-membered heterocyclyl; 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein the compound has the formula (Jd): 【Chemical 314】 where: R z is selected from H, —CH 3 , —CD 3 , —CH 2 F, —CHF 2 , —CF 3 , and —CH 2 CH 3 ; X 1 is selected from CR x1 and N; X 2 is selected from CR x1 R x2 , NR x2 , O, and S(O) 2 ; wherein R x1 is selected from H, and R b ; wherein R x2 is selected from H, C 1-4 alkyl, and C 1-4 haloalkyl; q is selected from 0, 1, 2, and 3; and r is selected from 0, 1, 2, and 3; 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

4. R 1 is 【Chemical 318】 2. The compound of claim 1 selected from:

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 5 are H.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 6 are each independently selected from F and —CH 3 .

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is F and R 6 is —CH 3 .

8. R 4 is substituted with 1 to 3 R b . 【Chemical 319】 2. The compound of claim 1, wherein:

9. R 4 is substituted with 1 to 3 R b . 【Chem.320】 where: each R b is independently selected from C 1-4 alkyl, C 1-4 alkoxyl, C 1-4 haloalkyl, and C 1-4 haloalkoxyl; 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

10. R 4 is a group substituted with —CF 3 . 【Chemistry 321】 2. The compound of claim 1, wherein:

11. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein Y 2 is N.

12. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein Y 4 is CH.

13. The compound according to claim 2 or 3, or a pharmaceutically acceptable salt thereof, wherein R z is —CH 3 .

14. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein X 1 is N.

15. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein X 2 is O.

16. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein q is 1 and R b is CF 3 .

17. R 15 is 【Chemical 323】 2. The compound of claim 1 selected from:

18. The compound of claim 17, 【Chemistry 18-1】 【Chemistry 18-2】 【Chemistry 18-3】 【Chemistry 18-4】 2. The compound of claim 1 selected from:

Images