Quinoline derivatives as alpha4beta7 integrin inhibitors

Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein. The invention also provides pharmaceutical compositions comprising a compound of formula (I), processes for the preparation of a compound of formula (I), and therapeutic methods for the treatment of inflammatory diseases. # imgabs0 #

Description

[0001] This application is a divisional application based on a patent application filed on October 29, 2019, with application number 201980071854.X (PCT / US2019 / 058573), and the invention name: "Quinoline derivatives as α4β7 integrin inhibitors".

[0002] Cross-reference to related applications

[0003] This application claims priority to U.S. Provisional Application No. 62 / 752,805, filed on October 30, 2018, and U.S. Provisional Application No. 62 / 823,987, filed on March 26, 2019, both of which are incorporated herein in their entirety for all purposes. Technical Field

[0004] The present invention generally relates to novel compounds with α4β7 integrin inhibitory effect, prodrugs of compounds with α4β7 integrin inhibitory effect, and methods of use and preparation thereof. Technical Background

[0005] Integrins are heterodimeric cell surface proteins involved in multiple cellular processes, including cell-cell and cell-extracellular matrix interactions. Upon binding to extracellular ligands, integrins mediate signal transduction into the cell interior, leading to lymphocyte recruitment, adhesion, and infiltration into tissues.

[0006] Integrins are heterodimeric proteins composed of α and β subunits. There are 18 known α subunits and 8 known β subunits. α4β7 integrin is expressed on the surface of lymphocytes and recognizes the extracellular ligand mucosal addressing cell adhesion molecule-1 (MAdCAM-1). α4β7 integrin controls lymphocyte migration to and retention in intestinal tissues through its interaction with MAdCAM-1, which is expressed on venules in the intestinal mucosa and high endothelial venules (HEVs) in the gut-associated lymphoid tissue (GALT). Inhibiting the interaction between integrins and their individual ligands has been proposed as an effective approach for treating various autoimmune and inflammatory diseases, and blocking the α4β7-MAdCAM-1 interaction has shown therapeutic benefit in inflammatory bowel diseases such as Crohn's disease and ulcerative colitis.

[0007] 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

[0008] The present invention provides compounds that are inhibitors of α4β7 integrin. The present invention also provides compositions (including pharmaceutical compositions), kits containing the compounds, and methods of using (or administering) and preparing the compounds. The compounds provided herein are used to treat diseases, disorders, or conditions mediated by α4β7 integrin. The present invention also provides compounds for use in therapy. The present invention also provides compounds for use in methods of treating diseases, disorders, or conditions mediated by α4β7 integrin. In addition, the present invention provides the use of compounds in the preparation of medicaments for treating diseases, disorders, or conditions mediated by α4β7 integrin.

[0009] In one aspect, provided is a compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof:

[0010]

[0011] L is selected from a bond, -O-, -OC(O)-*, -NH-, -C(O)-N(H)-*, and -N(H)-C(O)-*; wherein

[0012] *Indicates L to R 1 connection points;

[0013] R 1 Selected from A 1 、A 2 、A 3 and A 4 ;

[0014] A 1 is a 5-10 membered heteroaryl group containing one to five heteroatoms independently selected from S, N and O; wherein A 1 optionally containing one to three C(O); and wherein A 1 optionally substituted with one to six R a ;

[0015] A 2 C 6-10 Aryl, optionally substituted with one to six R a ;

[0016] A 3 C 5-10 Cycloalkyl or 5-14 membered heterocyclic group; wherein A 3 Optionally substituted with one to four independently selected from oxo and R a and

[0017] A 4 -NR a1 R a2 ;

[0018] Each of the Ra are independently selected from halogen, cyano, hydroxy, -NR a1 R a2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -S(O) m -C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -OC 3-8 Cycloalkyl, -O-(3-6 membered heterocyclic group), -OC 1-4 Alkylene-C 3-8 cycloalkyl and -O-phenyl;

[0019] where R a Every C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -OC 3-8 Cycloalkyl, -O-(3-6 membered heterocyclic group), -OC 1-4 Alkylene-C 3-8 Cycloalkyl and -O-phenyl are independently optionally substituted with one to three groups independently selected from the group consisting of halogen, cyano, hydroxy, -NR a1 R a2 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy;

[0020] and

[0021] where R a Every C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and -S(O) m -C 1-6 Alkyl is optionally substituted with one to three R a3 , where each R a3 are independently selected from halogen, cyano, hydroxy, -NR a1 R a2 、C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups;

[0022] where R a3 Every C 3-8 Cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with one to three R a4 ; and each R a4 are independently selected from halogen, cyano, hydroxy, -NR a1 R a2 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl and 3-6 membered heterocyclic group; each R 2 、R 3 、R 4 、R 5 and R 6 are independently selected from H, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-8 Halogenated alkyl, C 1-8 Haloalkoxy, -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 aryl, 5-6 membered heteroaryl and 3-12 membered heterocyclyl;

[0023] where R 2 、R 3 、R 4 、R 5 and R 6 Every C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-8 Haloalkyl and C 1-8 Haloalkoxy is optionally substituted with one to two R c ; Each of R c are independently selected from azido, oxo, cyano, halogen, hydroxyl, -NR a1 R a2 、C 1-4 Alkoxy, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclic group; wherein R c Every C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are optionally substituted with one to three groups independently selected from the group consisting of halogen, cyano, hydroxy, -NR a1 R a2 、C 1-4 Alkyl, C 1-6 Halogenated alkyl, C 1-4

[0024] Alkoxy and C 3-6 Cycloalkyl;

[0025] where R 2 、R 3 、R 4 、R 5 and R 6 Every C 6-10 Aryl and 5-6 membered heteroaryl are independently optionally substituted with one to five R b ;and

[0026] where R 2 、R 3 、R 4 、R 5 and R 6 Every C 3-12 Cycloalkyl and 3-12 membered heterocyclyl are independently optionally substituted with one to six groups independently selected from the following: =CR b1 R b2 and R b ;

[0027] Each of the R b are independently selected from azide, cyano, halogen, hydroxyl, -NR a1 R a2 、C 1-6 Alkyl, C 1-8 Halogenated alkyl, C 1-6 Alkoxy, C3-6 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclic group; wherein R b Every C 3-6 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are independently optionally substituted with one to three groups independently selected from the following: halogen, cyano, hydroxyl, -NR a1 R a2 、C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 alkoxy;

[0028] Each of the R b1 and R b2 Independently selected from H, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 3-8 membered heterocyclyl;

[0029] where R b1 and R b2 Every C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are independently optionally substituted with one to three groups independently selected from the following: halogen, cyano, hydroxyl, -NR a1 R a2 、C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl; and

[0030] where R b1 With R b2 Every C 1-8 Alkyl and C 1-8 Haloalkyl is optionally substituted with one to two R b5 ;

[0031] where R b3 C 1-4 alkylene;

[0032] where R b4 Selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclic group; wherein R b4Every C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are optionally substituted with one to three R b6 ;

[0033] Each of the R b5 Independently selected from cyano, hydroxy, C 1-4 Alkoxy, C 3-8 Cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl; and R b5 Every C 1-4 Alkoxy, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are optionally substituted with one to three groups independently selected from the group consisting of halogen, cyano, hydroxy, -NR a1 R a2 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 an alkoxy group and a phenyl group; and

[0034] Each of the R b6 independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, phenyl, 4-6 membered heterocyclic group and 5-6 membered heteroaryl; wherein R b6 Every C 3-6 Cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl are independently optionally substituted with one to three groups independently selected from the following: halogen, cyano, -NR a1 R a2 、C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 alkoxy; or

[0035] R 2 With R 3 、R 3 With R 4 , or R 5 With R 6 Together with the atoms it is bonded to, it forms C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl or 5-6 membered heterocyclic group; wherein each C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6The cycloalkyl and 5-6 membered heterocyclic groups are independently optionally substituted with one to three groups independently selected from the following groups: halogen, cyano, -NR a1 R a2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, C 1-4 Alkylene-C 3-8 Cycloalkyl, C 1-4 Alkylene-C 6-10 Aryl and C 1-4 Alkylene-(5-6 membered heteroaryl); each R 7 、R 8 、R 9 、R 10 、R 11 and R 12 independently selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and -NR a1 R a2 ;

[0036] R 13 Selected from H, C 1-4 Alkyl and C 1-4 haloalkyl; and

[0037] R 14 Selected from 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, 4-6 membered heterocyclic group and -C1-4 Alkylene-(4-6 membered heterocyclyl);

[0038] where R 14 Every C 3-8 Cycloalkyl, -C 1-4 Alkylene-C 3-8 Cycloalkyl, 4-6 membered heterocyclic group and -C 1-4 Alkylene-(4-6 membered heterocyclyl) is optionally substituted with one to three groups independently selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 haloalkyl; or

[0039] R 14 Combined with R 13 wherein the 5-membered heterocyclic group is optionally substituted with one to two groups independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 6-10 Aryl; wherein the C 6-10 Aryl is optionally substituted with one to three groups independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 alkyl halide;

[0040] Every R a1 and R a2 Independently selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0041] m is selected from 0, 1 and 2; and

[0042] n is selected from 1 and 2. Detailed Description of the Invention

[0043] Definitions and common parameters

[0044] The following description sets forth exemplary methods, parameters, etc. However, it should be recognized that this description is not intended to limit the scope of the invention, but is provided as a description of exemplary scenarios.

[0045] As used in this specification, the following words, phrases, and symbols are generally intended to have the meanings as set forth below, unless the context in which they are used dictates otherwise.

[0046] 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 via a carbon atom. A dash at the front or end of a chemical group is for convenience; a chemical group can be described with or without one or more dashes without losing its ordinary meaning. A wavy line passing through a line in a structure indicates the point of attachment of a group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality.

[0047] As shown below, for example chemical groups A curved line indicates a point of attachment, ie it shows a broken bond connecting the group to another described group.

[0048] The 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 1 to 8 carbon atoms.

[0049] As used herein, reference to "about" a value or parameter includes (and describes) embodiments relating to the value or parameter itself. In certain embodiments, the term "about" includes ±10% of the indicated amount. In other embodiments, the term "about" includes ±5% of the indicated amount. In certain other embodiments, the term "about" includes ±1% of the indicated amount. In addition, the term "about X" includes a description of "X". In addition, unless the context clearly indicates otherwise, the singular forms "a", "an" and "the" include plural references. Thus, for example, reference to a "compound" includes plural such compounds, and reference to an "assay" includes reference to one or more assays known to those skilled in the art and their equivalents.

[0050] "Alkyl" refers to a branched or straight saturated hydrocarbon chain. As used herein, an alkyl group has 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, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbon atoms is designated by chemical name or identified by molecular formula, all positional isomers having that number of carbon atoms are 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).

[0051] "Alkylene" (including those that are part of other groups) refers to branched and unbranched divalent "alkyl" groups. As used herein, alkylene has 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 (ie C 1-4 Alkylene). Examples include: methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, or 1,2-dimethylethylene. Unless otherwise stated, the definitions propylene and butylene include all possible isomeric forms of the group in question having the same number of carbon atoms. Thus, for example, propylene also includes 1-methylethylene, and butylene includes 1-methylpropylene, 1,1-dimethylethylene, and 1,2-dimethylethylene.

[0052] "Alkenyl" refers to a 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 (ie, C 2-8 alkenyl), 2 to 6 carbon atoms (ie, C 2-6 alkenyl) or 2 to 4 carbon atoms (ie C 2-4 Examples of the alkenyl group include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0053] "Alkynyl" refers to a 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 (ie, C 2-6 Alkynyl) or 2 to 4 carbon atoms (ie C 2-4 The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0054] "Alkoxy" refers to the radical "alkyl-O-." Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. "Haloalkoxy" refers to an alkoxy group as defined above in which one or more hydrogen atoms are replaced by a halogen.

[0055] "Acyl" refers to a group -C(=O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted (as defined herein). Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0056] "Aryl" refers to an aromatic carbocyclic radical having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, an aryl group has 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 anthracenyl. However, aryl does not in any way encompass or overlap with heteroaryl groups as defined below. If one or more aryl groups are fused to a heteroaryl ring, the resulting ring system is a heteroaryl group.

[0057] "Azide" refers to the group -N3.

[0058] "Cyano" refers to the radical -CN.

[0059] "Cycloalkyl" refers to a saturated or partially saturated cycloalkyl group having a single ring or multiple rings (including fused, bridged, and spiro ring systems). The term "cycloalkyl" includes cycloalkenyl groups (i.e., ring groups having at least one double bond). As used herein, a cycloalkyl group has 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 (ie C 3-6 Cycloalkyl). 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 ring and one non-aromatic ring, but do not include fully aromatic ring systems.

[0060] "Bridged" refers to ring fusions in which non-adjacent ring atoms are joined by a divalent substituent such as an alkylene or heteroalkylene group or a single heteroatom. Quinuclidinyl and adamantyl are examples of bridged systems.

[0061] The term "fused" refers to a ring that is bonded to an adjacent ring.

[0062] "Spirocyclic" refers to a ring substituent joined by two bonds at the same carbon atom. Examples of spirocyclic groups include 1,1-diethylcyclopentane, dimethyl-dioxane, and 4-benzyl-4-methylpiperidine, where the cyclopentane and piperidine, respectively, are spirocyclic substituents.

[0063] "Spirocyclic" also refers to a bicyclic moiety in which the two rings are linked by a single common atom. Spirocyclic compounds can be all carbocyclic or all heterocyclic. Examples of spirocyclic groups include 5-oxa-8-azaspiro[3.5]nonane, 7-oxa-4-azaspiro[2.5]octane, and 5λ- 2 -azaspiro[2.4]heptane.

[0064] "Halogen" or "halo" includes fluorine, chlorine, bromine and iodine. "Haloalkyl" refers to an unbranched or branched alkyl group as defined above in which one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two ("di") or three ("tri") halogen groups, which may, but need not be, identical halogens. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0065] As used herein, the term "heterocyclyl" or "heterocycle" refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic ring system having at least one heteroatom (i.e., at least one ring heteroatom selected from O, N, S, S(O), S(O)2, and N-oxide groups) in the ring. Unless otherwise indicated, a heterocyclyl group has 3 to about 20 ring atoms, such as 3 to 12 ring atoms, such as 3 to 10 ring atoms, such as 5 to 10 ring atoms, or such as 5 to 6 ring atoms. Thus, the term includes a single saturated or partially unsaturated ring (e.g., 3, 4, 5, 6, or 7-membered ring) having about 1 to 6 ring carbon atoms and about 1 to 3 ring heteroatoms (which are independently selected from O, N, S, S(O), S(O)2, and N-oxide groups on the ring). When valence requirements permit, the rings of multiple condensed ring (e.g., bicyclic heterocyclyl) systems may be connected to each other by fusion, spiro, and bridging bonds. Heterocycles include, but are not limited to, groups derived from azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, 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 ring and one non-aromatic ring, but excluding fully aromatic ring systems. Examples include dihydroquinolines, such as 3,4-dihydroquinoline; dihydroisoquinolines, such as 1,2-dihydroisoquinoline; dihydroimidazole; tetrahydroimidazole, etc.; dihydroindole; isoindole; isoindolinone (e.g., isoindolin-1-one); isatin; dihydrophthalazine; quinolinone; spiro[cyclopropane-1,1'-isoindolin]-3'-one, etc. Additional examples of heterocycles include, for example, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptyl, 3,6-diazabicyclo[3.1.1]heptyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonyl, and hexahydropyrazino[2,1-c][1,4]oxazinyl.

[0066] "Hydroxy" and "hydroxy" are used interchangeably and refer to -OH. "Oxo" refers to the group (=O) or (O). In cases where tautomeric forms of a compound exist, hydroxy and oxo are interchangeable.

[0067] "Heteroaryl" refers to an aromatic group, including groups having aromatic tautomers or resonance structures, single rings, multiple rings, or multiple fused rings, wherein at least one heteroatom in the ring, i.e., one or more ring heteroatoms, is independently selected from nitrogen, oxygen, and sulfur, wherein the nitrogen or sulfur may be oxidized. Thus, the term includes rings with one or more cyclic O, N, S, S(O), S(O)2, and N-oxide groups. The term includes rings with one or more cyclic C(O) groups. As used herein, heteroaryl includes 5 to 20 ring atoms (i.e., 5- to 20-membered heteroaryl), 5 to 12 ring atoms (i.e., 5- to 12-membered heteroaryl), or 5 to 10 ring atoms (i.e., 5- to 10-membered heteroaryl) and 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 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, pyridinyl, pyridazinyl, benzothiazolyl and pyrazolyl. Heteroaryl does not encompass or overlap with aryl as defined above.

[0068] "Sulfonyl" refers to the group -S(O)2R, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0069] Unless otherwise indicated, whenever a graphic representation of a group ends with a single-bonded nitrogen atom, the group represents an -NH group. Similarly, unless otherwise indicated, the presence of hydrogen atoms, where necessary to complete valency or provide stability, is implied and assumed, given the knowledge of those skilled in the art.

[0070] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" and divalent "aryl" may also be referred to as "alkylene" (alkylenyl) and "arylene" (arylenyl), respectively. In addition, unless otherwise expressly indicated, when a combination of groups is referred to herein as a moiety (e.g., arylalkyl), the last mentioned group includes the atom by which the moiety is attached to the rest of the molecule.

[0071] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. Additionally, the term "optionally substituted" means that any one or more hydrogen atoms on a designated atom or group may or may not be replaced by a moiety other than hydrogen.

[0072] The term "substituted" means that any one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents other than hydrogen, 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, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halogen, haloalkyl, assorted alkyl, heteroaryl, heterocyclic radical, hydroxyl, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate (thiocyanate), mercaptan, thioketone, or a combination thereof. It is not intended herein to include polymers or similar infinite structures obtained by defining substituents with other substituents (for example, substituted aryl with substituted alkyl, the substituted alkyl itself is substituted with substituted aryl, the substituted aryl is further substituted with substituted assorted alkyl, etc.) appended indefinitely. Unless otherwise noted, the maximum number of continuous substitutions of compounds described herein is three. For example, the aryl substituted by two other substituted aryl groups is limited to the aryl substituted by ((substituted aryl) substituted aryl). Similarly, the above definition is not intended to include substitution patterns that are not allowed (for example, methyl substituted with 5 fluorines or heteroaryl with two adjacent oxygen ring atoms). Such substitution patterns that are not allowed are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" can describe other chemical groups defined herein. For example, the term "substituted aryl" includes, but is not limited to "alkyl aryl". Unless otherwise specified, when a group is described as optionally substituted, any substituent of the group itself is unsubstituted.

[0073] In some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more of the following substituents, including hydroxy, halogen, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In additional embodiments, "substituted cycloalkyl" refers to a cycloalkyl group having one or more of the following substituents, including alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, halogen, oxo, and hydroxy; "substituted heterocyclyl" refers to a heterocyclyl group having one or more of the following substituents, including alkyl, haloalkyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halogen, oxo, and hydroxy; "substituted aryl" refers to a heterocyclyl group having one or more of the following substituents, including alkyl, haloalkyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halogen, oxo, and hydroxy; "substituted heteroaryl" refers to a heteroaryl group having one or more of the following substituents: halogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano; "substituted heteroaryl" refers to a heteroaryl group having one or more of the following substituents: halogen, alkyl, haloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano; and "substituted sulfonyl" refers to the group -S(O)2R, wherein R is substituted with one or more of the following substituents: alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halogen, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halogen, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0074] Some of the compounds exist in the form of tautomers. Tautomers are in equilibrium with each other. For example, amide-containing compounds can exist in equilibrium with imidic acid tautomers. No matter which tautomer is displayed, and no matter how the equilibrium properties between the tautomers are, those skilled in the art will interpret the compound as comprising both amide and imidic acid tautomers. Therefore, amide-containing compounds should be interpreted as including their imidic acid tautomers. Similarly, imidic acid-containing compounds should be interpreted as including their amide tautomers.

[0075] Any formula or structure given herein is also intended to represent unlabeled forms of the compound as well as isotopically labeled forms. Isotopically labeled compounds have structures depicted by the formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, 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 invention are, for example, compounds wherein a radioactive isotope (e.g. 3 H. 13 C and 14 C). These isotopically labeled compounds can be used in metabolism studies; reaction 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 analysis; or radiotherapy for patients.

[0076] The present invention also includes compounds of the present invention in which 1 to n hydrogens attached to carbon atoms are replaced by deuterium, where n is the number of hydrogens in the molecule. These compounds exhibit increased metabolic resistance and, therefore, can be used to increase the half-life of any compound of the present invention when administered to mammals (especially humans). See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci. 5(12): 524-527 (1984). These compounds are synthesized by methods known in the art, for example, by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0077] Deuterium-labeled or substituted therapeutic compounds of the present invention can have improved DMPK (drug metabolism and pharmacokinetics) properties, which are related to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes (such as deuterium) can obtain certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements and / or improvements in therapeutic index. 18 F-labeled compounds can be used in PET or SPECT studies. Isotopically labeled compounds of the present invention and their prodrugs can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below, by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents. It should be understood that deuterium in this context is considered a substituent of the compounds of the present invention.

[0078] The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. In the compounds of the present invention, any atom not explicitly designated as a specific isotope is intended to represent any stable isotope of that atom. Unless otherwise stated, when a position is explicitly designated as "H" or "hydrogen," it is understood that the position has hydrogen in its natural abundance isotopic composition. Thus, in the compounds of the present invention, any atom explicitly designated as deuterium (D) is intended to represent deuterium.

[0079] In many cases, the compounds of the present invention are capable of forming acid and / or base salts by virtue of the presence of amine and / or carboxyl groups or groups similar thereto.

[0080] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. By way of example only, salts derived from inorganic bases include 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, dienylamines, trialnylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, monocycloalkylamines, dicycloalkylamines, or tricycloalkylamines, monoarylamines, diarylamines, or triarylamines, or mixed amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0081] Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include salts of 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, and the like.

[0082] Salts (eg, TFA salts) can be converted to the free base / acid or other pharmaceutically acceptable salts.

[0083] 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, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any commonly used media or agents are incompatible with the active ingredient, their use in therapeutic compositions is contemplated. Supplementary active ingredients may also be incorporated into the compositions.

[0084] "Treatment" and "treatment" are approaches for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms produced by the disease or condition, and / or alleviating the extent of the disease or condition); b) slowing or curbing the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition (e.g., metastasis)); and / or c) alleviating the disease, i.e., causing clinical symptoms to subside (e.g., improving the disease state, providing partial or complete remission of the disease or condition, enhancing the effect of another drug, delaying disease progression, improving quality of life, and / or prolonging survival).

[0085] "Prevention" or "preventing" means any treatment of a disease or condition that prevents clinical symptoms of the disease or condition from developing. In some embodiments, the compound can be administered to a subject (including humans) at risk for the disease or condition or who has a family history of the disease or condition.

[0086] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation, or experiment. The methods described herein can be used for human treatment and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0087] The term "therapeutically effective amount" or "effective amount" of a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, means an amount sufficient to effect treatment to provide a therapeutic benefit (such as improvement in symptoms or slowing of disease progression) when administered to a subject. For example, a therapeutically effective amount can be an amount sufficient to reduce the symptoms of a disease or condition responsive to inhibition of α4β7 integrin activity. The therapeutically effective amount can vary depending on the subject and the disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the mode of administration, which can be readily determined by one skilled in the art.

[0088] The term "inhibit" indicates a decrease in the baseline activity of a biological activity or process. "Inhibit the activity of α4β7 integrin" or variants thereof refers to a decrease in the activity of α4β7 integrin in response to the presence of a compound of the present application, either directly or indirectly, relative to the activity of α4β7 integrin in the absence of a compound of the present application. "Inhibit α4β7" refers to a decrease in the activity of α4β7 integrin in response to the presence of a compound described herein, either directly or indirectly, relative to the activity of α4β7 integrin in the absence of a compound described herein. In some embodiments, the inhibition of α4β7 integrin activity can be compared to the same subject before treatment or to other subjects who have not received treatment.

[0089] Compound

[0090] Provided herein are compounds that function as α4β7 integrin inhibitors. In one aspect, provided are compounds having the structure of formula (I), or pharmaceutically acceptable salts thereof:

[0091]

[0092] 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 are as defined above.

[0093] In another aspect, there is provided a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0094]

[0095] L is selected from a bond, -O-, -OC(O)-*, -NH-, -C(O)-N(H)-*, and -N(H)-C(O)-*; wherein * indicates L to R 1 connection points;

[0096] R 1 Selected from A 1 、A 2 、A 3 and A 4 ;

[0097] A 1 is a 5-10 membered heteroaryl group containing one to five heteroatoms independently selected from S, N and O; wherein A1 optionally containing one to three C(O); and wherein A 1 Optionally replace

[0098] One to six R a ;

[0099] A 2 C 6-10 Aryl, optionally substituted with one to six R a ;and

[0100] A 3 C 5-10 Cycloalkyl or 5-14 membered heterocyclic group; wherein A 3 Optionally substituted with one to four independently selected from oxo and R a and

[0101] Each of the R a are independently selected from halogen, cyano, hydroxy, -NR a1 R a2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -S(O) m -C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -OC 3-8 Cycloalkyl, -O-(3-6 membered heterocyclic group), -OC 1-4 Alkylene-C 3-8 cycloalkyl and -O-phenyl;

[0102] where R a Every C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -OC 3-8 Cycloalkyl, -O-(3-6 membered heterocyclic group), -OC 1-4 Alkylene-C 3-8 Cycloalkyl and -O-phenyl are independently optionally substituted with one to three groups independently selected from the group consisting of halogen, cyano, hydroxy, -NR a1 R a2 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy;

[0103] and

[0104] where R a Every C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and -S(O) m -C 1-6 Alkyl is optionally substituted with one to three R a3 , where each R a3 are independently selected from halogen, cyano, hydroxy, -NR a1 R a2 、C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups;

[0105] where R a3 Every C 3-8 Cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with one to three R a4 ; and each R a4 are independently selected from halogen, cyano, hydroxy, -NR a1 R a2 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups;

[0106] Every R 2 、R 3 、R 4 、R 5 and R 6 are independently selected from H, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-8 Halogenated alkyl, C 1-8 Haloalkoxy, -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 、-CONRb1 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 aryl, 5-6 membered heteroaryl and 3-12 membered heterocyclyl;

[0107] where R 2 、R 3 、R 4 、R 5 and R 6 Every C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-8 Haloalkyl and C 1-8 Haloalkoxy is optionally substituted with one to two R c ; Each of R c are independently selected from azido, oxo, cyano, halogen, hydroxyl, -NR a1 R a2 、C 1-4 Alkoxy, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclic group; wherein R c Every C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are optionally substituted with one to three groups independently selected from the group consisting of halogen, cyano, hydroxy, -NR a1 R a2 、C 1-4 Alkyl, C 1-6 Halogenated alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl;

[0108] where R 2 、R 3 、R 4 、R 5 and R 6 Every C 6-10 Aryl and 5-6 membered heteroaryl are independently optionally substituted with one to five R b ;and

[0109] where R 2 、R 3 、R 4 、R 5 and R 6 Every C 3-12 Cycloalkyl and 3-12 membered heterocyclyl are independently optionally substituted with one to six groups independently selected from the following: =CR b1 R b2 and R b ;

[0110] Each of the R b are independently selected from azide, cyano, halogen, hydroxyl, -NR a1 R a2 、C 1-6 Alkyl, C 1-8 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclic group; wherein R b Every C 3-6 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are independently optionally substituted with one to three groups independently selected from the following: halogen, cyano, hydroxyl, -NR a1 R a2 、C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 alkoxy;

[0111] Each of the R b1 and R b2 Independently selected from H, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 3-8 membered heterocyclyl;

[0112] where R b1 and R b2 Every C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are independently optionally substituted with one to three groups independently selected from the following: halogen, cyano, hydroxyl, -NR a1 R a2 、C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-10aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl; and

[0113] where R b1 and R b2 Every C 1-8 Alkyl and C 1-8 Haloalkyl is optionally substituted with one to two R b5 ;

[0114] where R b3 C 1-4 alkylene;

[0115] where R b4 Selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclic group; wherein R b4 Every C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are optionally substituted with one to three R b6 ;

[0116] Each of the R b5 Independently selected from cyano, hydroxy, C 1-4 Alkoxy, C 3-8 Cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl; and R b5 Every C 1-4 Alkoxy, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are optionally substituted with one to three groups independently selected from the group consisting of halogen, cyano, hydroxy, -NR a1 R a2 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 an alkoxy group and a phenyl group; and

[0117] Each of the R b6 independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, phenyl, 4-6 membered heterocyclic group and 5-6 membered heteroaryl; wherein R b6 Every C 3-6Cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl are independently optionally substituted with one to three groups independently selected from the following: halogen, cyano, -NR a1 R a2 、C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 alkoxy; or

[0118] R 2 With R 3 、R 3 With R 4 , or R 5 With R 6 Together with the atoms it is bonded to, it forms C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl or 5-6 membered heterocyclic group; wherein each C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 The cycloalkyl and 5-6 membered heterocyclic groups are independently optionally substituted with one to three groups independently selected from the following groups: halogen, cyano, -NR a1 R a2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, C 1-4 Alkylene-C 3-8 Cycloalkyl, C 1-4 Alkylene-C 6-10 Aryl and C 1-4 Alkylene-(5-6 membered heteroaryl); each R 7 、R 8 、R 9 、R 10 and R 11 independently selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and -NR a1 R a2 ;

[0119] R 13 Selected from H, C 1-4 Alkyl and C 1-4 haloalkyl; and

[0120] R 14 Selected from H, C 1-6 Alkyl, -C 1-4 Alkylene-NRa1 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, 4-6 membered heterocyclic group and -C 1-4 Alkylene-(4-6 membered heterocyclyl);

[0121] where R 14 C 3-8 Cycloalkyl, -C 1-4 Alkylene-C 3-8 Cycloalkyl, 4-6 membered heterocyclic group and -C 1-4 Alkylene-(4-6 membered heterocyclyl) is optionally substituted with one to three groups independently selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 haloalkyl; or

[0122] R 14 Combined with R 13 wherein the 5-membered heterocyclic group is optionally substituted with one to two groups independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 6-10 Aryl; wherein the C 6-10 Aryl is optionally substituted with one to three groups independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 alkyl halide;

[0123] Every R a1 and R a2 Independently selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0124] m is selected from 0, 1 and 2; and

[0125] n is selected from 1 and 2.

[0126] In another aspect, there is provided a compound of formula (IIa) or a pharmaceutically acceptable salt thereof:

[0127]

[0128] where R 1 、R 2 、R 3 、R 5 、R 6 、R 14 、R b1 and R b2 As defined above in formula (I), (II) or elsewhere herein.

[0129] In another aspect, there is provided a compound of formula (IIb) or a pharmaceutically acceptable salt thereof:

[0130]

[0131] where R 1 、R 2 、R 3 、R 5 、R 6 、R 14 and R b As defined above in formula (I), (II) or elsewhere herein. 1 Selected from CR x1 and N; and X 2 Selected from CR x1 R x2 NR x2 , O and S(O)2. R x1 Selected from H and R b ; and R x2 Selected from H, C 1-4 Alkyl and C 1-4 haloalkyl. p is selected from the group consisting of 0, 1, and 2. q is selected from the group consisting of 0, 1, 2, 3, and 4.

[0132] In another aspect, provided is a compound of formula (IIc) or a pharmaceutically acceptable salt thereof:

[0133]

[0134] where R 1 、R 2 、R 3 、R 5 、R 6 、R 14 and R b4As defined above in formula (I), (II) or elsewhere herein.

[0135] In another aspect, provided is a compound of formula (IId) or a pharmaceutically acceptable salt thereof:

[0136]

[0137] Each Y 1 、Y 2 、Y 3 、Y 4 and Y 5 Independently selected from CR y and N. R y Selected from H and R a . R a 、R 2 、R 3 、R 4 、R 5 、R 6 and R 14 As defined above in formula (I), (II) or elsewhere herein.

[0138] In another aspect, provided is a compound of formula (IIe) or a pharmaceutically acceptable salt thereof:

[0139]

[0140] where R a 、R 2 、R 4 、R 6 and R 14 As defined above in formula (I), (II) or elsewhere herein. u is selected from the group consisting of 0, 1, 2, 3, 4 and 5.

[0141] In another aspect, provided is a compound of formula (IIf) or a pharmaceutically acceptable salt thereof:

[0142]

[0143] where R y Independently selected from H and R a . R a 、R 2 、R 4 、R 6 and R 14 As defined above in formula (I), (II) or elsewhere herein.

[0144] In another aspect, provided is a compound of formula (IIg) or a pharmaceutically acceptable salt thereof:

[0145]

[0146] where R a 、R 2 、R 3 、R 4 、R 5 、R 6 and R 14 As defined in formula (I), (II) or elsewhere herein. 3 、Y 4 and Y 5 As defined in formula (IId) or elsewhere herein. y Independently selected from H and R a .

[0147] In another aspect, provided is a compound of formula (IIh) or a pharmaceutically acceptable salt thereof:

[0148]

[0149] where R 2 、R 3 、R 4 、R 5 、R 6 and R 14 As defined in formula (I), (II) or elsewhere herein. y are independently as defined above in formula (IId) or elsewhere herein.

[0150] In another aspect, there is provided a compound of formula (IIi) or a pharmaceutically acceptable salt thereof:

[0151]

[0152] where R a 、R 2 、R 3 、R 4 、R 5 、R 6 and R 14 As defined above in formula (I), (II) or elsewhere herein. r is selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6.

[0153] 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)-*.

[0154] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1is selected from the group consisting of phenyl, naphthyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolyl, isoquinolyl, isoxazolyl, triazolyl, pyrazolyl, benzothiazolyl, pyridonyl, quinolinonyl, isoquinolinonyl, quinazolindione, pyrazinonyl, pyrimidonyl, pyrimidinedione, pyridazinonyl, quinazolinonyl, benzofuran, tetrahydrocyclopenta[b]pyridonyl, naphthyridinonyl, chromanyl, isochromanyl and chromenonyl. Each R 1 are independently optionally substituted with one to four R a In some embodiments, R 1 is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, quinolyl, isoxazolyl, pyridonyl, quinolinonyl, quinazolinedionyl, pyrazinonyl, pyrimidonyl, pyridazinonyl, quinazolinonyl, benzofuran and chromenone, and each R 1 are independently optionally substituted with one to four R a .

[0155] In some embodiments of Formula (I) or (II), "R 1 -L-" is selected from

[0156] Every “R 1 -L-" is optionally substituted with one to four R a In some embodiments, each R a Independently selected from halogen, cyano, hydroxy, NR a1 R a2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -OC 3-6 In some embodiments, each R a Independently selected from F, Cl, CN, OH, -NH2, -CH3, -CH2F, -CHF2, -CF3, -OCH3 and -OCF3.

[0157] In some embodiments of Formula (I) or (II), "R 1 -L-" is selected from

[0158] Every “R 1-L-" is optionally substituted with one to four R a In some embodiments, each R a Independently selected from halogen, cyano, hydroxy, NR a1 R a2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -OC 3-6 In some embodiments, each R a Independently selected from F, Cl, CN, OH, -NH2, -CH3, -CH2F, -CHF2, -CF3, -OCH3 and -OCF3.

[0159] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 Selected from Every R 1 Optionally substituted with one to four R a .

[0160] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 Selected from Every R 1 Optionally substituted with one to four R a .

[0161] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 Selected from Every R 1 Optionally substituted with one to four R a In some embodiments, each R a Independently selected from halogen, CN, -OH, NR a1 R a2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C3-6 Cycloalkyl, -OC 3-6 In some embodiments, each R a Independently selected from F, Cl, OH, CN, -NH2, -CH3, -CH2F, -CHF2, -CF3, -OCH3 and -OCF3.

[0162] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 Selected from Every R 1 Optionally substituted with one to four R a In some embodiments, each R a Independently selected from halogen, CN, -OH, NR a1 R a2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -OC 3-6 In some embodiments, each R a is independently selected from F, Cl, OH, CN, -NH2, -NH(CH3), -N(CH3)2, -CH3, -CH2F, -CHF2, -CF3, -OCH3, and -OCF3. In some embodiments, each R a Independently selected from F, Cl, -N(CH3)2, -CH3, -OCH3 and -CF3.

[0163] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 for which are optionally substituted with one to three R a In some embodiments, each R a In some embodiments, R 1 Substituted with -CH3.

[0164] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 Replaced with one to three R a , which are independently selected from halogen, CN, OH, NR a1 R a2 、C1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy and C 3-6 In some embodiments, each R a Independently selected from 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, -CH2OCH 3. -CH2OCH2CH3, -CH2OCH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -SO2CH3, -SO2CH2CH3, In some embodiments, each R a Independently selected from F, Cl, CN, -NH2, -CH3, -CH2F, -CHF2, -CF3, -OCH3, -CH2OCH2CH3 and -OCF3.

[0165] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 Selected from:

[0166]

[0167]

[0168] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 Selected from:

[0169]

[0170]

[0171] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 Selected from

[0172]

[0173]

[0174] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 Selected from

[0175]

[0176] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), R 1 Selected from:

[0177]

[0178] In some embodiments, R 1 for

[0179] In some embodiments of Formula (I), (II), (IIa), (IIb), or (IIc), “R 1 -L-" is -OC(O)-NR a1 R a2 In some embodiments, each R a1 With R a2 Independently selected from H and C 1-4 In some embodiments, each R a1 With R a2 is independently selected from H, CH3, -CH2CH3, -CH(CH3)2, and -C(CH3)3. In some embodiments, each R a1 With R a2 In some embodiments, R a1 With R a2 In some embodiments, "R 1 -L-" is -OC(O)-N(CH3)2.

[0180] In some embodiments of Formula (I) or (II), R 2 and R 3 Formation C 3-6 In some embodiments, the 5-6 membered heterocyclyl or 5-6 membered heteroaryl group contains one or two N. In some embodiments, C 3-6Cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl substituted with one or two groups independently selected from the following groups: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 1-4 In some embodiments, C 3-6 The cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is substituted with one or two groups independently selected from the group consisting of Cl, -CH3, cyclopropyl and -CH2-phenyl.

[0181] In some embodiments of Formula (I) or (II), R 3 and R 4 Formation C 3-6 In some embodiments, the 5-6 membered heterocyclyl or 5-6 membered heteroaryl group contains one or two N. In some embodiments, C 3-6 Cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl substituted with one or two groups independently selected from the following groups: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 1-4 In some embodiments, C 3-6 The cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is substituted with one or two groups independently selected from the group consisting of Cl, -CH3, cyclopropyl and -CH2-phenyl.

[0182] In some embodiments of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIg), (IIh), or (IIi), each R 2 、R 3 、R 4 、R 5 and R 6 Independently selected from H, halogen, CN, OH, -NR b1 R b2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 In some embodiments, each R 2 、R 3 、R 4 、R 5 and R 6 Independently selected from H, halogen, CN, OH, -NR b1 R b2 、C1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 In some embodiments, each R 2 、R 3 、R 4 、R 5 and R 6 is independently selected from H, F, Cl, CN, OH, -NH2, -N(CH3)2, -CH3, CD3, -CH2F, -CHF2, -CF3, -OCH3, and -OCF3. In some embodiments, each R 2 With R 6 Independently selected from H, halogen, CN, OH, -NR b1 R b2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 In some embodiments, each R 2 With R 6 is independently selected from F, Cl, CN, OH, -NH2, -N(CH3)2, -CH3, -CH2F, -CHF2, -CF3, -OCH3, and -OCF3. In some embodiments, R 2 With R 6 In some embodiments, R 6 In some embodiments, each R 3 With R 5 Independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and C 3-6 In some embodiments, each R 3 With R 5 Independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 In some embodiments, each R 3 With R 5 In some embodiments, R 3 With R 5 Both are H.

[0183] In some embodiments of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIg), (IIh), or (IIi), R 2 is F, and R 6 is -CH3.

[0184] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 Selected from H, -NR b1 R b2 、-NR b1 S(O) n R b4 and 3-8 membered heterocyclyl. In some embodiments, R 4 The 3-8 membered heterocyclic group contains one to two heteroatoms or groups independently selected from S, N, O and S(O)2.

[0185] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 -NR b1 R b2 In some embodiments, each R b1 With R b2 Independently selected from H, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-6 In some embodiments, the 3-8 membered heterocyclyl contains one to two atoms independently selected from N and O. In some embodiments, R b1 Selected from H, C 1-4 Alkyl and C 1-6 In some embodiments, R b1 In some embodiments, R b2 Selected from C 1-6 Alkyl, C 1-8 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 In some embodiments, R b2 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 In some embodiments, R b1 H and R b2 Selected from C 1-6 Alkyl, C 1-8 Halogenated alkyl, C 3-6In some embodiments, R b1 H and R b2 C 1-6 In some embodiments, R b2 -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 -C 1-5 Alkylene -CF3, substituted with one to two R b5 In some embodiments, each R b5 Independently selected from hydroxyl, C 1-4 Alkoxy, C 3-6 In some embodiments, each R b5 Independently selected from C 3-6 Cycloalkyl, 4-6 membered heterocyclic group and phenyl. b5 Every C 3-6 Cycloalkyl, 4-6 membered heterocyclyl and phenyl are independently optionally substituted with one to three groups independently selected from the following groups: halogen, hydroxy, cyano, -NR b1 R b2 、C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 In some embodiments, R b5 is selected from cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl, tetrahydrofuranyl and phenyl; and each R b5 is optionally substituted with a group selected from the group consisting of F, Cl, CN, -CH3, -CH2F, -CHF2, and -CF3. b5 In some embodiments, R b5 is phenyl substituted with one or two groups independently selected from the group consisting of F, Cl, CN, -CH3, -CH2F, -CHF2, and -CF3. b5 is phenyl, substituted with one or two groups independently selected from the group consisting of F, Cl, CN, and -CF3. b5 is an unsubstituted phenyl group.

[0186] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 Selected from

[0187] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 Selected from

[0188] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 for

[0189] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 is a 3-8 membered heterocyclic group, which is optionally substituted with one to three R b ; and each R b are independently selected from halogen, hydroxy, cyano, -NR a1 R a2 、C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 In some embodiments, each R 4 Optionally substituted with one to two groups independently selected from the group consisting of F, Cl, CN, -OH, -CH3, -CH(CH3)2, and -CF3.

[0190] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 is a 3-8 membered spirocyclic, fused or bridged heterocyclic group. 4 is selected from the group consisting of azetidinyl, aziridine, imidazolidinyl, morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrazolidinyl, piperidinyl, pyrrolidinyl, pyrrolidonyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydropyridinyl, tetrahydropyridinyl, 1,1-dioxide-thiomorpholinyl, and quinuclidinyl; and each R 4 Optionally substituted with one to three R b In some embodiments, R 4 is selected from morpholinyl, piperidinyl, tetrahydropyranyl and pyrrolidinyl; each R 4 Optionally substituted with one to three R b In some embodiments, each Rb are independently selected from halogen, hydroxy, cyano, -NR a1 R a2 、C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 In some embodiments, each R b Independently selected from F, Cl, CN, -OH, -CH3, -CH(CH3)2 and -CF3.

[0191] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 is a spirocyclic group, which is optionally substituted with one to three R b In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, each R b are independently selected from halogen, hydroxy, cyano, -NR a1 R a2 、C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 In some embodiments, each R b Independently selected from F, Cl, CN, -OH, -CH3, -CH(CH3)2 and -CF3.

[0192] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 is a fused or bridged heterocyclic group optionally substituted with one to three R b In some embodiments, each R 4 is independently selected from azabicyclo[3.1.0]hexanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.2.2]octanyl and oxa-azabicyclo[2.2.2]octanyl; each R 4 Optionally substituted with one to three R b . Every R b are independently selected from halogen, hydroxy, cyano, -NR a1 R a2 、C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 In some embodiments, each R bIndependently selected from F, Cl, CN, -OH, -CH3, -CH(CH3)2 and -CF3.

[0193] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 Selected from And each R 4 Optionally substituted with one to three groups independently selected from the group consisting of halogen, OH, CN, -NR a1 R a2 、C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkyl.

[0194] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 Selected from And each R 4 optionally substituted with one to three groups independently selected from the group consisting of F, Cl, OH, CN, NH2, -CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, C 3-6 Cycloalkyl and -CH2C 3-6 Cycloalkyl.

[0195] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 Selected from

[0196] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 Selected from

[0197]

[0198] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 Selected from

[0199] In some embodiments, R 4 for

[0200] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 -NHS(O)2R b4 In some embodiments, R b4 Selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 In some embodiments, R b4 In some embodiments, the phenyl group is optionally substituted with a pyridyl group, which is optionally substituted with one or two groups independently selected from the group consisting of halogen and C 1-4 In some embodiments, the pyridyl group is optionally substituted with one or two groups independently selected from the group consisting of F and -CH3.

[0201] In some embodiments of Formula (I), (II), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 4 Selected from

[0202] In some embodiments of Formula (IIb), X 1 is CH or N. In some embodiments, X 1 is N. In some embodiments, X 2 Selected from CH2, NR x2 , O and S(O) 2. In some embodiments, X 1 is N and X 2 Is O. In some embodiments, X 1 is N and X 2 In some embodiments, X 1 is N and X 2 is S(O)2. In some embodiments, each R bIndependently selected from F, OH, -CH3, -CH(CH3)2, -CH2F, -CHF2 and -CF3.

[0203] 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.

[0204] In some embodiments of Formula (IId), Y 1 、Y 2 、Y 3 、Y 4 and Y 5 CR y In some embodiments, Y 1 、Y 2 、Y 3 、Y 4 and Y 5 At least one of is N. In some embodiments, Y 1 is N; and Y 2 、Y 3 、Y 4 and Y 5 CR y In some embodiments, Y 2 is N; and Y 1 、Y 3 、Y 4 and Y 5 CR y In some embodiments, Y 3 is N; and Y 1 、Y 2 、Y 4 and Y 5 CR y In some embodiments, Y 1 and Y 5 is N; and Y 1 、Y 2 and Y 3 CR y .

[0205] In some embodiments of Formula (IId), (IIf), (IIg), or (IIh), each R y Independently selected from H, halogen, hydroxy, CN, -NR a1 R a2 、C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 In some embodiments, each R yIndependently selected from 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, -CH2OC H3, -CH2OCH2CH3, -CH2OCH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -SO2CH3, -SO2CH2CH3, In some embodiments, each R y is independently selected from H, F, Cl, OH, CN, -NH2, -CH3, -CH2F, -CHF2, -CF3, -OCH3, -CH2OCH2CH3 and -OCF3. In some embodiments, each R y Independently selected from H, F, -CH3, -CH2F, -CHF2, -CF3, -OCH3, -CH2OCH2CH3 and -OCF3.

[0206] In some embodiments of Formula (IIe), u is selected from 1, 2, and 3. In some embodiments, u is 3.

[0207] In some embodiments of Formula (IIg), Y 3 、Y 4 and Y 5 Independently selected from CR y and N; where R y Selected from H and R a In some embodiments, Y 3 is N; and Y 4 and Y 5 CR y In some embodiments, Y 5 is N; and Y 3 and Y 4 CR y In some embodiments, each R yis independently selected from H, F, Cl, CN, -NH2, -N(CH3)2, -CH3, -CH2F, -CHF2, -CF3, and -OCH3. In some embodiments, each R x1 Independently selected from H, F, Cl, -NH2, -N(CH3)2, -CH3, -CF3, -OCH3 and -OCF3.

[0208] In some embodiments of Formula (IIi), r is selected from 1, 2, and 3. In some embodiments, r is 3.

[0209] In some embodiments of Formula (I) or (II), each R 7 、R 8 、R 9 、R 10 and R 11 is independently selected from H, F, Cl, CN, -NH2, -N(CH3)2, -CH3, -CH2F, -CHF2, -CF3, -OCH3, and -OCF3. In some embodiments, each R 7 、R 8 、R 9 、R 10 and R 11 is selected from the group consisting of H, F, CN, -N(CH3)2, -CH3, and -CF3. In some embodiments, each R 7 to R 11 is selected from H, F and -N(CH3)2. In some embodiments, R 7 to R 11 is H. In some embodiments, R 7 is selected from the group consisting of H, F, CN, -N(CH3)2, -CH3 and -CF3. In some embodiments, R 7 is F. In some embodiments, R 8 is selected from the group consisting of H, F, CN, -N(CH3)2, -CH3 and -CF3. In some embodiments, R 8 is F. In some embodiments, R 10 is selected from the group consisting of H, F, CN, -N(CH3)2, -CH3 and -CF3. In some embodiments, R 10 is F or -N(CH3)2. In some embodiments, R 11 is -CH3.

[0210] In some embodiments of Formula (I), R 12 is H. In some embodiments, R 12 is -CH3.

[0211] In some embodiments of Formula (I), R 13is H. In some embodiments, R 13 is -CH3.

[0212] In some embodiments of Formula (I), each R 7 、R 8 、R 9 、R 10 、R 11 、R 12 and R 13 For H.

[0213] In some embodiments of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 14 Selected from C 1-6 Alkyl, C 3-8 In some embodiments, R 14 Every C 3-8 Cycloalkyl and 4-6 membered heterocyclyl are optionally substituted with one to three groups independently selected from the following groups: halogen, C 1-4 Alkyl and C 1-4 In some embodiments, R 14 Selected from -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 ester produces an alkyl group wherein R 14 It is the active ingredient of hydrogen.

[0214] In some embodiments of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), or (IIi), R 14selected from 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, In some embodiments, R 14 Selected from H, -CH2-OC(O)C(CH)3, -CH(CH3)-OC(O)-O-CH3,

[0215] In some embodiments, R 14 Combined with R 13 In some embodiments, the 5-membered heterocyclic group is substituted with one or two independently selected groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 6-10 In some embodiments, the 5-membered heterocyclic group is substituted with one to two groups independently selected from the following groups: CH3, CH2CH3, -OCH3, -OCH2CH3 and phenyl. In some embodiments, the 5-membered heterocyclic group is substituted with phenyl, and the phenyl group is optionally substituted with one to three groups independently selected from the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl.

[0216] In some embodiments, R 14 For H.

[0217] In some embodiments, R 14 is CH3 or CH2CH3. In some embodiments, R 14 is CH3. In some embodiments, R 14 It is CH2CH3.

[0218] In some embodiments, the compound of the present invention is selected from Examples 1-354.

[0219] In some embodiments, the compound of the present invention is selected from Examples 355-406. In some embodiments, the compound of the present invention is selected from Examples 407-496.

[0220] In some embodiments, the compound of the present invention is selected from:

[0221]

[0222]

[0223] In another aspect, provided is a compound of formula (J) or a pharmaceutically acceptable salt thereof:

[0224]

[0225] in:

[0226] L is selected from a bond, -O-, -OC(O)-*, -NH-, -C(O)-N(H)-*, and -N(H)-C(O)-*; wherein * indicates L to R 1 connection points;

[0227] R 1 Selected from A 1 、A 2 、A 3 and A 4 ;

[0228] A 1 is a 5-10 membered heteroaryl group containing one to five heteroatoms independently selected from S, N and O; wherein A 1 optionally containing one to three C(O); and wherein A 1 Optionally replace

[0229] One to six R a ;

[0230] A 2 C 6-10 Aryl, optionally substituted with one to six R a ;

[0231] A 3 C 5-10 Cycloalkyl or 5-14 membered heterocyclic group; wherein A 3 Optionally substituted with one to four independently selected from oxo and R a and

[0232] A 4 -NR a1 R a2 ;

[0233] Each of the R a are independently selected from halogen, cyano, hydroxy, -NR a1 R a2 、C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -S(O) m -C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -OC 3-8 Cycloalkyl, -O-(3-6 membered heterocyclic group), -OC 1-4 Alkylene-C 3-8 cycloalkyl and -O-phenyl;

[0234] where R a Every C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -OC 3-8 Cycloalkyl, -O-(3-6 membered heterocyclic group), -OC 1-4 Alkylene-C 3-8 Cycloalkyl and -O-phenyl are independently optionally substituted with one to three groups independently selected from the group consisting of halogen, cyano, hydroxy, -NR a1 R a2 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy;

[0235] and

[0236] where R a Every C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and -S(O) m -C 1-6 Alkyl is optionally substituted with one to three R a3 , where each R a3 are independently selected from halogen, cyano, hydroxy, -NR a1 R a2 、C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups;

[0237] where R a3 Every C 3-8Cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with one to three R a4 ; and each R a4 independently selected from halogen,

[0238] Cyano, hydroxy, -NR a1 R a2 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups;

[0239] Every R 2 、R 3 、R 4 、R 5 and R 6 are independently selected from H, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-8 Halogenated alkyl, C 1-8 Haloalkoxy, -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 aryl, 5-6 membered heteroaryl and 3-12 membered heterocyclyl;

[0240] where R 2 、R 3 、R 4 、R 5 and R 6 Every C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-8 Haloalkyl and C 1-8 Haloalkoxy is optionally substituted with one to two R c ; Each of R c are independently selected from azido, oxo, cyano, halogen, hydroxyl, -NR a1 R a2 、C 1-4 Alkoxy, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclic group; wherein R c Every C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are optionally substituted with one to three groups independently selected from the group consisting of halogen, cyano, hydroxy, -NR a1 R a2 、C 1-4 Alkyl, C 1-6 Halogenated alkyl, C 1-4

[0241] Alkoxy and C 3-6 Cycloalkyl;

[0242] where R 2 、R 3 、R 4 、R 5 and R 6 Every C 6-10 Aryl and 5-6 membered heteroaryl are independently optionally substituted with one to five R b ;and

[0243] where R 2 、R 3 、R 4 、R 5 and R 6 Every C 3-12 Cycloalkyl and 3-12 membered heterocyclyl are independently optionally substituted with one to six groups independently selected from the following: =CR b1 R b2 and R b ;

[0244] Each of the R b are independently selected from azide, cyano, halogen, hydroxyl, -NR a1 R a2 、C 1-6 Alkyl, C 1-8 Halogenated alkyl, C 1-6 Alkoxy, C3-6 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclic group; wherein R b Every C 3-6 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are independently optionally substituted with one to three groups independently selected from the following: halogen, cyano, hydroxyl, -NR a1 R a2 、C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 alkoxy;

[0245] Each of the R b1 With R b2 Independently selected from H, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 3-8 membered heterocyclyl;

[0246] where R b1 With R b2 Every C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are independently optionally substituted with one to three groups independently selected from the following: halogen, cyano, hydroxyl, -NR a1 R a2 、C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl; and

[0247] where R b1 With R b2 Every C 1-8 Alkyl and C 1-8 Haloalkyl is optionally substituted with one to two R b5 ;

[0248] where R b3 C 1-4 alkylene;

[0249] where R b4 Selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclic group; wherein R b4Every C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are optionally substituted with one to three R b6 ;

[0250] Each of the R b5 Independently selected from cyano, hydroxy, C 1-4 Alkoxy, C 3-8 Cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl; and R b5 Every C 1-4 Alkoxy, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are optionally substituted with one to three groups independently selected from the group consisting of halogen, cyano, hydroxy, -NR a1 R a2 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 an alkoxy group and a phenyl group; and

[0251] Each of the R b6 independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, phenyl, 4-6 membered heterocyclic group and 5-6 membered heteroaryl; wherein R b6 Every C 3-6 Cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl are independently optionally substituted with one to three groups independently selected from the following: halogen, cyano, -NR a1 R a2 、C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 alkoxy; or

[0252] R 2 With R 3 、R 3 With R 4 , or R 5 With R 6 Together with the atoms it is bonded to, it forms C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl or 5-6 membered heterocyclic group; wherein each C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6The cycloalkyl and 5-6 membered heterocyclic groups are independently optionally substituted with one to three groups independently selected from the following groups: halogen, cyano, -NR a1 R a2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, C 1-4 Alkylene-C 3-8 Cycloalkyl, C 1-4 Alkylene-C 6-10 Aryl and C 1-4 Alkylene-(5-6 membered heteroaryl); each R 7 、R 8 、R 9 、R 10 、R 11 and R 12 independently selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and -NR a1 R a2 ;

[0253] R 13 Selected from H, C 1-4 Alkyl and C 1-4 alkyl halide;

[0254] R 15 Selected from H, C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-10 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 ;

[0255] Among them L 1 Selected from -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)-C1-4 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 -;and

[0256] where R 16 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl;

[0257] where R 15 With R 16 Every C 3-10 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one to four groups independently selected from halogen, hydroxy, -COOR b7 、-NR a1 R a2 、-S(O)2R a5 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy and -C 1-4 Alkylene-NR a1 R a2 ;

[0258] Every R a1 With R a2 Independently selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0259] R a5 C 1-6 alkyl;

[0260] R b7 Independently selected from H and C 1-6 alkyl;

[0261] m is selected from 0, 1 and 2; and

[0262] n is selected from 1 and 2.

[0263] In some embodiments of Formula (J) or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (Ja):

[0264]

[0265] Each of the Y 1 、Y 2 、Y 3 and Y 4 Independently selected from CR y and N; where each R y Independently selected from H and R a ; and where R z Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 cycloalkyl and 3-6 membered heterocyclic groups.

[0266] In some embodiments of Formula (J) or (Ja), or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (Jb):

[0267]

[0268] Each of the Y 2 With Y 4 Independently selected from CR y and N. Each R y Independently selected from H and R a . R z Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic group. 1 Selected from CR x1 and N. X 2 Selected from CR x1 R x2 NR x2 , O and S(O)2. R x1 Selected from H and R b ; and R x2 Selected from H, C 1-4 Alkyl and C 1-4 haloalkyl. q is selected from the group consisting of 0, 1, 2, and 3; and r is selected from the group consisting of 0, 1, and 2.

[0269] In some embodiments of Formula (J) or (Ja), or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (Jc):

[0270]

[0271] where R z Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 cycloalkyl and 3-6 membered heterocyclyl; and wherein r is selected from 0, 1, 2 and 3.

[0272] In some embodiments of Formula (J), (Ja), (Jb) or (Jc), or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (Jd):

[0273]

[0274] where R z is selected from H, -CH3, -CD3, -CH2F, -CHF2, -CF3 and -CH2CH3; X 1 Selected from CR x1 and N. X 2 Selected from CR x1 R x2 NR x2 , O and S(O)2. R x1 Selected from H and R b ; and R x2 Selected from H, C 1-4 Alkyl and C 1-4 haloalkyl. q is selected from the group consisting of 0, 1, 2, and 3; and r is selected from the group consisting of 0, 1, 2, and 3.

[0275] In some embodiments of Formula (J), (Ja), (Jb), (Jc), or (Jd), or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (Je):

[0276]

[0277] where X 1 Selected from CR x1 and N. X 2 Selected from CR x1 R x2 NR x2 , O and S(O)2. R x1 Selected from H and R b ; and R x2 Selected from H, C 1-4 Alkyl and C1-4 haloalkyl, q is selected from 0, 1, 2 and 3.

[0278] In some embodiments of Formula (J) or (Ja), or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (Jf):

[0279]

[0280] Each of the Y 1 and Y 4 Independently selected from CR y and N. Each R y Independently selected from H and R a . R z is selected from the group consisting of H, -CH3, -CD3, -CH2F, -CHF2, -CF3 and -CH2CH3. 1 Selected from CR x1 and N. X 2 Selected from CR x1 R x2 NR x2 , O and S(O)2. R x1 Selected from H and R b ; and R x2 Selected from H, C 1-4 Alkyl and C 1-4 haloalkyl. q is selected from the group consisting of 0, 1, 2, and 3; and r is selected from the group consisting of 0, 1, and 2.

[0281] In some embodiments of Formula (J) or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (Jg):

[0282]

[0283] Each of the Z 1 、Z 2 、Z 3 and Z 4 Independently selected from CR y1 R y2 NR z1 and O; each of which R y1 and R y2 Independently selected from H and R a ; and each of R z and R z1 Independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 cycloalkyl and 3-6 membered heterocyclic groups.

[0284] In some embodiments of Formula (I) or (J) or a pharmaceutically acceptable salt thereof, R 1 Selected from Each of the R 1 Replace one to four R a In some embodiments, R a C 1-4 In some embodiments, R a In some embodiments, R 1 Selected from

[0285] In some embodiments of Formula (I) or (J) or a pharmaceutically acceptable salt thereof, R 1 Selected from Every R 1 Optionally substituted with one to four R a In some embodiments, each R a Independently selected from halogen, CN, -OH, NR a1 R a2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -OC 3-6 In some embodiments, each R a is independently selected from F, Cl, OH, CN, -NH2, -NH(CH3), -N(CH3)2, -CH3, -CH2F, -CHF2, -CF3, -OCH3, and -OCF3. In some embodiments, each R a Independently selected from -N(CH3)2, -CH3, -OCH3 and -CF3.

[0286] In some embodiments of Formula (I) or (J), R 1 Selected from: In some embodiments, R 1 for

[0287] In some embodiments of Formula (I) or (J) or a pharmaceutically acceptable salt thereof, R 1 for It is substituted with one or two R a . Every R a Independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 3-6 In some embodiments, R 1 for

[0288] In some embodiments of Formula (J), (Ja), or (Jc), or a pharmaceutically acceptable salt thereof, R 3 and R 5 For H.

[0289] In some embodiments of Formula (J), (Ja), (Jb), (Jc), (Jd), (Je), or (Jf), or a pharmaceutically acceptable salt thereof, each R 2 and R 6 independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 In some embodiments, each R 2 and R 6 is independently selected from F, Cl, -CH3, -CD3, -CH2CH3, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -NH2, and -N(CH3)2. In some embodiments, each R 2 and R 6 In some embodiments, R 2 is F, and R 6 In some embodiments, each R 2 and R 6 In some embodiments, R 2 and R 6 For F.

[0290] In some embodiments of Formula (J), (Ja), (Jb), (Jc), (Jd), (Je), or (Jf), or a pharmaceutically acceptable salt thereof, R 4 for It is substituted with one to three R bIn some embodiments, each R b Independently selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 In some embodiments, R b In some embodiments, R b In some embodiments, R 4 for

[0291] 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 CR y In some embodiments of Formula (Ja), Y 1 、Y 2 、Y 3 and Y 4 At least one of is N. In some embodiments, Y 4 In some embodiments of Formula (Ja), Y 1 、Y 2 、Y 3 and Y 4 CR y .

[0292] 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 All are N.

[0293] In some embodiments of Formula (Ja), (Jb), (Jc), (Jd), or (Jf), or a pharmaceutically acceptable salt thereof, R z is -CH3.

[0294] In some embodiments of Formula (Jb), (Jd), (Je), or (Jf), or a pharmaceutically acceptable salt thereof, X 1 is N.

[0295] In some embodiments of Formula (Jb), (Jd), (Je), or (Jf), or a pharmaceutically acceptable salt thereof, X 2Is O. In some embodiments, X 1 is N, and X 2 It is O.

[0296] In some embodiments of Formula (Jb), (Jd), (Je), or (Jf), or a pharmaceutically acceptable salt thereof, q is 1.

[0297] In some embodiments of Formula (Jb), (Jd), (Je), or (Jf), each R b Independently selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 In some embodiments, R b C 1-4 In some embodiments, R b In some embodiments, R b It is CF3.

[0298] In some embodiments of Formula (J), (Ja), (Jb), (Jc), (Jd), (Je), or (Jf), or a pharmaceutically acceptable salt thereof, R 15 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group and C 6-10 In some embodiments, R 15 Selected from H, C 1-6 and phenyl; and phenyl is optionally substituted with one to three groups independently selected from the following: halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 In some embodiments, R 15 is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl and phenyl. In some embodiments, R 15 In some embodiments, R 15 is H. In some embodiments, R 15 In some embodiments, R 15 In some embodiments, R 15 In some embodiments, R 15is phenyl substituted with a group selected from the group consisting of F, -CH3, -CF3, -OCF3, and -(CH2)2N(CH2CH3)2. In some embodiments, R 15 It is -CH2CH2N(CH2CH3)2.

[0299] In some embodiments of Formula (J), (Ja), (Jb), (Jc), (Jd), (Je), or (Jf), or a pharmaceutically acceptable salt thereof, R 15 -L 1 -R 16 In some embodiments, L 1 Selected from -CH2-, -CH2CH2-, -CH(CH3)-, -CH2-OC(O)-C 1-4 Alkyl and -CH2-OC(O)-OC 1-4 In some embodiments, R 16 R is selected from -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH3, phenyl, pyridyl, imidazolyl, tetrahydrofuranyl, morpholinyl and tetrahydropyranyl. 16 Each of the phenyl, pyridyl, imidazolyl, tetrahydrofuranyl, morpholinyl and tetrahydropyranyl groups is optionally substituted with one to two groups independently selected from the group consisting of F, -CH3, -CH2CH3, hydroxyl and -COOH.

[0300] In some embodiments of Formula (J), (Ja), (Jb), (Jc), (Jd), (Je), or (Jf), or a pharmaceutically acceptable salt thereof, R 15 Selected from H, -CH3, -CH2CH3,

[0301]

[0302] 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, -CH3 and -CH2CH3. In some embodiments, R 15 is H. In some embodiments, R 15 It is -CH2CH3.

[0303] 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, Z4 is O. In some embodiments, Z 1 NR z1 In some embodiments, Z 2 NR z1 In some embodiments, Z 3 NR z1 In some embodiments, Z 4 NR z1 In some embodiments, R z1 is selected from H, -CH3 and -CH2CH3. In some embodiments, R z1 For H.

[0304] In some embodiments of Formula (Jg) or a pharmaceutically acceptable salt thereof, R z is -CH3.

[0305] In some embodiments of Formula (Jg) or a pharmaceutically acceptable salt thereof, R 3 and R 5 For H.

[0306] In some embodiments of Formula (Jg) or a pharmaceutically acceptable salt thereof, each R 2 and R 6 independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 In some embodiments, each R 2 and R 6 is independently selected from F, Cl, -CH3, -CD3, -CH2CH3, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -NH2, and -N(CH3)2. In some embodiments, each R 2 and R 6 In some embodiments, R 2 is F, and R 6 In some embodiments, each R 2 and R 6 In some embodiments, R 2 and R 6 For F.

[0307] In some embodiments of Formula (Jg) or a pharmaceutically acceptable salt thereof, R 4 for It is substituted with one to three R b In some embodiments, each R b Independently selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 In some embodiments, R b In some embodiments, R b In some embodiments, R 4 for

[0308] In some embodiments of Formula (Jg) or a pharmaceutically acceptable salt thereof, R 15 is selected from H, -CH3, -CH2CH3 and -CH2CH2CH3. In some embodiments, R 15 is H. In some embodiments, R 15 In some embodiments, R 15 In some embodiments, R 15 It is -CH2CH2CH3.

[0309] In some embodiments, the compound of the present invention is selected from:

[0310]

[0311]

[0312]

[0313]

[0314] In some embodiments, the compound of the present invention is selected from:

[0315]

[0316]

[0317] Also provided are compounds described herein or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein 1 to n hydrogen atoms attached to a carbon atom can be replaced by deuterium atoms, or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. These compounds can increase resistance to metabolism and, therefore, can be used to increase the half-life of a compound described herein or a pharmaceutically acceptable salt, isomer, or mixture 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). These compounds are synthesized by methods known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0318] In some embodiments, the compounds of the invention contain one to six deuterium ( 2 H or D). In some embodiments, R 2 、R 3 、R 4 、R 5 and R 6 One of contains one to six D. In some embodiments, R 6 Contains one to six D. In some embodiments, R 6 It's CD3.

[0319] Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other substances that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts formed with inorganic acids and salts formed with organic acids. In addition, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by alkalizing 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 produced by dissolving the free base in an appropriate organic solvent and treating the solution with an acid according to conventional methods for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts.

[0320] A "solvate" is formed by the interaction of a solvent with a compound. Also provided are solvates of the salts of the compounds described herein. Also provided are hydrates of the compounds described herein.

[0321] A "prodrug" is a biologically inactive derivative of a drug; after administration to the human body, it is converted into the biologically active parent drug according to certain chemical or enzymatic pathways.

[0322] In certain embodiments, optical isomers, racemates, or other mixtures of the compounds described herein, or pharmaceutically acceptable salts thereof, or mixtures thereof, are provided. In these cases, single enantiomers or diastereomers (i.e., optically active forms) can be obtained by asymmetric synthesis or 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 chromatographic separation 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, for all carbon-carbon double bonds and hydroxyamidine bonds, even if only one designation is named, Z and E forms are included.

[0323] Where chirality is not specified but exists, it is understood that the embodiment is directed to the specific diastereomeric or enantiomerically enriched form; or the racemic or scalemic mixture of these compounds.

[0324] "Enantiomers" are a pair 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 that is not in a 1:1 ratio is a "non-racemic" mixture.

[0325] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of one another.

[0326] "Hindered isomers" are stereoisomers that arise due to hindered rotation about a single bond, where the resistance to rotation about that bond is sufficiently high to allow isolation of the individual stereoisomers.

[0327] In certain embodiments, sterically hindered isomers of the compounds or pharmaceutically acceptable salts described herein are provided.

[0328] The compounds provided herein, including the compounds described herein or their pharmaceutically acceptable salts, isomers, or mixtures thereof, may include racemic mixtures, mixtures of enantiomers containing an enantiomeric excess of one, single diastereomers, or diastereomeric mixtures. All such isomeric forms of these compounds are expressly included herein as if each and every isomeric form were specifically and individually listed.

[0329] In certain embodiments, chelates, non-covalent complexes, and mixtures thereof of the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, are also provided. 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, wherein a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonds, and electrostatic interactions (also known as ionic bonds).

[0330] Therapeutic uses of compounds

[0331] The methods described herein can be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, such as an animal or human. In this context, the methods described herein can be used therapeutically in an individual. "Ex vivo" means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. These 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 biopsies thereof. 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 dosing schedule and / or dosage of an α4β7 integrin inhibitor for a given indication, cell type, individual, and other parameters. The information gleaned from these uses can be used for experimental purposes or in the clinic to establish in vivo treatment regimens. Other ex vivo uses for which the present invention may be suitable are described below or should be apparent to those skilled in the art. Selected compounds can be further characterized to examine safety or tolerable doses in human or non-human subjects. These properties can be examined using methods generally known to those skilled in the art.

[0332] In some embodiments, the compounds described herein, e.g., compounds of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), or (III), or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, or deuterated analogs thereof, can be used to treat patients having or suspected of having disease states, disorders, and conditions (also collectively referred to as "indications") that are responsive or believed to be responsive 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 an excessive or destructive immune response or the growth or proliferation of cells (e.g., cancer cells) or to inhibit immunosuppression.

[0333] In some embodiments, the compounds described herein, such as compounds of Formula (J), (Ja), (Jb), (Jc), (Jd), (Je), or (Jf), or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, or deuterated analogs thereof, can be used to treat patients having or suspected of having disease states, disorders, and conditions (also collectively referred to as "indications") that are responsive or believed to be responsive 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 an excessive or destructive immune response or the growth or proliferation of cells (e.g., cancer cells), or to inhibit immunosuppression.

[0334] method

[0335] In some embodiments, the present invention provides compounds described herein that are useful as inhibitors of α4β7 integrin. In some embodiments, the present invention provides methods of treating inflammatory diseases or conditions comprising administering a compound described herein.

[0336] In some embodiments, the present invention provides pharmaceutical compositions comprising a compound described herein and a pharmaceutically acceptable carrier.

[0337] In some embodiments, the present invention provides pharmaceutical compositions comprising a compound described herein and at least one additional therapeutic agent and at least one pharmaceutically acceptable excipient.

[0338] The present invention provides compounds described herein for use in therapy.

[0339] In another embodiment, the present invention provides a compound as described herein for use in the preparation of a medicament for the treatment of a disease or condition as described herein.

[0340] In some embodiments, compounds described herein are provided that can be used to treat diseases or conditions in patients amenable to treatment by inhibition of 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.

[0341] In some embodiments, compounds described herein are provided that are useful for treating an inflammatory disease or condition in a patient that is mediated at least in part by α4β7 integrin.

[0342] "Administering" or "administration" refers to the delivery of one or more therapeutic agents to a patient. In some embodiments, administration is monotherapy, in which a compound described herein is the only active ingredient administered to a patient in need of therapy. In another embodiment, administration is co-administration, which results in the delivery of two or more therapeutic agents together during the course of treatment. In some embodiments, two or more therapeutic agents can be co-formulated into a single dosage form or "combination dosage unit," or formulated separately and then combined into a combination dosage unit, as typically used for intravenous or oral administration (in a single or bilayer tablet or capsule).

[0343] In some embodiments, an effective amount of a compound described herein is administered to a human patient in need thereof, e.g., from about 0.1 mg to about 1000 mg of the compound per dose. In some embodiments, the effective amount is from about 0.1 mg to about 400 mg per dose. In some embodiments, the effective amount is from about 0.1 mg to about 300 mg per dose. In some embodiments, the effective amount is from about 0.1 mg to about 200 mg per dose. In some embodiments, the effective amount is from about 0.1 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.

[0344] 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, said effective amount being independently about 0.1 mg to about 1000 mg of compound per dose or about 0.1 mg to about 1000 mg of each compound per dose formulation. In some embodiments, the effective amount of the combination therapy of a compound described herein and the additional compound is independently about 0.1 mg to about 200 mg of each compound per dose. In some embodiments, the effective amount of the combination therapy of a compound described herein and the additional compound is independently about 1 mg to about 100 mg of each compound per dose. In other embodiments, the effective amount of the combination therapy of a compound described herein and the additional compound 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 500 mg of each component per dose.

[0345] In some embodiments, the dose of the compound described herein and / or the combination of the dose of the compound described herein and / or the dose of the additional therapeutic agent is administered once a day, twice a day, or three times a day. In yet another embodiment, the dose of the compound described herein and / or the dose of the additional therapeutic agent is administered with a loading dose of about 0.1 mg to about 1000 mg of each compound on the first day and daily or every other day or weekly for up to one month, followed by a conventional regimen of the compound described herein and / or one or more additional therapeutic agents or therapies. For each component of the multi-component drug regimen, the maintenance dose can be about 0.1 mg to about 1000 mg once a day, twice a day, three times a day, or weekly. A qualified caregiver or treating physician knows what dosage regimen is best for a particular patient or a particular presenting condition and will make an appropriate treatment regimen decision for the patient. Therefore, in another embodiment, a qualified caregiver is able to tailor the dosage regimen of the compound described herein and / or the additional therapeutic agent (as disclosed herein) to match the specific needs of the patient. Thus, it will be understood that the actual dosage amounts of the compounds described herein and the additional therapeutic agents administered will generally be determined by the physician based on relevant circumstances, including the condition to be treated, the route of administration chosen, the actual compound (e.g., salt or free base) administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0346] Co-administration can also include administering component drugs, for example, one or more compounds described herein with one or more additional (e.g., second, third, fourth, or fifth) therapeutic agents. These combinations of one or more compounds described herein with one or more additional therapeutic agents can be administered simultaneously or sequentially (one after another) within a reasonable time for each administration (e.g., about 1 minute to 24 hours), depending on the pharmacokinetic and / or pharmacodynamic properties of each agent or combination. Co-administration can also involve treatment with a fixed combination, wherein the agents of the treatment regimen can be combined in a fixed dose or in a combined dose medium (e.g., solid, liquid, or aerosol). In some embodiments, a kit can be used to administer a drug or drug component.

[0347] Thus, some embodiments of the present invention are methods of treating a disease or condition mediated at least in part by α4β7 integrin, comprising administering to a patient in need thereof (including, for example, via a kit) a therapeutically effective amount of one or more compounds described herein in combination with one or more additional therapeutic agents. It should be understood that a qualified caregiver will administer or supervise the administration of a therapeutically effective amount of any compound of the invention or any combination of compounds of the invention.

[0348] "Intravenous administration" is the administration of a substance directly into a vein, or "IV." The intravenous (IV) route is a faster way to deliver fluids and medications throughout the body than other routes of administration. An infusion pump allows precise control over the flow rate and total amount of medication delivered. However, if variations in flow rate are not critical, or if a pump is unavailable, a drip flow is often simply achieved by placing the bag above the patient's level and using a clamp to adjust the flow rate. Alternatively, if the patient requires a high flow rate and the IV access device is large enough to accommodate it, a rapid syringe can be used. This is an inflatable cuff placed around the bag of fluid, forcing the fluid into the patient; or a similar electronic device that can also heat the fluid being infused. Intermittent infusions, which do not require additional fluid, are used when the patient only requires medication at specific times. They can use the same techniques as an IV drip (pump or gravity-fed), but the tubing is disconnected from the IV access device after the full dose of medication has been administered. Some drugs are also administered by IV push or bolus injection, meaning that a syringe is connected to an IV access device and the drug is injected directly (or slowly if it might irritate the vein or cause too rapid an effect). Once the drug is injected into the fluid stream of the IV tubing, there must be some way to ensure that the drug enters the patient's body from the tubing. Typically, this is achieved by allowing the fluid to flow normally, thereby allowing the drug to enter the bloodstream; however, sometimes a second injection of fluid is used as a "flush" after the injection to push the drug into the bloodstream more quickly. Therefore, in some embodiments, the compounds or compound combinations described herein can be administered by IV alone, or in combination with certain components of the treatment regimen by oral or parenteral routes.

[0349] "Oral administration" is a route of administration in which a substance is taken in by mouth, and includes buccal, sublabial, and sublingual administration, as well as enteral administration and administration via the respiratory tract, unless by, for example, tubing, such that the drug does not directly contact any oral mucosa. Typical forms for 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 used by the oral route alone, or in combination with certain components of a therapeutic regimen by IV or parenteral administration.

[0350] pharmaceutical preparations

[0351] The compounds described herein are contemplated to be administered in pharmaceutical formulations.The pharmaceutical formulations / compositions described herein comprise, in addition to a carrier, a compound described herein or a compound described herein, optionally in combination with an additional therapeutic agent.

[0352] Pharmaceutical preparations / compositions of the present invention can also be used for injection, and include aqueous solutions, oily suspensions, emulsions (containing 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 commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols (and their suitable mixtures), cyclodextrin derivatives and vegetable oils can also be used. For example, by using a coating (such as lecithin), by maintaining the desired particle size (in the case of a dispersion) and / or by using a surfactant, appropriate fluidity can be maintained. By various antibacterial and antifungal agents (for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.), the effect of preventing microorganisms can be achieved.

[0353] Sterile injectable solutions are prepared by incorporating the required amounts of the component compounds into a suitable solvent along with various other ingredients listed above or as needed, followed by filtration sterilization. Typically, dispersions can be prepared by incorporating various sterilized active ingredients into a sterile vehicle containing an alkaline dispersion medium and the other ingredients listed above as needed. In the case of sterile powders for the preparation of sterile injectable solutions, preferred methods of preparation are vacuum drying and freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredients from a previously sterile filtered solution thereof.

[0354] In preparing pharmaceutical compositions (which contain the compounds described herein, optionally in combination with additional agents / therapies for therapeutic purposes, or pharmaceutically acceptable salts thereof), the active ingredient is typically diluted with an excipient or carrier and / or enclosed in and / or mixed with a carrier in the form of a capsule, sachet, paper bag or other container. When the excipient serves as a diluent, it can be a solid, semi-solid or liquid substance (as described above) that acts as a vehicle, carrier or medium for the active ingredient. Thus, these compositions can be tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 20% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

[0355] Examples of some suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, sterile water, syrup and methylcellulose. The formulation may also include: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; sweeteners; and flavoring agents.

[0356] The compositions of the present invention can be prepared by adopting steps known in the art to provide rapid, continuous or delayed release of active ingredients after administration to the patient. In some embodiments, sustained release formulations can be used. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer coating reservoirs or drug-polymer matrix formulations.

[0357] Certain compositions are preferably formulated in unit dosage form. The term "unit dosage form" or "combination dosage unit" refers to a physically discrete unit suitable for use as a single dose in human subjects and other mammals, each unit containing a predetermined amount of one or more active ingredients (e.g., a compound described herein calculated to produce the desired therapeutic effect, optionally in combination with an additional therapeutic agent, in association with a suitable pharmaceutical excipient, such as a tablet, capsule, ampoule or vial). However, it should be understood that the actual amount of each active agent administered will be determined by the physician based on the relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound administered and its relative activity, the patient's age, weight and response, the severity of the patient's symptoms, etc.

[0358] To prepare solid compositions such as tablets, one or more principal active ingredients are mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredients are dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0359] Tablets or pills comprising the compounds described herein (optionally in combination with a second agent) can be coated or otherwise compounded to provide a dosage form that provides an advantage of prolonged duration of action or protection from the acidic environment of the stomach. For example, a tablet or pill can comprise an inner dosage and an outer dosage element, the latter being in the form of a coating on the former. In some embodiments, the inner dosage element can include a compound described herein, and the outer dosage element can include a second or additional therapeutic agent, or vice versa. Alternatively, a combined dosage unit can be a side-by-side configuration, such as in a capsule or tablet, wherein a portion or half of the tablet or capsule is filled with a compound described herein, while another portion or half of the tablet or capsule comprises an additional therapeutic agent.

[0360] A variety of materials can be used for such enteric or coating layers, such materials including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate. Those skilled in the art know the techniques and materials for preparing dosages of the formulations disclosed herein.

[0361] A "sustained release formulation" or "extended 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 skilled in the art will be able to develop sustained release formulations of the compounds of the invention without undue experimentation. Thus, in some embodiments, the compounds or compound combinations described herein can be delivered alone via a sustained release formulation, or delivered by oral, IV, or parenteral routes in combination with certain components of a therapeutic regimen.

[0362] Lyophilized formulations can also be used to administer the compounds described herein alone or in combination with additional therapeutic agents. One skilled in the art knows how to prepare and use lyophilized formulations of pharmaceuticals suitable for lyophilization.

[0363] Spray-dried formulations can also be used to administer the compounds described herein alone or in combination with additional therapeutic agents. Those skilled in the art know how to prepare and use spray-dried formulations of drugs suitable for spray drying. Other known formulation techniques can also be used to formulate the compounds or combinations of compounds disclosed herein.

[0364] The compounds disclosed herein can be used to treat diseases or conditions that are mediated at least in part by α4β7 integrin. Non-limiting examples of diseases or conditions that are mediated at least in part by α4β7 integrin include, but are not limited to, acne, acid-induced lung damage, Addison's disease, adrenal hyperplasia, adrenocortical insufficiency, adult-onset Still's disease, adult respiratory distress syndrome (ARDS), age-related macular degeneration, aging, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopulmonary disease, 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, anti-glomerular basement membrane disease, antigen-antibody complex-mediated diseases, ankylosing spondylitis, antiphospholipid syndrome, Aphrodisiacs, Other stomatitis, appendicitis, arthritis, ascites, aspergillosis, asthma, atherosclerosis, atherosclerotic plaques, atopic dermatitis, atrophic thyroiditis, autoimmune diseases, autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria), autoimmune polyendocrine disease, autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia), autoimmune hepatitis, autoimmune thyroid disease, autoinflammatory diseases, back pain, anthrax infection, Behçet's disease, inflammation caused by bee stings, Behçet's syndrome, Bell's palsy, berylliosis, Blau's syndrome, bone pain, bronchiolitis, bullous pemphigoid (BP), asthma, burns, bursitis, cardiac hypertrophy hypertrophy, carpal tunnel syndrome, Castleman's disease, catabolic disorder, cataract, Celiac disease, cerebral aneurysm, chemical-induced inflammation, chorioretinitis, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, chronic heart failure, chronic lung disease of prematurity, chronic obstructive pulmonary disease (COPD), chronic pancreatitis, chronic prostatitis, chronic recurrent multifocal osteomyelitis, scarring alopecia, colitis, complex regional pain syndromeregional pain syndrome, organ transplant complications, conjunctivitis, connective tissue diseases, contact dermatitis, corneal allograft angiogenesis, corneal ulcers, Crohn's disease, cryopyrin-associated periodic syndromes, cutaneous lupus erythematosus (CLE), cryptococcosis, cystic fibrosis, interleukin-1 receptor antagonist (DIRA) deficiency, dermatitis, dermatitis endotoxemia, dermatomyositis, diabetic macular edema, diverticulitis, eczema, encephalitis, endometriosis, endotoxemia, eosinophilic pneumonias, epicondylitis, epidermolysis bullosa, erythema multiforme, erythroblastopenia, esophagitis, familial amyloidotic polyneuropathy polyneuropathy, familial coldurticarial, familial Mediterranean fever, fetal growth retardation, fibromyalgia, fistulizing Crohn's disease, food allergies, giant cell arteritis, glaucoma, neuroblastoma, glomerular disease, glomerular nephritis (glomerulonephritis), gluten-sensitive enteropathy, gout, gouty arthritis, graft-versus-host disease (GVHD), granulomatous hepatitis, Graves' disease, growth plate injury, Guillain-Barré syndrome, intestinal disorders, hair loss, Hashimoto's thyroiditis, head injury, headache, hearing loss, heart disease, hemangioma, hemolytic anemia, hemophilic joint disease joint), Henoch-Scholein purpura, hepatitis, hereditary periodic fever syndromes, hereditary connective tissue disorders, herpes zoster and herpes simplex, hidradenitis suppurativasuppurativa (HS), hip replacement, Hodgkin's disease, Huntington's disease, hyaline membrane disease, hyperactive inflammatory response, hyperammonemia, hypercalcemia, hypercholesterolemia, hypereosinophilic syndrome (HES), hyperimmunoglobulinemia D with recurrent fever (HIDS), hypersensitivity pneumonitis, hypertrophic skeletal abnormalities, dysplastic and other anemias, hypoplastic anemia, ichthyosis, idiopathic demyelinating polyneuropathy demyelinating polyneuropathy), idiopathic inflammatory muscle disease (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 (IP), mononucleosis), infectious diseases including those caused by diseases such as AIDS (HIV infection), hepatitis A, B, C, D, and E, inflammation, CNS inflammation, 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 (such as rhinitis or sinusitis), inflammatory diseases of the respiratory tract, inflammatory ischemic events such as stroke or cardiac arrest, inflammatory lung disease, inflammatory muscle disease such as myocarditis, inflammatory liver disease, inflammatory neuropathy, inflammatory pain, inflammation caused by insect bites, interstitial cystitis, interstitial lung disease, iritis, irritation-induced inflammation, ischemia / reperfusion, joint replacement, juvenile arthritis, juvenile rheumatoid arthritis, keratitis, kidney damage caused by parasitic infection, kidney transplant rejection, leptospirosis, leukocyte adhesion defects, lichen sclerosus sclerosus, LS), Lambert-Eaton myasthenic syndromesyndrome, Loeffler's syndrome, lupus, lupus nephritis, Marfan syndrome (MFS), mast cell activation syndrome, mastocytosis, meningitis, meningioma, mesothelioma, mixed connective tissue disease, Muckle-Wells syndrome (urticaria, deafness, amyloidosis), mucositis, multiple organ damage syndrome, multiple sclerosis, muscle wasting, muscular dystrophy, myasthenia gravis (MG), myelodysplastic syndrome, myocarditis, myositis, sinusitis, necrotizing enterocolitis enterocolitis, neonatal-onset multisystem inflammatory disease (NOMID), neovascular glaucoma, nephrotic syndrome, neuritis, neuropathological disorders, non-allergenic asthma, obesity, ocular allergy, optic neuritis, organ transplant rejection, Osier-Weber syndrome, osteoarthritis, osteogenesis imperfecta, osteonecrosis, osteoporosis, osterarthritis, otitis media, pachyonychia congenita, Paget's disease, Paget's disease of bone, pancreatitis, Parkinson's disease, pediatric rheumatology, pelvic inflammatory disease, pemphigus, pemphigus vulgaris (PV), bullous pemphigoid (BP), pericarditis, periodic fever, periodontitis, peritoneal endometriosis endometriosis), pernicious anemia (Addison's disease), whooping cough, PFAPA (periodic febrile aphthous pharyngitis and cervical lymphadenopathy), pharyngitis and adenitis (PFAPA syndrome), plant-induced inflammation, Pneumocystis infection, pneumonia, pneumonia, poison ivy / urushiol oil-induced inflammation, polyarthritis nodosa, polychondritis, polycystic kidney disease, polymyalgia rheumatica, giant cell arteritisarteritis, polymyositis, pouchitis, reperfusion injury and transplant rejection, primary biliary cirrhosis, primary pulmonary hypertension, primary sclerosing cholangitis (PSC), proctitis, psoriasis, psoriasis vulgaris, psoriatic arthritis, psoriatic epidermis, psychosocial stress disease, lung disease, pulmonary fibrosis, pulmonary hypertension, pyoderma gangrenosum, pyogenic granuloma retrolental fibroplasias, suppurative sterile arthritis, Raynaud's syndrome, Reiter's disease disease), reactive arthritis, nephropathy, renal transplant rejection, reperfusion injury, respiratory distress syndrome, retinopathy, retrolental fibroplasia, Raynaud's syndrome, rheumatic myocarditis, rheumatic diseases, rheumatic fever, rheumatoid arthritis, rhinitis, rhinitis psoriasis, rosacea, sarcoidosis, Schnitzler syndrome, scleritis, sclerosis, scleroderma, scoliosis, seborrhea, sepsis, septic shock, severe pain, Sézary syndrome, sickle cell anemia, silica-induced disease (silicosis), Sjögren's syndrome syndrome), skin diseases, skin irritation, rash, skin sensitivity (contact dermatitis or allergic contact dermatitis), sleep apnea, spinal cord injury, spinal stenosis, spondyloarthropathy, sports injuries, sprains and strains, Stevens-Johnson syndrome (SJS), stroke, subarachnoid hemorrhage, sunburn, synovitis, systemic inflammatory response syndrome (SIRS), systemic lupus erythematosus, systemic mast cell hyperplasia (SMCH), and inflammatory bowel disease.disease (SMCD), systemic vasculitis, systemic juvenile idiopathic arthritis, temporal arteritis, tendinitis, tenosynovitis, thrombocytopenia, thyroiditis, tissue transplantation, toxoplasmosis, trachoma, transplant rejection, traumatic brain injury, tuberculosis, tubulointerstitial nephritis, tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), type 1 diabetes mellitus, type 2 diabetes mellitus, complications of type 1 or type 2 diabetes mellitus, ulcerative colitis, urticaria, uterine fibroids, uveitis, uveoretinitis, vascular restenosis, vasculitis, vasculitis (NHLBI), vitiligo, Wegener's granulomatosis, and Whipple's disease.

[0365] In another embodiment, a method for alleviating the symptoms of a disease or condition mediated at least in part by α4β7 integrin is provided. In some embodiments, the method comprises identifying a mammal having symptoms of a disease or condition mediated at least in part by α4β7 integrin, and providing the mammal with an amount of a compound described herein effective to improve the symptoms (i.e., reduce the severity of the symptoms).

[0366] In some embodiments, the disease or condition mediated at least in part by α4β7 integrin is an inflammatory disease or LPS-induced endotoxin shock. In some embodiments, the disease is an autoimmune disease. In specific 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, Sjogren's syndrome, autoimmune hemolytic anemia, asthma or chronic obstructive pulmonary disease (COPD), ankylosing spondylitis, acute gout and ankylosing spondylitis, reactive arthritis, monoarticular arthritis, osteoarthritis, gouty arthritis, juvenile arthritis, juvenile rheumatoid arthritis, juvenile rheumatoid arthritis or psoriatic arthritis. In other embodiments, the disease is inflammation. In yet other embodiments, the disease is an excessive or destructive immune response, such as asthma, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease (COPD), and lupus.

[0367] In some embodiments, the disease or condition mediated at least in part by α4β7 integrin is inflammatory bowel disease (IBD). As used herein, the term "inflammatory bowel disease" or "IBD" is a collective term describing inflammatory disorders of the gastrointestinal tract, the most common forms of which are ulcerative colitis and Crohn's disease. Other forms of IBD that can be treated using the compounds, compositions, and methods disclosed herein include divertic colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autistic enterocolitis, indeterminate colitis, Behçet's disease ( 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, and chronic diarrhea.

[0368] Treatment or prevention of IBD also includes improving or alleviating one or more IBD symptoms. As used herein, term " IBD symptom " refers to detected symptoms (such as abdominal pain, diarrhea, rectal bleeding, weight loss, fever, loss of appetite), and other more serious complications (such as dehydration, anemia and malnutrition) detected. Some such symptoms are quantitatively analyzed (for example, weight loss, fever, anemia, etc.). Some symptoms are easy to determine by blood tests (for example, anemia) or the chemical analysis (test) of detecting blood presence (such as rectal bleeding). Term " wherein said symptom alleviating " refers to the qualitative or quantitative alleviating of detectable symptoms, including but not limited to the detectable impact on disease recovery rate (for example, weight gain rate). This diagnosis is usually determined by pathological examination of mucosal endoscopic observation and endoscopic biopsy specimens.

[0369] The course of IBD varies and is often interspersed with periods of remission and exacerbation. Various methods have been described for characterizing the disease activity and severity of IBD and the response to treatment in subjects with IBD. Treatment according to the present methods is generally applicable to subjects with IBD at any level or degree of disease activity.

[0370] In some embodiments, the diseases or conditions treated by administering a compound 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 pain due to endometriosis, BRAF-resistant melanoma, brain stem glioma or pituitary adenoma, burns, bursitis, anal area cancer, endocrine system cancer, kidney cancer or ureter cancer (e.g., renal cell carcinoma and renal pelvis cancer), penile cancer, small intestine cancer, thyroid cancer, urethral cancer, blood cancer (e.g., acute myeloid leukemia), tongue cancer, cervical cancer, endometrial cancer, transfusion cancer, Fallopian tube cancer, renal pelvis cancer, vaginal cancer, and vulvar cancer, chronic myeloid leukemia, chronic or acute leukemia, chronic pain, classic Bartter syndrome, common cold conjunctivitis, coronary heart disease, skin or intraocular melanoma, dermatitis, dysmenorrhea, eczema, endometriosis, familial adenomatous polyposis, fibromyalgia, fungal infection, gout, gynecological cancer, uterine sarcoma, fallopian tube cancer, headache, hemophilic arthropathy, Parkinson's disease, AIDS, herpes zoster, Hodgkin's disease, Huntington's disease, hyperprostaglandin E syndrome Esyndrome), influenza, iritis, juvenile arthritis, juvenile-onset rheumatoid arthritis, juvenile rheumatoid arthritis, low back and neck pain, lymphocytic lymphoma, myofascial disease, myositis, neuralgia, neurodegenerative diseases (such as Alzheimer's disease), neuroinflammatory diseases, neuropathic pain, vulvar cancer, Parkinson's disease, pediatric malignancies, pulmonary fibrosis, rectal cancer, rhinitis, pulmonary 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 (such as influenza), and wound healing.

[0371] Criteria for assessing disease activity in subjects with ulcerative colitis are described, for example, in Truelove et al. (1955) Br Med J 2: 1041-1048. Using these criteria, disease activity in subjects with IBD can be characterized as mild disease activity or severe disease activity. Subjects who do not meet all criteria for severe disease activity and who exceed the criteria for mild disease activity are classified as having moderate disease activity.

[0372] The therapeutic method disclosed in the present invention can also be applied to any point in the course of disease. In some embodiments, the method is applied to a subject suffering from IBD in the remission phase (i.e., inactive disease). In these embodiments, the method of the present invention provides benefits by extending the remission phase (e.g., extending the time 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 suffering from IBD in the active disease phase. These methods provide benefits by shortening the duration of the active disease phase, reducing or improving one or more symptoms of IBD or treating IBD.

[0373] Measures for determining the efficacy of IBD treatment in clinical practice have been described and include, for example, the following: symptom control; fistula closure; extent of corticosteroid treatment required; and improvement in quality of life. Health-related quality of life (HRQL) can be assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ), which is widely used in clinical practice to assess the quality of life of subjects with IBD. (See Guyatt et al. (1989) Gastroenterology 96:804-810). In some embodiments, the disease or condition is immune-mediated liver damage, disease, or disorder.

[0374] 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 develops 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 (such as prednisolone) and phosphodiesterase inhibitors (e.g., pentoxifylline) can be used to treat alcoholic hepatitis. The compounds described herein can be used as a stand-alone treatment for alcoholic hepatitis or in combination with current treatments to treat alcoholic hepatitis.

[0375] In one aspect, the present invention provides a method for 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.

[0376] 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 diseases or symptoms of SLE. Symptoms of systemic lupus erythematosus include joint pain, joint swelling, arthritis, fatigue, hair loss, mouth sores, swollen lymph nodes, sensitivity to sunlight, rash, headache, numbness, tingling, seizures, vision problems, personality changes, abdominal pain, nausea, vomiting, arrhythmia, coughing up blood and difficulty breathing, patchy skin color and Raynaud's phenomenon.

[0377] Combination therapy

[0378] Also provided are methods of treatment in which a compound described herein is administered to a patient in combination with one or more additional active agents or therapies.

[0379] Thus, in some embodiments, a method of treating a disease or condition mediated at least in part by α4β7 integrin and / or a disease or condition that is co-occurring with or aggravated or triggered by a disease or condition mediated at least in part by α4β7 integrin (e.g., an allergic disease and / or an autoimmune disease and / or an 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), which can be used to treat a disease or condition mediated at least in part by α4β7 integrin, an allergic disease and / or an autoimmune disease and / or an inflammatory disease and / or an acute inflammatory response associated with or co-occurring with a disease or condition mediated at least in part by α4β7 integrin. Treatment with a second, third, fourth, or fifth active agent can be performed before, concomitantly with, or after treatment with a compound described herein. In some embodiments, the compound described herein is combined with another active agent in a single dosage form. Suitable therapies that can be used in combination with the compounds described herein include, but are not limited to, the therapeutic agents provided herein, or a combination comprising at least one therapeutic agent provided herein.

[0380] Included herein are methods of treatment in which the compounds described herein are administered in combination with an agent for treating an inflammatory disease or condition. Examples of agents for treating an inflammatory disease or condition 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; glucose metabolism regulators; 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 prostaglandin receptor antagonists; F1F0 ATP synthase modulators; farnesoid X receptor (FXR and NR1H4) agonists or modulators; fecal microbiota transplantation (FMT); recombinant human membrane-bound chemokine (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 proline hydroxylase inhibitors; histone deacetylase inhibitors; HLA class II antigen modulators; hypoxia-inducible factor-1 stimulators; ICAM1 gene inhibitors; IL-1β ligand modulators; IL-12 antagonists; IL-13 antagonists; IL-18 antagonists; IL-22 agonists; IL-23 antagonists; IL-23A inhibitors; IL-6 antagonists agonists; IL-7 receptor antagonists; IL-8 receptor antagonists; integrin α-4 / β-1 antagonists; integrin α-4 / β-7 antagonists; integrin antagonists; interleukin ligand inhibitors; interleukin receptor 17A antagonists; interleukin-1β ligands; interleukin 1-like receptor 2 inhibitors; IL-6 receptor modulators; JAK tyrosine kinase inhibitors; Jak1 tyrosine kinase inhibitors; Jak3 tyrosine kinase inhibitors; lactoferrin stimulators; LanC-like protein 2 modulators; leukocyte elastase inhibitors; leukocyte proteinase-3 inhibitors; MAdCAM inhibitors; melanin-concentrating hormone (MCH-1) antagonists; melanocortin agonists; metalloproteinase-9 inhibitors; microbiome-targeting therapies therapeutics); natriuretic peptide receptor C agonists; neuregulin-4 ligands; NLPR3 inhibitors; NKG2 D-activated NK receptor antagonists; nuclear factor κB inhibitors; opioid receptor antagonists; OX40 ligand inhibitors; oxidoreductase inhibitors;P2X7 purinergic receptor modulators; PDE4 inhibitors; Pellino homolog 1 inhibitors; PPARα / δ agonists; PPARγ 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 transglutaminase) inhibitors; TLR-3 antagonists; TLR-4 antagonists; Toll-like receptor 8 (TLR8) inhibitors; TLR-9 agonists; TNFα ligand inhibitors; TNF ligand inhibitors; TNFα 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; capsaicin VR1 antagonists; and zonulin inhibitors, and combinations thereof.

[0381] Adenosine A3 receptor antagonists include PBF-677.

[0382] Adrenomedullin ligands include adrenomedullin.

[0383] Antibiotics include ciprofloxacin, clarithromycin, metronidazole, vancomycin, rifamycin, rifaximin, and tosufloxacin.

[0384] ASK1 inhibitors include GS-4997.

[0385] α-fetoprotein modulators include ACT-101.

[0386] Anti-CD28 inhibitors include JNJ-3133 and abatacept.

[0387] β-adrenergic receptor antagonists include NM-001.

[0388] BTK inhibitors include GS-4059.

[0389] Calcineurin inhibitors include tacrolimus and cyclosporine.

[0390] Glucose metabolism regulators include ASD-003.

[0391] Cathepsin S inhibitors include VBY-129.

[0392] CCR9 chemokine antagonists include CCX-507.

[0393] CD233 modulators include GSK-2831781.

[0394] CD29 modulators include PF-06687234.

[0395] CD3 antagonists include NI-0401.

[0396] CD4 antagonists include IT-1208.

[0397] CD40 ligand inhibitors include SAR-441344 and letolizumab.

[0398] CD40 gene inhibitors include NJA-730.

[0399] CD40 ligand receptor antagonists include FFP-104 and BI-655064.

[0400] Chaperonin binding immunoglobulin proteins include IRL-201805.

[0401] Chemokine CXC ligand inhibitors include LY-3041658.

[0402] CHST15 gene inhibitors include STNM-01.

[0403] Collagen regulators include ECCS-50 (DCCT-10).

[0404] COT protein kinase inhibitors include GS-4875.

[0405] CSF-1 antagonists include JNJ-40346527 (PRV-6527) and SNDX-6352.

[0406] CX3CR1 chemokine modulators include E-6130.

[0407] Ecobiotics includes SER-287.

[0408] Eotaxin ligand inhibitors include bacitrazumab.

[0409] EP4 prostaglandin receptor antagonists include KAG-308.

[0410] F1F0 ATP synthase modulators include LYC-30937EC.

[0411] Recombinant human membrane-bound chemokine (fractalkine) ligand inhibitors include quemolimab (E-6011).

[0412] Free fatty acid receptor 2 antagonists include GLPG-0974.

[0413] GATA 3 transcription factor inhibitors include SB-012.

[0414] Glucagon-like peptide-2 agonists include teduglutide and apraglutide.

[0415] Glucocorticoid receptor agonists include budesonide, beclomethasone dipropionate, and dexamethasone sodium phosphate.

[0416] Glucocorticoid receptor modulators / TNF ligand inhibitors include ABBV-3373.

[0417] Guanylate cyclase receptor agonists include dolcanatide.

[0418] HIF prolyl hydroxylase inhibitors include DS-1093 and AKB-4924.

[0419] HIF prolyl hydroxylase-2 inhibitors / hypoxia-inducible factor-1 stimulators include GB-004.

[0420] Histone deacetylase inhibitors include gilvestrastat.

[0421] Histone deacetylase-6 inhibitors include CKD-506.

[0422] HLA class II antigen modulators include HLA class II protein modulators.

[0423] ICAM1 inhibitors include alicaforsen.

[0424] IL-12 antagonists include ustekinumab (IL12 / IL23).

[0425] IL-13 antagonists include tralokinumab.

[0426] IL-18 antagonists include GSK-1070806.

[0427] IL-22 agonists include RG-7880.

[0428] IL-23 antagonists include tildrakizumab, risankizumab (BI-655066), mirikizumab (LY-3074828), brazikumab (AMG-139), and PTG-200.

[0429] IL-23A inhibitors include guselkumab.

[0430] IL-6 antagonists include ololituzumab.

[0431] IL-7 receptor antagonists include OSE-127.

[0432] IL-8 receptor antagonists include clotrimazole.

[0433] Integrin alpha-4 / beta-1 antagonists include natalizumab.

[0434] Integrin α-4 / β-7 antagonists include etrolizumab (a4b7 / aEb7), vedolizumab, carotegast methyl, TRK-170 (a4b7 / a4b1), PN-10943, and PTG-100.

[0435] Integrin antagonists include E-6007.

[0436] Interleukin ligand inhibitors include bimekizumab (IL-17A / IL-17F).

[0437] Interleukin receptor 17A antagonists include brodalumab.

[0438] Interleukin-1β ligands include K(D)PT.

[0439] Interleukin 1-like receptor 2 inhibitors include BI-655130.

[0440] IL-6 receptor modulators include olamkicept.

[0441] JAK tyrosine kinase inhibitors include tofacitinib (1 / 3), peficitinib (1 / 3), TD-3504, and TD-1473. Jak1 tyrosine kinase inhibitors include the compounds disclosed in WO2008 / 109943. Examples of other JAK inhibitors include, but are not limited to, AT9283, AZD1480, baricitinib, BMS-911543, fizotinib, 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 brepocitinib (PF-06700841) (JAK1 / Tyk2).

[0442] Jak3 tyrosine kinase inhibitors include PF-06651600.

[0443] Lactoferrin stimulators include recombinant human lactoferrin (VEN-100).

[0444] LanC-like protein 2 modulators include BT-11.

[0445] Leukocyte elastase inhibitors / leukocyte proteinase-3 inhibitors include tiprelestat.

[0446] MAdCAM inhibitors include SHP-647 (PF-547659).

[0447] Melanin-concentrating hormone (MCH-1) antagonists include CSTI-100.

[0448] Melanocortin MC1 receptor agonists include ASP-3291 and PL-8177.

[0449] Metalloproteinase-9 inhibitors include GS-5745.

[0450] Microbiome modulators include ABI-M201.

[0451] Natriuretic peptide receptor C agonists include plecanatide.

[0452] Neuregulin-4 ligands include NRG-4.

[0453] NKG2 D-activated NK receptor antagonists include JNJ-4500.

[0454] NLPR3 inhibitors include dapansutrile, BMS-986299, SB-414, MCC-950, IFM-514, JT-194, PELA-167, and NBC-6.

[0455] Farnesoid X receptor (FXR and NR1H4) agonists or modulators include AGN-242266, cilofexortromethamine (GS-9674), EDP-305, EYP-001, GNF-5120, MET-409, nidufexor (LMB-763), obeticholic acid, TERN-101, and tropifexor.

[0456] NF-κB inhibitors include Thetanix.

[0457] Opioid receptor antagonists include naltrexone and IRT-103.

[0458] OX40 ligand inhibitors include KHK-4083.

[0459] Oxidoreductase inhibitors include olsalazine.

[0460] Pellino homolog 1 inhibitors include BBT-401.

[0461] P2X7 purinergic receptor modulators include SGM-1019.

[0462] PDE 4 inhibitors include apremilast.

[0463] PPARα / δ agonists include elafibranor (GFT-1007).

[0464] PPARγ agonists include GED-0507-34-Levo.

[0465] Protein fimH inhibitors include sibofimloc (EB-8018).

[0466] P-selectin glycoprotein ligand-1 inhibitors include SEL-K2, AbGn-168H, and neihulizumab.

[0467] Ret tyrosine kinase receptor inhibitors include GSK-3179106.

[0468] RIP-1 kinase inhibitors include GSK-2982772.

[0469] RIP-2 kinase inhibitors include GSK-2983559.

[0470] Sphingosine 1-phosphate phosphatase 1 stimulators include etrasimod.

[0471] Sphingosine-1-phosphate receptor-1 agonists include ozanimod, mocravimod (KRP-203), and BMS-986166.

[0472] Sphingosine-1-phosphate receptor-1 agonists / sphingosine-1-phosphate receptor-5 agonists include ozanimod.

[0473] Sphingosine-1-phosphate receptor-1 antagonists include amiselimod (MT-1303).

[0474] Sphingosine-1-phosphate receptor-1 modulators include OPL-002.

[0475] Stem cell antigen-1 inhibitors include Ampion (DMI-9523).

[0476] Superoxide dismutase modulators include midismase.

[0477] Syk inhibitors include GS-9876.

[0478] Tissue transglutaminase inhibitors include zampilimab.

[0479] TLR-3 antagonists include PRV-300.

[0480] TLR-4 antagonists include JKB-122.

[0481] 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.

[0482] TLR-9 agonists include cobitolimod, IMO-2055, IMO-2125, lefitolimod, linimod, MGN-1601, and PUL-042.

[0483] TNFα ligand inhibitors include adalimumab, certolizumab pegol, infliximab, golimumab, DLX-105, Debio-0512, HMPL-004, CYT-020-TNFQb, Hemay-007, and V-565.

[0484] TNF antagonists include AVX-470, tulinercept, and etanercept.

[0485] TPL-2 inhibitors include GS-4875.

[0486] Tumor necrosis factor 14 ligand modulators include AEVI-002.

[0487] Tumor necrosis factor 15 ligand inhibitors include PF-06480605.

[0488] Tyk2 tyrosine kinase inhibitors include PF-06826647 and BMS-986165.

[0489] TrkA receptor antagonists include SNA-125.

[0490] Type I IL-1 receptor antagonists include anakinra.

[0491] Zonulin inhibitors include larizolide acetate.

[0492] Included herein are methods of treatment in which the compounds described herein are administered in combination with an anti-inflammatory agent, including, but not limited to, NSAIDs, nonspecific cyclooxygenase inhibitors and COX-2 specific cyclooxygenase inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptor antagonists, immunosuppressants, and methotrexate.

[0493] 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, nabmetone sodium, sulfasalazine, tolmetin sodium, and hydroxychloroquine. Examples of NSAIDs also include COX-2 specific inhibitors (i.e., compounds that inhibit COX-2, which target the IC of COX-1). 50 At least higher than the IC for COX-2 50 50 times higher), such as celecoxib, valdecoxib, lumiracoxib, etoricoxib and / or rofecoxib.

[0494] In another embodiment, the anti-inflammatory agent is a salicylate. Salicylates include, but are not limited to, acetylsalicylic acid or aspirin, sodium salicylate and choline, and magnesium salicylate.

[0495] The anti-inflammatory agent can also be a corticosteroid. For example, the corticosteroid can be selected from cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate and prednisone.

[0496] In some embodiments, the anti-inflammatory therapeutic agent is a gold preparation such as gold sodium thiomalate or auranofin.

[0497] In some embodiments, the anti-inflammatory agent is a metabolic inhibitor such as a dihydrofolate reductase inhibitor (eg, methotrexate) or a dihydroorotate dehydrogenase inhibitor (eg, leflunomide).

[0498] In some embodiments, the anti-inflammatory compound is an anti-C5 monoclonal antibody (such as eculizumab (eculizumab) or pexelizumab)), a TNF antagonist (such as etanercept), or infliximab (which is an anti-TNFα monoclonal antibody).

[0499] Included herein are methods of treatment wherein the compounds described herein are administered in combination with an immunosuppressant. In some embodiments, the immunosuppressant is methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, or mycophenolate mofetil.

[0500] Included herein are methods of treatment in which the compounds described herein are administered in combination with classes of agents for treating IBD. Examples of classes of agents for treating IBD that can be used in combination with the compounds described herein include ASK1 inhibitors, β-adrenergic receptor antagonists, BTK inhibitors, β-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 regulators, CSF-1 antagonists, cyclooxygenase inhibitors, cytochrome P450 3A4 inhibitors, eosinophil chemoattractant ligand inhibitors, EP4 prostaglandin receptor antagonists, erythropoietin receptor agonists, recombinant human membrane-bound chemokine (fractalkine) ligand inhibitors, free fatty acid receptor 2 antagonists, GATA 3 transcription factor inhibitors, 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 α-4 / β-1 antagonists, integrin α-4 / β-7 antagonists, integrin α-E antagonists, integrin antagonists, integrin β-7 antagonists , interleukin ligand inhibitors, interleukin-2 ligands, interleukin receptor 17A antagonists, interleukin-1β ligands, interleukin-1β ligand modulators, IRAK4 inhibitors, JAK tyrosine kinase inhibitors, Jak1 tyrosine kinase inhibitors, Jak3 tyrosine kinase inhibitors, LanC-like protein 2 modulators, lipoxygenase modulators, MAdCAM inhibitors, matrix metalloproteinase inhibitors, melanocortin agonists, metalloproteinase-9 inhibitors, natriuretic peptide receptor C agonists, neuregulin-4 ligands, NKG2 D-activated NK receptor antagonists, opioid receptor antagonists, opioid receptor delta antagonists, oxidoreductase inhibitors, P2X7 purinergic receptor antagonists, PDE4 inhibitors, phagocytosis-stimulating peptide modulators, potassium channel inhibitors, PPARα agonists, PPARδ agonists, PPARγ 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, TGFβ1 ligand inhibitors, thymosin agonists, TLR antagonists, TLR agonists, TNFα ligand inhibitors, TNF antagonists, tumor necrosis factor 14 ligand modulators, type II TNF receptor modulators, Tpl 2 inhibitors, and zonulin inhibitors.

[0501] Included herein are methods of treatment in which the compounds described herein are administered in combination with an agent for treating IBD. Examples of agents for treating IBD that can be used in combination with the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, enantiomers, or deuterated analogs thereof, include those provided herein for treating inflammatory diseases or conditions, and 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 pegol; ChAdOx2-HAV, dexamethasone sodium phosphate, DNVX-078, etanercept; cibinetide; Clostridium butyricum; ETX-201, golimumab; GS-4997, GS-9876, GS-4875, GS-4059, infliximab; mesalamine, HLD-400, LYC-30937EC; IONIS-JBI1-2.5Rx, JNJ-64304500, JNJ-4447, naltrexone; natalizumab; neihulizumab, 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; Thetanix; TOP-1288; VBY-129; 99mTc-annexin V-128; bacitrazumab; DLX-105; dolcanatide; FFP-104; filgotinib (filgotinib); foralumab; GED-0507-34-Levo; givista; GLPG-0974; iberogast; JNJ-40346527; K(D)PT; KAG-308; KHK-4083; KRP-203; larizolide 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; zhukasaixin; ABT-494; Ampion; BI-655066; carotegast methyl; cobitolimod; elafibranor; etrolizumab; GS-5745; HMPL-004; LP-02, ozanimod; peficitinib; quemolimab (E-6011); RHB-104; rifaximin; tirazumab; tralokinumab; brodalumab; laquinimod; plecanatide; vidofludimus; and AZD-058.

[0502] Included herein are methods of treatment in which the compounds described herein are administered in combination with an agent for treating graft-versus-host disease. Examples of agents for treating graft-versus-host disease that can be used in combination with the compounds described herein include those provided herein for treating inflammatory diseases or conditions, and [18F]F-AraG, AM-01, alpha 1 antitrypsin stimulators: AAT-IV and CSL-964; Allocetra, efavaleukin alfa (AMG-592), arsenic trioxide, ATIR-101, belatacept, belimumab; beta-lactamase modulators: ribaxamase, bortezomib, brentuximab vedotin), brimonidine, brimonidine tartrate, 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, miracitumomab, 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 C1 subcomponent inhibitor: CE-1145, sutimlimab, Cinryze, BIVV-009; B lymphocyte Cell antigen CD20 inhibitors: obinutuzumab and rituximab; CASP9 gene stimulator: rivogenlecleucel; CD3 antagonist or CD7 inhibitor: T-Guard; complement factor C5a inhibitor: olendalizumab; dipeptidyl peptidase IV inhibitor: begelomab; JAK1 / 2 tyrosine kinase inhibitor: ruxolitinib; Jak1 tyrosine kinase inhibitor: itacitinib; interleukin-2 ligand: aldesleukin; interleukin-22 ligand: F-652; IL-2 receptor α subunit inhibitors: basiliximab and inomucomab; IL-6 receptor agonist: PLX-1; IL-6 receptor antagonist: clazakizumab;OX40 ligand inhibitor: KY-1005; examples of such OX40 inhibitors are compounds disclosed in US Pat. No. 8,450,460, the entire contents of which are incorporated herein by reference; signal transduction CD24 regulator: CD24-IgFc; somatostatin receptor agonist: rabbit anti-human thymocyte immunoglobulin (Thymoglobulin); and sphingosine-1-phosphate receptor-1 agonist: ponesimod.

[0503] Included herein are methods of treatment in which a compound described herein is administered in combination with an agent that treats primary sclerosing cholangitis. Examples of agents useful in treating primary sclerosing cholangitis in combination with the compounds described herein include those provided herein for the treatment of inflammatory diseases or conditions, and BTT-1023, CM-101, docosahexaenoic acid, GRI-0124, HTD-1801, HTD-2802, hydroxymethylcoumarol, IDN-7314, NGM-282, norursodeoxycholic acid, ORBCEL-C, integrin α-V / β-1 and β-6 antagonists: PLN-74809; PPARδ agonists: seladelpar lysine; SCT-5-27, PTGS2 gene and TGFβ1 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 antagonist: DUR-928; and CCR5 / CCR2 chemokine antagonist: cenicriviroc.

[0504] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of: HIV combination drugs, other drugs for treating HIV, HIV protease inhibitors, inhibitors of HIV non-nucleoside or non-nucleotide reverse transcriptases, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversing agents, 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 regulators, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, TAT protein inhibitors, HIV-1 Nef regulators, Hck tyrosine kinase regulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor regulators, COMM domain-containing protein 1 regulators, HIV ribonuclease H inhibitors, retrocyclin regulators, CDK-9 inhibitors, dendritic ICAM-3 capture non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or pharmaceutically acceptable salts thereof, or any combination thereof.

[0505] In some embodiments, the one or more additional therapeutic agents are selected from compounds that inhibit HIV protease, HIV non-nucleoside reverse transcriptase inhibitors, HIV non-nucleotide reverse transcriptase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers and other drugs used to treat HIV, or pharmaceutically acceptable salts of the foregoing, or any combination thereof.

[0506] In some embodiments, one or more additional therapeutic agents are immunomodulators, e.g., immunostimulators or immunosuppressants. In certain other embodiments, immunomodulators are agents that alter immune checkpoint function, including CTLA-4, LAG-3, B7-H3, B7-H4, Tim3, BTLA, KIR, A2aR, CD200, and / or PD-1 pathways. In other embodiments, immunomodulators are immune checkpoint modulators. Exemplary immune checkpoint regulators 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 -CD86 antibodies, anti-B7RP1 antibodies, anti-B7-H3 antibodies, anti-HVEM antibodies, anti-CD137 or -CD137L antibodies, anti-OX40 or -OX40L antibodies, anti-CD40 or -CD40L antibodies, anti-GAL9 antibodies, anti-IL-10 antibodies, and A2aR drugs. For certain of these immune pathway gene products, it is contemplated that antagonists or agonists of such gene products will be used, as well as small molecule regulators of such gene products. In some embodiments, immunomodulatory agents include those that alter the function of mediators in cytokine-mediated signaling pathways.

[0507] In some embodiments, a compound as disclosed herein (e.g., a compound described herein) can be combined with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents at any dose of the compound described herein (e.g., 10 mg to 1000 mg of the compound).

[0508] The compounds described herein can be combined with the agents provided herein (at any dose of the compound (e.g., 50 mg to 500 mg of the compound, as if each dose were individually and specifically listed).

[0509] In some embodiments, there is provided a kit comprising a pharmaceutical composition, the pharmaceutical composition comprising a compound as described herein or a compound as 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, there is provided a kit comprising a compound disclosed herein or a pharmaceutically acceptable salt, stereoisomer, a mixture of stereoisomers, a tautomer or a deuterated analog thereof, which is combined with one or more (e.g., one, two, three, four, one or two, or one to three or one to four) additional therapeutic agents. Any pharmaceutical composition provided by the present invention can be used in a kit, as each and every composition used in the kit is specifically and individually listed. In some embodiments, the kit includes instructions for treating an inflammatory disease or condition. In some embodiments, the instructions in the kit relate to the use of a pharmaceutical composition for treating IBD.

[0510] List of abbreviations and acronyms

[0511] Abbreviation meaning

[0512] % Percent

[0513] ℃ degrees Celsius

[0514] Ac acetyl

[0515] AcOH acetic acid

[0516] ACN / CH3CN / MeCN acetonitrile

[0517] ADME absorption, distribution, metabolism and excretion

[0518] AIBN 2,2′-azobis(2-methylpropionitrile)

[0519] Aq. Water-based

[0520] ASK apoptosis signal-regulating kinase

[0521] Bicarb

[0522] Bn benzyl

[0523] BOC / Boc tert-Butoxycarbonyl

[0524] Bpin pinacol borane

[0525] br broad peak

[0526] CAS Chemical Abstracts Service

[0527] cataCXiumA Di(1-adamantane)-n-butylphosphine

[0528] CNS Central Nervous System

[0529] COPD Chronic Obstructive Pulmonary Disease

[0530] CREST calcinosis, Raynaud's syndrome, esophageal dysmotility,

[0531] Digital sclerosis and telangiectasia

[0532] CVP cyclophosphamide, vincristine, prednisone

[0533] d Twin Peaks

[0534] D / d deuterium

[0535] DAST Diethylaminosulfur trifluoride

[0536] 1,4-diazabicyclo[2.2.2]octane

[0537] DCC N,N′-dicyclohexylcarbodiimide

[0538] DCE dichloroethane

[0539] DCM Dichloromethane / Methylene Chloride

[0540] dd doublet

[0541] DIEA N,N-Diisopropylethylamine

[0542] DIPEA N,N-Diisopropylethylamine

[0543] DMA N,N-dimethylacetamide

[0544] DMAP 4-dimethylaminopyridine

[0545] DME dimethoxyethane

[0546] DMF dimethylformamide

[0547] DMPK Drug Metabolism and Pharmacokinetics

[0548] DMSO dimethyl sulfoxide

[0549] DPPA diphenylphosphonazide

[0550] dppf 1,1'-bis(diphenylphosphino)ferrocene

[0551] dppp 1,3-bis(diphenylphosphino)propane

[0552] EC 50 half maximum effective concentration

[0553] equiv / eq equivalent

[0554] EA Ethyl acetate

[0555] Et ethyl

[0556] Et2O diethyl ether

[0557] EtOAc / AcOEt ethyl acetate

[0558] EtOH

[0559] F Fahrenheit

[0560] FBS fetal bovine serum

[0561] g grams

[0562] Gp glycoprotein

[0563] h / hr hour

[0564] HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo

[0565] [4,5-b]pyridinium 3-oxide hexafluorophosphate)

[0566] hex hexane

[0567] HPLC High-pressure liquid chromatography

[0568] Hz Hertz

[0569] IL interleukin

[0570] IUPAC International Union of Pure and Applied Chemistry

[0571] J coupling constant (MHz)

[0572] JAK Janus kinase

[0573] Kg / kg kilogram

[0574] KOAc potassium acetate

[0575] L liter

[0576] LCMS / LC-MS liquid chromatography-mass spectrometry

[0577] LHMDS Lithium Hexamethyldisilazide

[0578] LiMg-TMP 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex

[0579] M Moore

[0580] m multiplet

[0581] M+ mass peak

[0582] M+H mass peak hydrogenation

[0583] m-CPBA m-chloroperbenzoic acid

[0584] Me methyl

[0585] Me2N dimethylamine

[0586] MeI iodomethane

[0587] MeOH methanol

[0588] MeOTs Methyl p-toluenesulfonate

[0589] mg milligrams

[0590] MHz Megahertz

[0591] min / m minutes

[0592] ml / mL milliliter

[0593] mM millimolar concentration

[0594] mmol millimole

[0595] mol mole

[0596] MS

[0597] MS multiple sclerosis

[0598] MsCl methanesulfonyl chloride

[0599] MTBE methyl tert-butyl ether

[0600] M / Z mass / charge

[0601] N equivalent concentration

[0602] NADH reduced nicotinamide adenine dinucleotide

[0603] NaOH sodium hydroxide

[0604] NBS N-bromosuccinimide

[0605] ng nanogram

[0606] NIS N-iodosuccinimide

[0607] nM nanomolar concentration

[0608] NMR Nuclear Magnetic Resonance

[0609] ON Overnight

[0610] PEG polyethylene glycol

[0611] PET Positron emission tomography

[0612] Ph Phenyl

[0613] PhMe toluene

[0614] PhNO2 Nitrobenzene

[0615] PhNTf2 N-phenylbis(trifluoromethanesulfonimide)

[0616] pH indicates how acidic or basic a solution is

[0617] prep

[0618] RA rheumatoid arthritis

[0619] Rf retention factor

[0620] RPM revolutions per minute

[0621] RT / r Room temperature

[0622] RuPhos 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl

[0623] s seconds

[0624] s single peak

[0625] sat. saturated

[0626] SFC Supercritical Fluid Chromatography

[0627] SLE Systemic lupus erythematosus

[0628] SPECT Single Photon Emission Computed Tomography

[0629] SPhos Pd G3 Methanesulfonic Acid (2-Biscyclohexylphosphino-2′,6′-dimethoxybiphenyl)

[0630] [2-(2′-amino-1,1′-biphenyl)]palladium(II)

[0631] SYK spleen tyrosine kinase

[0632] t Triplet

[0633] TBACl Tetrabutylammonium chloride

[0634] TBS / TBDMS tert-butyldimethylsilyl

[0635] TBTU 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoro

[0636] borate

[0637] tBuOH tert-butyl alcohol

[0638] tBuBrettPhos Pd G3 methanesulfonic acid [(2-di-tert-butylphosphine-3,6-dimethoxy

[0639] -2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)

[0640] benzene)] palladium(II)

[0641] TCA trichloroacetic acid

[0642] TEA / NEt3 triethylamine

[0643] temp. temperature

[0644] TES triethylsilane

[0645] TFA trifluoroacetic acid

[0646] TFAA trifluoroacetic anhydride

[0647] THF Tetrahydrofuran

[0648] TLC thin layer chromatography

[0649] TMP Tetramethylpiperidine

[0650] TMS trimethylsilyl

[0651] Tol Toluene

[0652] TPL2 Tumor Progression Locus 2

[0653] Kinase

[0654] trityl triphenylmethyl

[0655] Vac

[0656] w / v weight / volume

[0657] w / w weight / weight

[0658] XPhos Pd G3 methanesulfonic acid (2-dicyclohexylphosphine-2′,4′,6′-triisopropyl

[0659] -1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

[0660] δ chemical shift (ppm)

[0661] μg microgram

[0662] μL / μl microliter

[0663] μM micromolar concentration

[0664] μm micrometer

[0665] μmol micromole

[0666] synthesis

[0667] The compounds of the present invention can be prepared using the methods disclosed herein and conventional modifications thereof, which are obvious in view of the disclosure herein and methods known in the art; in addition to the teachings herein, conventional and well-known synthetic methods can also be used. The synthesis of typical compounds of formula (I), such as compounds having a structure described by one or more formulas (I), or other formulas or compounds disclosed herein, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, enantiomers, tautomers or deuterated analogs thereof, can be accomplished as described in the following examples.

[0668] Salts (eg, TFA salts) can be converted to the free base / acid or other pharmaceutically acceptable salts.

[0669] General solution

[0670] According to the embodiment of the typical compound of the present invention, the compound can be synthesized using general synthesis scheme and / or the examples described below. In view of the description herein, it is apparent that the general scheme can be changed by replacing the starting material with other materials with similar structures, so as to obtain corresponding different products. The following description of synthesis provides many examples, illustrating how the starting material changes to provide corresponding products. Starting material is usually obtained from commercial sources, or synthesized using the disclosed method (which is an embodiment of the present invention) of synthesizing compounds, and the structure of the compound to be synthesized will provide the identification of each substituent. According to the examples herein, the determination of the final product will usually make the determination of the required starting material become apparent by a simple inspection process.

[0671] General Solution 1

[0672]

[0673] Scheme 1 describes a general route for preparing some compounds of formula I. Starting from the intermediate AA1 having a hydroxyl or halogen as Z and a halogen group as X, amino acid esters (AA2) can be prepared under a variety of conditions (e.g., Scholkopf, Maruoka, etc.). After suitable protection of the free amine with a protecting group (PG) (e.g., triphenylmethyl, Boc, etc.), AA2 is converted to a boronic acid or boronate ester (AA3) under standard conditions (e.g., Miyaura). R is introduced under various cross-coupling conditions. 1 After removal of the amine protecting group (PG) under appropriate conditions, the amine is coupled with an acid to provide the heterocyclic compound AA5.

[0674] General Solution 2

[0675]

[0676] Scheme 2 describes a general route for the preparation of some compounds of formula I. Starting from the intermediate BB1 ​​with a halogen as Z and a halogen group as X, amino acid esters (BB2) can be prepared under a variety of conditions (mainly Negishi). After appropriate removal of the protecting group (e.g., benzyloxycarbonyl, CBZ), BB2 is converted to the free amine (BB3) under standard conditions (e.g., Pd / H2). R is introduced with an appropriate carboxyl or amine under various urea-forming conditions. 1 After removal of the amine protecting group (PG) under appropriate conditions, the amine is coupled with a carboxylic acid or an acid chloride to provide the heterocyclic compound BB5. Example

[0677] Example 1

[0678] Synthesis of 8-bromo-5-methylquinoline (1A): at room temperature, to the 2-bromo-5-methylaniline (1200g, 6.45mol) of stirring at nitrobenzene (660mL) and 75% H SO (3.6L) solution add glycerol (1180g, 6.45mol) and then slowly heat to 150 ℃ and continue 3h.This mixture is cooled to room temperature and poured into ice water, while maintaining temperature below 10 ℃.With the 10N NaOH aqueous solution, pH is adjusted to about 10 and the product is extracted with ethyl acetate.The organic layer washed with salt water that merges, use anhydrous Na SO Dry and concentrate under vacuum to obtain material, it is dissolved in DCM / hexane (5:1) and stirred 30 minutes.Filter out solid and evaporated under reduced pressure filtrate to obtain 1A.

[0679]

[0680] 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 h. The reaction mixture 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 Na2SO4 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 obtain 1B.

[0681] 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) at room temperature was added (-)-cinchonidine (35 g, 0.12 mol). The reaction mixture was cooled to 10°C, 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 minutes. DCM was added and the organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The material was purified by 100-200 mesh silica gel column chromatography and eluted with 10-15% ethyl acetate in hexanes to give compound 1C.

[0682] Synthesis of (S)-2-amino-3-(8-bromoquinolin-5-yl)methyl propanoate (1D): To a stirred solution of 1C (400 g, 845 mmol) in methanol (2 L) was added HCl (2.8 L, 4 N) in 1,4-dioxane, keeping the temperature below 5 ° C. The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was concentrated under reduced pressure, dissolved in water, and washed with ethyl acetate. The aqueous layer was adjusted to about 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 obtain a 70:30 mixture of racemic 1D. The suspension of the substance in MTBE was heated to reflux and maintained for 1 h. The reaction mixture was cooled to room temperature, the solid was filtered out and the filtrate was evaporated under reduced pressure to obtain a solid, which was stirred again with MTBE at room temperature. The solid was filtered out and the filtrate was evaporated under reduced pressure to obtain 1D. This material was dissolved in ethyl acetate, cooled to 0°C, followed by addition of 4N HCl and allowed to stir at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and triturated with MTBE to afford ID.

[0683] Synthesis of (S)-2-amino-3-(8-(2-chloro-4-cyanophenyl)quinoline-5-yl)methyl propanoate (1E): 1D (50 mg, 0.145 mmol), (2-chloro-4-cyanophenyl)boric acid (45 mg, 0.246 mmol), Pd(PPh 3 ) 4 (8 mg, 0.007 mmol) and Na CO 3 aqueous solution (0.217 mL, 2 M) in DME (2 mL) were added to a microwave vial. 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 salt water, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The material was purified by silica gel chromatography using 0-30% MeOH in EA to obtain the title compound.

[0684] 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.

[0685] 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 h and then concentrated under reduced pressure. The material was purified by reverse phase HPLC to obtain the title compound. MS (m / z) 488.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ9.03(d,J=8.4Hz,1H),8.84(dd,J=4.2,1.6Hz,1H),8.64(dd ,J=8.7,1.7Hz,1H),8.16(d,J=1.7Hz,1H),7.90(d,J=7.9Hz,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=6.7Hz,2H),4.82(t,J=9.9 Hz, 1H), 3.39 (d, J = 12.9Hz, 1H), 2.65 (s, 1H), 2.31 (s, 1H), 2.07 (s, 1H), 1.96 (s, 3H).

[0686] Example 2

[0687]

[0688] 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 presented method 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 (400MHz, DMSO-d6) δ9.27(d,J=8.3Hz,1H),8.84(dd,J=4.1,1.6Hz,1H),8. 65(dd,J=8.6,1.7Hz,1H),8.16(dd,J=1.7,0.4Hz,1H),7.91(d,J=7.9Hz,1H),7 .68-7.60(m,3H),7.54(d,J=7.9Hz,1H),7.42(td,J=8.3,6.1Hz,1H),7.30-7. 19(m,2H),4.82(s,1H),3.77(d,J=14.7Hz,1H),3.38(dd,J=14.6,10.6Hz,1H).

[0689] Example 3

[0690] Synthesis of (S)-methyl 3-(8-bromoquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (3A): The title compound was prepared according to the procedure presented for the synthesis of compound 1F starting with 2,6-difluorobenzoyl chloride and 1D.

[0691] Synthesis of (S)-methyl 3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (3B): The title compound was prepared according to the procedure presented for the synthesis of compound 1E starting from 3A.

[0692]

[0693] Synthesis of (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoic acid (3): The title compound was prepared according to the presented method for the synthesis of compound 1F starting with 3B. MS (m / z) 492.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.25(d,J=8.1Hz,1H),8.84(dd,J=4.1,1.6Hz,1H),8.64(dd,J=8.8,1.7Hz,1H),8.15(d,J=1.7Hz,1H),7.90(dd,J= 8.0,1.7Hz,1H),7.66-7.61(m,3H),7.57(d,J=7.9Hz,1H),7.53-7.41(m,1H),7.10(t,J=8.0Hz,2H),4.77(s,1H),3.76(s,1H),3.41(s,1H).

[0694] Example 4

[0695]

[0696] (S)-Methyl 3-(8-bromoquinolin-5-yl)-2-(2,6-dichlorobenzamido)propanoate (4A): The title compound was prepared according to the procedure presented for the synthesis of compound 3A starting with 2,6-dichlorobenzoyl chloride and ID.

[0697] 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)Cl2 (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 hours. EA was added followed by filtration through celite and concentration under reduced pressure to afford the title compound, which was used without further purification.

[0698] 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 aqueous K3PO4 (0.6 mL, 1 M). The reaction mixture was degassed with nitrogen and heated at 90°C for 30 min. The reaction mixture was concentrated under reduced pressure to give the title compound, which was used without further purification.

[0699] Synthesis of (S)-3-(8-(2,6-dichloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-dichlorobenzamido)propanoic acid (4): The title compound was prepared according to the presented method for the synthesis of compound 1, starting with 4C. MS (m / z) 558.0 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ9.28(d,J=8.4Hz,1H),8.82(dd,J=4.2,1.6Hz,1H),8.65(dd,J=8.7,1.6Hz,1H),8.25-8.15(m,2H),7.74-7.62(m,2H ), 7.60 (d, J = 7.3Hz, 1H), 7.45-7.32 (m, 3H), 4.83 (ddd, J = 11.8, 8.6, 3.7Hz, 1H), 3.78 (dd, J = 14.5, 3.8Hz, 1H), 3.38 (dd, J = 14.5, 11.0Hz, 1H).

[0700] Example 5

[0701] 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 procedure presented for the synthesis of compound 4B in Example 4, starting with 3A.

[0702] Synthesis of (S)-methyl 3-(8-(4,5-dichloro-2-methoxyphenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (5B): To a microwave vial were added 5A (145 mg, 0.234 mmol), 1-bromo-4,5-dichloro-2-methoxybenzene (50 mg, 0.195 mmol), Pd(PPh3)4 (11 mg, 0.01 mmol) and aqueous Na2CO3 solution (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 Na2SO4, and concentrated under reduced pressure to obtain the title compound.

[0703] 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 according to the presented method for the synthesis of compound 1, starting with 5B. MS (m / z) 530.7 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.27(d,J=8.1Hz,1H),8.86(dd,J=4.3,1.6Hz,1H),8. 73-8.61(m,1H),7.66(dd,J=8.6,4.3Hz,1H),7.60(q,J=7.4Hz,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=14.5,4.4Hz,1H),3.64(s,3H),3.39(dd,J=14.6,10.1Hz,1H),1.05(s,1H).

[0704]

[0705] Synthesis of 2-bromo-5-fluoro-1-methoxy-3-(trifluoromethyl)benzene (6A): To a solution of stirred 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 salt water, dried over anhydrous NaSO, and concentrated under reduced pressure and purified by silica gel chromatography using hexane / EA as a gradient.

[0706] 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 according to the procedure presented for the synthesis of compound 5B starting from 5A and 6A.

[0707] 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 according to the procedure presented for the synthesis of compound 1, starting with 6B. MS (m / z) 549.1 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.28(dd,J=12.4,8.1Hz,1H),8.81(dd,J=4.2,1.6Hz,1H),8.67 (d,J=8.7Hz,1H),7.67-7.56(m,2H),7.49(dqd,J=8.2,6.6,1.6Hz,2H),7.41-7.34(m,1H ),7.29(dd,J=9.1,2.5Hz,1H),7.11(ddd,J=8.3,7.4,3.8Hz,2H),4.84-4.75(m,1H),3. 76(dd,J=31.6,4.3Hz,1H), 3.59(d,J=5.7Hz,3H), 3.42(ddd,J=21.3,14.6,10.4Hz,1H).

[0708] Examples 7 and 8

[0709]

[0710] 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 25% EtOH / TFA cosolvent at a flow rate of 50 mL / min on an AD-H 5 μm 21 x 250 mm column. The title compound was identified as the first eluting peak. MS (m / z) 549.1 [M+H] +. 1H NMR (400MHz, methanol-d4) δ9.36 (dd, J=8.7, 1.6Hz, 1H), 8.95 (dd, J=5.0, 1.5Hz, 1H) ,8.00(dd,J=8.7,5.0Hz,1H),7.89(d,J=7.4Hz,1H),7.78(dd,J=7.4,0.9Hz,1 H),7.45(tt,J=8.4,6.4Hz,1H),7.32(s,1H),7.30(s,1H),7.02-6.95(m,2H), 5.12(dd,J=9.8,5.2Hz,1H), 4.03(dd,J=14.4,5.2Hz,1H), 3.71-3.63(m,4H).

[0711] 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 25% EtOH / TFA cosolvent at a flow rate of 50 mL / min on an AD-H 5 μm 21 x 250 mm column. The title compound was identified as the second eluting peak. MS (m / z) 549.1 [M+H] + . 1H NMR (400MHz, methanol-d4) δ9.35(dd,J=8.7,1.5Hz,1H),8.95(dd,J=5.0,1.5Hz,1H),7.99(dd,J=8.6,5.0Hz,1H),7.86(d,J=7.4Hz,1H),7.77(d,J=7.4Hz,1H) ,7.45(tt,J=8.6,6.4Hz,1H),7.32(s,1H),7.29(s,1H),7.03-6.96(m,2H),5 .14(dd,J=9.9,5.0Hz,1H),4.04(dd,J=14.6,5.1Hz,1H),3.69-3.61(m,4H).

[0712] Example 9

[0713]

[0714] Synthesis of (S)-methyl 2-(2,6-difluorobenzamido)-3-(8-(3-methoxynaphthalen-2-yl)quinolin-5-yl)propanoate (9A): The title compound was prepared according to the procedure presented for the synthesis of compound 5B starting with 2-bromo-3-methoxynaphthalene and 5A.

[0715] Synthesis of (S)-2-(2,6-difluorobenzamido)-3-(8-(3-methoxynaphthalen-2-yl)quinolin-5-yl)propanoic acid (9): The title compound was prepared according to the presented method for the synthesis of compound 1, starting with 9A. MS (m / z) 513.0 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ9.30(d,J=8.2Hz,1H),8.86(d,J=4.8Hz,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, 6.9,1.2Hz,1H),7.17-7.08(m,2H),4.80(ddd,J=10.1,8.1,4.4Hz,1H),3.80(dd,J=14.6,4.5Hz,1H),3.71(s,3H),3.45(dd,J=14.6,10.1Hz,1H).

[0716] Example 10

[0717]

[0718] 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 was added KCO (2.3 g, 16.4 mmol) and (bromomethyl)cyclopropane (0.82 g, 6.0 mmol). The reaction mixture was stirred at 70 ° C for 2 hours. 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 a gradient.

[0719] 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 according to the procedure presented for the synthesis of compound 5B starting from 10A and 5A.

[0720] 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 procedure presented for the synthesis of compound 1, starting with 10B. MS (m / z) 538.6 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.81(s,1H),9.28(d,J=8.1Hz,1H),8.89(d,J=4.1Hz,1H),8.69(s,2H ),7.66(d,J=7.3Hz,2H),7.60(d,J=7.4Hz,1H),7.55-7.45(m,1H),7.37-7.21(m,2H),7.16-7.0 8(m,2H),4.76(td,J=10.3,9.2,4.2Hz,1H),3.78-3.74(m,2H),3.41(dd,J=14.6,10.0Hz,1H), 3.10(p,J=4.8Hz,2H),0.81(d,J=4.8Hz,1H),0.24(dt,J=9.0,2.9Hz,2H),-0.01--0.05(m,2H).

[0721] Example 11

[0722] 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 procedure presented for the synthesis of compound 4C of Example 4 starting with 2-bromo-3,5,6-trimethylpyridine and 5A.

[0723]

[0724] 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 according to the presented method for the synthesis of compound 1, starting with 11A. MS (m / z) 476.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.33(d,J=8.3Hz,1H),8.89(dd,J=4.2,1.6Hz,1H),8.78- 8.72(m,1H),8.36(s,1H),7.92(d,J=7.5Hz,1H),7.78-7.69(m,2H),7.49(tt,J=8 .5,6.6Hz,1H),7.11(dd,J=8.4,7.6Hz,2H),4.84-4.74(m,1H),3.85(dd,J=14.3, 4.2Hz, 1H), 3.43 (dd, J = 14.4, 10.4Hz, 1H), 2.64 (s, 3H), 2.46 (s, 3H), 2.05 (s, 3H).

[0725] Example 12

[0726]

[0727] 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 according to the method presented for the synthesis of compound 4C of Example 4 starting with 2-bromo-5,6-dimethyl-3-(trifluoromethyl)pyridine and 5A and Pd XPhos G4.

[0728] 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 according to the presented method for the synthesis of compound 1, starting with 12A. MS (m / z) 530.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.28(d,J=8.1Hz,1H),8.77(dd,J=4.1,1.6Hz,1H),8.62(dd,J=8.7,1.6Hz,1H),8.02(s,1H),7.62-7.54(m,3 H),7.52-7.43(m,1H),7.11(dd,J=8.5,7.5Hz,2H),4.74(td,J=9.0,4.3Hz,1H),3.75(m,1H),3.40(m,1H),2.50(s,3H),2.41(s,3H).

[0729] Example 13

[0730]

[0731] 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 for the synthesis of compound 4C of Example 4 presented, starting with 3-bromo-4-methoxy-1-methylpyridin-2(1H)-one and 5A.

[0732] 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 according to the presented method for the synthesis of compound 1, starting with 13A. MS (m / z) 464.1 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ9.32 (d, J=7.9Hz, 1H), 9.08-8.98 (m, 1H), 8.96 (d, J= 4.6Hz,1H),7.95(d,J=7.7Hz,1H),7.91-7.83(m,1H),7.75-7.65(m,2H),7.5 0(tt,J=8.4,6.5Hz,1H),7.16-7.08(m,2H),6.49(dd,J=7.7,3.5Hz,1H),4.8 4-4.72(m,1H),3.85-3.75(m,1H),3.68(d,J=7.5Hz,3H),3.55-3.40(m,4H).

[0733] Example 14

[0734]

[0735] 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 with 3-bromo-1-methylquinolin-2(1H)-one and 5A.

[0736] Synthesis of (S)-2-(2,6-difluorobenzamido)-3-(1-methyl-2-oxo-1,2-dihydro-[3,8'-biquinolin]-5'-yl)propanoic acid (14): The title compound was prepared according to the procedure presented for the synthesis of compound 1, starting with 14A. MS (m / z) 514.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ9.30(d,J=8.1Hz,1H),8.88(d,J=4.3Hz,1H),8.77(s,1H),7 .98(s,1H),7.78(dd,J=7.8,1.5Hz,1H),7.74(d,J=7.3Hz,1H),7.70-7.56(m,3H),7 .49(tt,J=8.4,6.5Hz,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=14.5,4.5Hz,1H),3.68(s,3H),3.44(dd,J=14.5,9.9Hz,1H).

[0737] Example 15

[0738] Synthesis of (S)-methyl 2-(2,6-difluorobenzamido)-3-(5'-fluoro-[8,8'-biquinolin]-5-yl)propanoate (15A): The title compound was prepared according to the procedure presented for the synthesis of compound 3B starting with (5-fluoroquinolin-8-yl)boronic acid and 3A.

[0739] Synthesis of (S)-2-(2,6-difluorobenzamido)-3-(5'-fluoro-[8,8'-biquinolin-5-yl)propanoic acid (15): The title compound was prepared according to the procedure presented for the synthesis of compound 1, starting with 15A. MS (m / z) 502.9 [M+H] + . 1HNMR(400MHz,DMSO-d6)δ9.32(d,J=8.1Hz,1H),8.74(dd,J=4.2,1.8Hz,1H),8.70(s,1H),8.56(d,J=8 .7Hz,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).

[0740]

[0741] Example 16

[0742]

[0743] 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 were 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 hr. The reaction mixture was concentrated under reduced pressure and used without further purification.

[0744] Synthesis of (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(3-(difluoromethoxy)-2,6-difluorobenzamido)propanoic acid (16): The title compound was prepared according to the procedure presented for the synthesis of compound 1, starting with 16A. MS (m / z) 559.9 [M+H] +. 1H NMR(400MHz, DMSO-d6)δ8.16(m,J=8.4Hz,3H),7.67(d,J=8.5Hz,2H),7.56-7.21(m, 6H), 4.75 (ddd, J=11.7, 8.4, 3.7Hz, 1H), 3.10 (m, 2H) 2.99 (dd, J=14.3, 11.3Hz, 1H).

[0745] Example 17

[0746]

[0747] 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 presented method 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] + . 1H NMR (400MHz, DMSO-d6) δ9.37(d,J=8.4Hz,1H),8.84(dd,J=4.1,1.6Hz,1H),8.64(dd,J=8.6,1.6Hz,1H),8.16(dd,J=1.6,0.4Hz,1H),7.91(d,J=7.8Hz, 1H),7.67-7.64(m,1H),7.63(s,2H),7.55(d,J=7.9Hz,1H),7.33(td,J=8.7 ,3.8Hz,1H),4.83(s,1H),3.84-3.74(m,1H),3.38(dd,J=14.6,10.6Hz,1H).

[0748] Example 18

[0749]

[0750] 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 presented method 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] +. 1H NMR (400MHz, DMSO-d6) δ13.09(s,1H),9.30(d,J=8.1Hz,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 .4Hz,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=14.7,10.1Hz,1H),1.21(t,J=7.0Hz,3H).

[0751] Example 19

[0752]

[0753] 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 presented method 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] + . 1H NMR (400MHz, DMSO-d6) δ13.02(s,1H),9.26(d,J=8.1Hz,1H),8.82(dd,J=4.1,1.6Hz,1H),8.68-8.58(m,1H),7.70-7.59(m,3H),7.57(d,J=7.3Hz,1 H),7.47(tt,J=8.5,6.5Hz,1H),7.15-7.03(m,2H),4.78(ddd,J=10.2,8.1 ,4.4Hz,1H),3.76(dd,J=14.5,4.4Hz,1H),3.41(dd,J=14.6,10.3Hz,1H).

[0754] Example 20

[0755]

[0756] 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 presented method 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 (400MHz, DMSO-d6) δ9.27(d,J=8.2Hz,1H),8.83(dd,J=4.1,1.6Hz,1H),8.75(d,J=2.4Hz,2H),8.66(dd,J=8.7,1.7Hz,1H),7.69-7.60(m,3H),7.4 7(tt,J=8.5,6.5Hz,1H),7.09(dd,J=8.4,7.5Hz,2H),4.80(ddd,J=10.4,8. 2, 4.4Hz, 1H), 3.78 (dd, J = 14.5, 4.4Hz, 1H), 3.43 (dd, J = 14.6, 10.4Hz, 1H).

[0757] Example 21

[0758] 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 presented method 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] + . 1H NMR (400MHz, DMSO-d6) δ9.41(s,1H),8.62(s,1H),8.30(s,1H),8.15-7.98(m,4H),7.11(d,J=6.7Hz,3H),6.82(d,J=9.1Hz,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=7.0Hz,3H).

[0759]

[0760] Example 22

[0761] 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 presented method for the synthesis of compounds 3A, 3B, and 3 starting with 2,6-dichloro-4-fluorobenzoyl chloride and ID. MS (m / z) 541.9 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ9.26(d,J=8.5Hz,1H),8.83(dd,J=4.1,1.6Hz,1H),8.65(dd,J=8.7,1.7Hz,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=8.6Hz,3H),4.84(s,1H),3.76(dd,J=14.5,4.1Hz,1H),3.37(s,1H).

[0762]

[0763] Example 23

[0764]

[0765] 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 presented method for the synthesis of compounds 1F and 1, starting with 2-fluoro-6-methoxybenzoyl chloride and 1E. MS (m / z) 504.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.92(d,J=8.1Hz,1H),8.84(dd,J=4.1,1.6Hz,1H),8.64(dd,J =8.7,1.7Hz,1H),8.16(dd,J=1.6,0.4Hz,1H),7.90(dd,J=7.9,1.7Hz,1H),7.68-7.64( m,2H),7.58(d,J=7.6Hz,1H),7.35(td,J=8.4,6.8Hz,1H),6.84(d,J=8.5Hz,1H),6.78( t,J=8.6Hz,1H),4.80-4.68(m,1H),3.69-3.65(m,1H),3.63(s,3H),3.50-3.40(m,1H).

[0766] Example 24

[0767]

[0768] 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 were added acetone (1.8 mL), Pd(OAc)2 (18 mg, 0.081 mmol), Cs2CO3 (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 N2 for 5 min and then heated to 100°C for 2.5 hours. The reaction mixture was filtered through celite, rinsed with EA and purified by silica gel chromatography using EA in hexanes as eluent to give the title compound.

[0769] Synthesis of 2,6-difluoro-4-(2-hydroxypropyl)benzoic acid methyl ester (24B): To a stirred solution of 24A (306.4 mg, 1.34 mmol) in MeOH, ammonium acetate (1.04 g, 13.43 mmol) was added. NaBH (83.81 mg, 2.22 mmol) was then slowly added to prevent a large amount of heat release. The reaction mixture was stirred at room temperature for 2 hours, and NaOH (1 M) and DCM were then added. The organic layer was washed with salt water, dried, and concentrated under reduced pressure. The material was purified by silica gel chromatography using EA and hexane as eluents to obtain the title compound.

[0770] 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, 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.

[0771] (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 presented method 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)δ9.18(d,J=8.1Hz,1H),8.84(dd,J=4.2,1.6Hz,1H),8.64(d d,J=8.6,1.6Hz,1H),8.16(d,J=1.6Hz,1H),7.90(dd,J=7.9,1.6Hz,1H),7.68-7.5 9(m,3H),7.57(d,J=7.9Hz,1H),6.94(d,J=8.8Hz,2H),4.80-4.69(m,1H),3.80(pd ,J=8.9,7.6,3.0Hz,2H),3.40(s,1H),2.62(d,J=6.2Hz,2H),1.02(d,J=6.1Hz,3H).

[0772] Example 25

[0773] 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 presented method for the synthesis of compound 16A starting with 4-(tert-butoxycarbonyl)-2,6-difluorobenzoic acid and 1E.

[0774] 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 obtain the title compound.

[0775]

[0776] (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 presented procedure for the synthesis of compound 1 starting with 25B. MS (m / z) 535.8 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ9.40(d,J=8.2Hz,1H),8.84(dd,J=4.1,1.6Hz,1H),8.64(dd,J=8.7,1.7Hz,1H),8.16(d,J=1.6Hz,1H),7.95-7. 86(m,1H),7.64(t,J=4.3Hz,1H),7.61(d,J=5.1Hz,1H),7.57(dd,J=7.7,6.0Hz,2H),4.80(t,J=11.5Hz,1H),3.79(s,1H),3.41(s,1H).

[0777] Example 26

[0778]

[0779] (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 presented procedure for the synthesis of compounds 16A and 16, starting with 25B and aniline. MS (m / z) 611.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ10.35(s,1H),9.41(d,J=8.3Hz,1H),8.88-8.80(m,1H),8.65(d,J=8.7Hz,1H),8.16(d,J=1.6Hz,1H),7.91(d,J=8. 2Hz,1H),7.76-7.61(m,7H),7.57(d,J=7.9Hz,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).

[0780] Example 27

[0781]

[0782] Synthesis of (R)-methyl 2,6-difluoro-4-((1-phenylethyl)carbamoyl)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-phenylethane-1-amine (13.46 mg, 0.11 mmol), HATU (42 mg, 0.11 mmol) and TEA (0.06 mL, 0.463 mmol). The reaction mixture was stirred at room temperature for 1 h, concentrated under reduced pressure, and then purified by silica gel chromatography using DCM / MeOH as eluent.

[0783] 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 eluent.

[0784] (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 presented method for the synthesis of compounds 16A and 16, starting with 27B. MS (m / z) 639.2 [M+H]+. 1H NMR(400MHz,DMSO-d6)δ9.35(d,J=8.3Hz,1H),8.98(d,J=7.9Hz,1H),8.84(dd, J=4.1,1.6Hz,1H),8.64(d,J=7.7Hz,1H),8.16(d,J=1.6Hz,1H),7.90(d,J=7.7 Hz,1H),7.66-7.53(m,6H),7.32(dt,J=15.1,7.5Hz,4H),7.21(t,J=7.1Hz,1H) ,5.11(t,J=7.3Hz,1H),4.80(s,1H),3.50-3.40(m,1H),1.45(d,J=7.0Hz,3H).

[0785] Example 28

[0786]

[0787] (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 presented method for the synthesis of compounds 16A and 16, starting with 25B. MS (m / z) 616.9 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ9.38(d,J=8.3Hz,1H),9.29(t,J=6.4Hz,1H),8.84(dd,J=4.2,1.6Hz,1H),8.68-8.60(m,1H),8.16(d,J=1.6Hz,1H),7.9 0(d,J=8.1Hz,1H),7.64(d,J=4.6Hz,1H),7.62-7.58(m,3H),7.57(d,J= 7.9Hz, 1H), 4.80 (s, 1H), 4.09 (dd, J = 9.8, 6.4Hz, 1H), 3.75-3.60 (m, 1H).

[0788] Example 29

[0789] 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 procedure presented for the synthesis of compound 16A starting with 2,6-dichloro-4-iodobenzoic acid and 1E.

[0790] Synthesis of (S)-methyl 3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-dichloro-4-(3-hydroxy-3-methylbutyl-1-ynyl-1-yl)benzamido)propanoate (29B): To a stirred solution of 29A (60 mg, 0.09 mmol) in THF was added 2-methylbutyl-3-ynyl-2-ol (0.02 ml, 0.27 mmol), CuI (3.44 mg, 0.02 mmol), PdCl(PPh) (12.71 mg, 0.02 mmol) and DIEA (0.08 ml, 0.45 mmol). The reaction mixture was stirred at 60 ° C for 1 h and then concentrated under reduced pressure and used without further purification.

[0791] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-dichloro-4-(3-hydroxy-3-methylbutyl-1-ynyl-1-yl)benzamido)propanoic acid (29): The title compound was prepared according to the procedure presented for the synthesis of compound 1, starting with 29B. MS (m / z) 606.0 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ13.04(s,1H),9.30(d,J=7.9Hz,1H),8.83(dd,J=4.1,1. 6Hz,1H),8.64(dd,J=8.6,1.7Hz,1H),8.18-8.13(m,1H),7.91(d,J=8.2Hz,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,1 H), 3.76 (dd, J = 14.4, 4.2Hz, 1H), 3.39 (t, J = 12.4Hz, 1H), 1.43 (d, J = 3.7Hz, 6H).

[0792]

[0793] Example 30

[0794] Synthetic quinoline-5-methyl-formiate (30A): to the 3-nitrobenzoic acid (244.0g, 1.46mol) of stirring at dense H SO (750mL) solution adds glycerol (1.17L, 15.33mol) and 3-aminobenzoic acid (500.0g, 3.65mol).The reaction mixture obtained is heated to 150 ℃ and keeps 7h.Then the reaction mixture is cooled to 0 ℃ and processed with methyl alcohol (5.0L), and the reaction mixture obtained is heated to reflux 12h.The reaction mixture is cooled to 0 ℃ and quenched with frozen water, and use solid Na CO Neutralization.This solution is extracted with EA (4Lx2), and the organic layer is separated, uses Na SO Drying and under reduced pressure concentrate.This material is carried out to purification by column chromatography, and it uses EA / petroleum ether to obtain 30A.

[0795] Synthesis of 5-(methoxycarbonyl)quinoline 1-oxide (30C): At 0°C, 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). The resulting reaction mixture was warmed to room temperature and stirred for 6 h. 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 eluent to obtain 30C.

[0796]

[0797] 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 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The compound was washed with EA to obtain compound 30D.

[0798] Synthesis of 3-aminoquinoline-5-methyl formate (30E): At 70 ℃, Fe powder (39.38g, 0.705mol) and concentrated HCl (50.0mL) are added to a solution of compound 30D (25.0g, 0.1mol) in a mixture of ethanol (500mL) and water (500mL) and the reaction mixture obtained is stirred for 18h. The reaction mixture is cooled to room temperature, filtered with diatomaceous earth, concentrated under reduced pressure and extracted with DCM. The organic layer is separated and concentrated under vacuum with Na2SO4 dry propionate. The compound is purified by column chromatography using 50% EA in petroleum ether as eluent to obtain 30E.

[0799] Synthesis of 3-fluoroquinoline-5-methyl formate (30F): At 0 ° C, a solution of sodium nitrite (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). The reaction mixture was warmed to room temperature and stirred for 2 h, then filtered under vacuum. The filtered compound was added to chlorobenzene, and the reaction mixture was refluxed at 125 ° C and kept for 2 h. Chlorobenzene was removed by distillation to obtain a material dissolved in DCM and water. The organic layer was washed with water and salt water, used Na SO Drying and concentrated under vacuum. The compound was purified by column chromatography using 4-5% EA in petroleum ether as eluent to obtain 30F.

[0800] 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. The resulting reaction mixture was warmed to room temperature and stirred for 24 h. The reaction mixture was poured onto crushed ice, and the resulting solid was filtered and dried under reduced pressure to afford compound 30G.

[0801] Synthesis of (8-bromo-3-fluoroquinoline-5-yl)methanol (30H): at 0 ° C, 2M LiBH was slowly added to a solution of 30G (26.0 g, 0.091 mol) in THF (260 mL) that was stirred In THF (137 mL, 0.274 mol). The reaction mixture was heated to 40 ° C and kept for 2 h and then cooled to 0 ° C, quenched with ice water and stirred for 30 minutes. The reaction mixture was acidified with 2N HCl (pH 4-5), and heated to 40 ° C and kept for 2 h. The reaction mixture was cooled to room temperature and alkalized with saturated NaHCO solution (pH 8-9), extracted with DCM (250 mLx2). The organic layer was separated, dried and concentrated under reduced pressure using Na SO. The compound was washed with pentane to obtain 31H.

[0802] 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. 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 with saturated NaCO solution (pH 8-9) to give a solid, which was filtered and dried under vacuum to afford 30I.

[0803] 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, 0.072 I) were added and the mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with water (200 mL) and stirred for 15 minutes. 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 obtain 30J.

[0804] Synthesis of (S)-methyl 2-amino-3-(8-bromo-3-fluoroquinolin-5-yl)propanoate free base (30K): 4M 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 x 2 L). The aqueous layer was separated and basified with saturated Na2CO3 (pH approximately 8) and extracted with DCM (500 mL x 5). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain 30K.

[0805] Chiral purification of (S)-methyl 2-amino-3-(8-bromo-3-fluoroquinolin-5-yl)propanoate hydrochloride (30K): 30K was enriched in the desired enantiomer by supercritical fluid chromatography using 50% (0.5% TEA in IPA) co-solvent at a flow rate of 100 mL / min using a Chiralpak IC (30x250 mm), 5 μm column.

[0806] Synthesis of (S)-methyl 2-amino-3-(8-bromo-3-fluoroquinolin-5-yl)propanoate hydrochloride (30K): The free amine was dissolved in DCM (300 mL) at 0 °C and treated with 4 M HCl in 1,4-dioxane (100 mL) and the mixture was stirred at room temperature for 30 min and then concentrated under reduced pressure to afford 30K as the HCl salt.

[0807] Synthesis of (S)-methyl 3-(8-bromo-3-fluoroquinolin-5-yl)-2-(2,6-dichlorobenzamido)propanoate (30L): The title compound was prepared according to the procedure presented for the synthesis of compound 1F starting with 30K and 2,6-dichlorobenzoyl chloride.

[0808] 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 presented procedures for the synthesis of compounds 3B and 3 starting with 30L. MS (m / z) 542.0 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ9.24(d,J=8.4Hz,1H),8.90(d,J=2.7Hz,1H),8.46(d,J=10.3Hz,1H),8.16(dd,J=1.6,0.4Hz,1H),7.92(d,J=7.9Hz,1H),7. 73(d,J=7.4Hz,1H),7.62(d,J=7.3Hz,1H),7.53(d,J=7.9Hz,1H),7.43-7 .24(m,3H),4.87(s,1H),3.69(dd,J=14.6,4.2Hz,1H),3.45-3.35(m,1H).

[0809] Example 31

[0810] Synthesis of 5-bromo-8-iodo-2-methylquinoline (31A): At room temperature, 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 butyl-2-enal (2.35 g, 34 mmol) and then slowly heated to 150°C and maintained for 3 h. Note: Strong 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 about 12 with solid KOH, and the obtained material was collected. The material was washed three times with water, then extracted with ethyl acetate and filtered. The organic solution was concentrated and then purified by flash chromatography, which was washed with a linear gradient of 5-100% DCM / hexane to obtain 31A.

[0811]

[0812] 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 2M sodium carbonate in water (2.44 mL, 4.9 mmol), and the reaction mixture was degassed with dry nitrogen. Tetrakis(triphenylphosphine)palladium(0) (141 mg, 0.12 mmol) was added, the reaction was sealed, and 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 5-50% ethyl acetate / hexane linear gradient to obtain 31B.

[0813]

[0266] Synthesis of methyl 2-((tert-butoxycarbonyl)amino)-3-(8-(4-(ethoxymethyl)-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 mixture 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 / hexanes to afford compound 31C.

[0814] 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 p-toluenesulfonylhydrazide (781 mg, 4 mmol) in THF (3 mL) was added dropwise sodium acetate (609 mg, 4 mmol) in water (3 mL) at 60 ° C., and the reaction mixture was heated to reflux overnight. It was partitioned between ethyl acetate and water, and the aqueous layer was 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 twice more to obtain 31D.

[0815] 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 mixture was stirred at room temperature overnight. It was diluted with EA, and the resulting solid was collected by trituration to obtain 31E.

[0816] 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 procedure presented for the synthesis of compound 1F starting with 31E and 2,6-difluorobenzoyl chloride.

[0817] Synthesis of 2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinolin-5-yl)propanoic acid (31G): Synthesis was carried out by sodium hydroxide method to obtain 31G.

[0818] 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 cosolvent to afford the desired enantiomer 31H as the second eluting peak. MS (m / z) 565.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ8.56(d,J=8.7Hz,1H),7.51-7.41(m,1H),7.38(d,J=7.4Hz,1H),7.32(d,J=8.7Hz,1H),7.26(d,J=7.3Hz,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=7.0Hz,3H).

[0819] Example 32

[0820]

[0821] Synthesis of (8-bromo-3-fluoroquinoline-5-yl)methanol (32A): Use N2 to sweep the flask containing 8-bromo-3-fluoroquinoline-5-methyl formate (1.06g, 3.73mmol) in THF (19mL), then disposable add LiBH4 (813mg, 37.3mmol). After stirring at room temperature for 1h, the reaction mixture is cooled to 0°C and water (6mL) is added, followed by dropwise addition of 1MHCl (84mL). The reaction mixture is heated to 40°C and kept for 2.5 hours, then cooled to room temperature before diluting with water and EA. The solution is extracted and the organic layer is dried with anhydrous MgSO4 and concentrated under reduced pressure. The material is purified by silica gel chromatography using 0-100% EA in hexane to obtain the title compound.

[0822] Synthesis of 8-bromo-5-(bromomethyl)-3-fluoroquinoline (32B): Triphenylphosphine (1.12 g, 4.27 mmol) and CBr (1.42 g, 4.27 mmol) were added to a stirred solution of 32A (729 mg, 2.85 mmol) in DCM (5.7 mL) and stirred at room temperature for 20 min. The reaction mixture was then chromatographed on silica gel using 0-40% EA in hexanes to give the title compound.

[0823]

[0266] 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 with an ice bath before the addition of 50% aqueous KOH (1.8 mL), followed by the addition of 32B (321 mg, 1.01 mmol). The reaction was stirred in an ice bath and slowly warmed to room temperature. After 3.5 hours, the reaction mixture was diluted with water and DCM, and the solution was extracted. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The material was purified by silica gel chromatography using 0-30% EA in hexanes to obtain the title compound.

[0824] 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), K3PO4 (91 mg, 0.426 mmol), SPhosPdG3 (95 mg, 0.122 mmol) were dissolved in toluene (2.4 mL) and heated to 100 ° C for 3 hours. 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 obtained residue was purified by silica gel chromatography using 0-50% EA in hexanes to give the title compound.

[0825] Synthesis of (S)-tert-butyl 2-amino-3-(8-(2,6-dichloro-4-fluorophenyl)-3-fluoroquinolin-5-yl)propanoate (32E): 2M 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 hours, saturated NaHCO and EA were added. The solution was extracted and the organic layer was dried over MgSO and concentrated under reduced pressure. The material was purified by silica gel chromatography using 0-90% EA in hexanes containing 1% TEA to obtain the title compound.

[0826] 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 mixture was cooled to 0 ° C before the dropwise addition of 2,6-difluorobenzoyl chloride (15 μL, 0.121 mmol). After stirring at room temperature for 1.25 hours, water and DCM were added. The aqueous layer was extracted and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The material was purified by silica gel chromatography using 0-40% EA in hexanes to give the title compound.

[0827]

[0266] 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, more TFA (0.06 mL, 0.81 mmol) was added. The reaction mixture was stirred at room temperature for an additional hour and then concentrated under reduced pressure. The material was purified by preparative HPLC using 0-100% MeCN in water with 1% TFA to obtain the title compound. MS (m / z) 537.0 [M+H]. 1H NMR (400MHz, DMSO-d6) δ13.04(s,1H),9.27(d,J=8.2Hz,1H),8.90(d,J=2.7Hz,1 H),8.45(dd,J=10.5,2.8Hz,1H),7.70(d,J=7.4Hz,1H),7.65(d,J=8.6Hz,2H),7 .59(d,J=7.3Hz,1H),7.48(ddd,J=8.5,6.5,1.9Hz,1H),7.15-7.05(m,2H),4.82 (ddd,J=10.2,8.1,4.5Hz,1H),3.78-3.55(m,1H),3.43(dd,J=14.7,10.3Hz,1H).

[0828] Example 33

[0829]

[0830] 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 procedure presented for the synthesis of compound 16A starting with 1E and 4-acetyl-2,6-difluorobenzoic acid.

[0831] (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 presented method for the synthesis of compounds 24B and 16, starting with 33A. MS (m / z) 563.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ9.19(d,J=8.2Hz,1H),8.83(dd,J=4.2,1.6Hz,1H),8.63(dd,J=8.7,1.6Hz,1H),8.16(dd,J=1.6, 0.4Hz, 1H), 7.90 (d, J = 7.6Hz, 1H), 7.73-7.50 (m, 4H), 7.03 (d, J = 8.8Hz, 2H), 4.71 (d, J = 6.5Hz, 1H), 1.27 (d, J = 6.5Hz, 3H).

[0832] Example 34

[0833] Synthesis of 8-bromo-7-fluoro-5-methylquinoline (34A): The title compound was prepared according to the procedure presented for the synthesis of compound 1A in Example 1 starting with 2-bromo-3-fluoro-5-methylaniline. MS (m / z) 240.0 [M+H] + .

[0834] Synthesis of 8-bromo-5-(bromomethyl)-7-fluoroquinoline 34B: The title compound was prepared according to the procedure presented for the synthesis of compound 1B in Example 1, starting with 34A. MS (m / z) 317.9 [M+H] + .

[0835]

[0266] 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 stirring and positive nitrogen pressure. The 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 THF solution (1.0 M). After 30 minutes, the reaction mixture was removed from the cold bath, quenched with saturated aqueous NH4Cl solution, and allowed to warm to room temperature under 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 afford the title compound. MS (m / z) 422.1 [M+H] + .

[0836] Synthesis of (S)-methyl 2-amino-3-(8-bromo-7-fluoroquinolin-5-yl)propanoate dihydrogen hydrochloride (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 afford the title compound (as a mixture with valine methyl ester hydrochloride), which was used in the next step without further purification. MS (m / z) 327.0 [M+H] + .

[0837]

[0838] Synthesis of (S)-methyl 3-(8-bromo-7-fluoroquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (34E): The title compound was prepared according to the procedure presented for the synthesis of compound 1F in Example 1, starting with 34. MS (m / z) 467.0 [M+H] + .

[0839] 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 presented method for the synthesis of compounds 3B and 3, starting with 34E. MS (m / z) 510.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.27(dd,J=8.3,1.3Hz,1H),8.87(dt,J=3.9,1.8Hz,1H),8.67(d d,J=8.6,1.6Hz,1H),8.24(t,J=1.9Hz,1H),7.95(ddd,J=7.9,4.2,1.7Hz,1H),7.67-7.57 (m,3H),7.49(ttd,J=8.7,6.6,2.3Hz,1H),7.16-7.08(m,2H),4.82(dddd,J=10.8,8.4,4. 2, 2.2Hz, 1H), 3.85 (ddd, J = 18.1, 14.5, 4.1Hz, 1H), 3.42 (ddd, J = 19.5, 14.6, 10.8Hz, 1H).

[0840] Example 35

[0841]

[0842] 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 procedure presented for the synthesis of compound 5A starting with 30L.

[0843] 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 presented method 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(400MHz,DMSO-d6)δ9.60(d,J=3.4Hz,1H),9.29(dd,J=14.2,8.4Hz,1H),8.81(dd,J=3.4,2.8Hz ,1H),8.46(ddd,J=10.1,6.9,2.8Hz,1H),8.38(dd,J=8.2,1.1Hz,1H),8.18(d,J=8.6Hz,1H),8.10- 8.01(m,1H),7.94-7.85(m,1H),7.74(d,J=7.4Hz,1H),7.69(dd,J=7.3,1.9Hz,1H),7.45-7.35(m,3 H), 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, 10.1Hz, 1H).

[0844] Example 36

[0845] 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 obtained residue was dissolved in DCM and washed with saturated aqueous NaHCO 3 solution, and the solution was back-extracted twice with DCM. The combined organic layers were absorbed on silica gel and purified by silica gel chromatography using 0-100% EA in hexanes to obtain the title compound. MS (m / z) 575.0 [M + H] +.

[0846] 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 under microwave irradiation for 30 min. The reaction mixture was then cooled to room temperature, diluted with EA and saturated aqueous NaCl solution, and filtered through celite. The phases were separated, and the aqueous layer was further extracted twice with EA. The combined organic layers were concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography using 0-40% EA in hexanes to obtain the title compound. MS (m / z) 474.0 [M + H] +.

[0847]

[0848] 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 procedure presented for the synthesis of compound 18, starting with 36B. MS (m / z) 576.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ9.27(d,J=8.1Hz,1H),9.21(d,J=2.1Hz,1H),9.02(d,J =2.0Hz,1H),7.69(d,J=7.4Hz,1H),7.63(d,J=7.4Hz,1H),7.49(tt,J=8.4,6.6H z,1H),7.15-7.08(m,2H),6.71(q,J=1.3Hz,2H),4.82(ddd,J=10.0,8.2,4.5Hz ,1H),4.52(s,2H),3.77-3.70(m,1H),3.61-3.45(m,9H),1.21(t,J=7.0Hz,3H).

[0849] Example 37

[0850] 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 gasket lid, and purged with nitrogen for 15 min. DMF (1 mL, previously degassed by sparging 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 diatomaceous earth. The obtained filtrate was washed with saturated NaHCO3 aqueous solution, and the aqueous layer was stripped twice with EA. The combined organic layers were adsorbed on silica gel and purified by silica gel chromatography using 0-50% EA in hexanes to obtain the title compound. MS (m / z) 517.1 [M+H] +.

[0851]

[0852] 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 presented for the synthesis of compound 18, starting with 37A. MS (m / z) 619.2 [M+H] +. 1H NMR(400MHz,DMSO-d6)δ9.31(d,J=8.0Hz,1H),9.08-9.06(m,1H),8.97(dd,J=2.3, 1.1Hz,1H),7.70(d,J=7.5Hz,1H),7.63(d,J=7.3Hz,1H),7.50(tt,J=8.5,6.6Hz,1 H),7.15-7.08(m,2H),6.72(q,J=1.3Hz,2H),4.78(ddd,J=9.7,8.0,4.6Hz,1H),4. 53(s,2H),3.77(dd,J=14.8,4.6Hz,1H),3.61-3.43(m,9H),1.22(t,J=7.0Hz,3H).

[0853] Example 38

[0854] Synthesis of 4-((2-bromo-5-methylphenyl)amino)-1,1,1-trifluorobutyl-3-enyl-2-one (38A): To a stirred solution of 2-bromo-5-methylaniline (2.149 g, 12 mmol) and 4-(tert-butylamino)-1,1,1-trifluorobutyl-3-enyl-2-one (2.05 g, 10.5 mmol) in glacial acetic acid (4 mL) was added TFA (4 mL) and the reaction mixture 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 obtain 38A.

[0855] 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 mixture was heated to 100° C. overnight. It was poured into a 2M solution of 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 1-20% ethyl acetate / hexane to afford 38B.

[0856] 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 mixture was heated to reflux under a tungsten work lamp for 16 hours. 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. It was purified by flash chromatography eluting with a linear gradient of 5-70% DCM / hexane to obtain compound 38C.

[0857]

[0858]

[0266] 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 mixture 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 mixture was warmed to room temperature and stirred for 16 hours. It was quenched by the addition of saturated ammonium chloride and partitioned between water and ethyl acetate. The solution was extracted with ethyl acetate and the combined organics were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. This was purified by flash chromatography eluting with a linear gradient of 5-50% ethyl acetate in hexanes to afford compound 38D.

[0859] Synthesis of tert-butyl 2-amino-3-(8-bromo-2-(trifluoromethyl)quinolin-5-yl)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 mixture was stirred at room temperature for 1 h. It was diluted with water and washed once with diethyl ether. The solution was treated with 1 M sodium hydroxide in water until a pH of approximately 8 was obtained and extracted twice with diethyl ether. The combined extracts were washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 38E.

[0860] 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 procedure presented for the synthesis of compound 1F starting with 38E and 2,6-difluorobenzoyl chloride.

[0861]

[0266] 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 2M sodium carbonate in water (0.5 mL, 0.67 mmol), and the reaction mixture was degassed with nitrogen. XPhos Pd G3 (14 mg, 0.017 mmol) was added, the reaction was sealed, and heated to 85 °C for 1 h. It was cooled to room temperature and purified by flash chromatography eluting with a linear gradient of 1-10% MeOH / DCM to afford 38G.

[0862] 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 mixture was stirred at room temperature for 4 hours. It was concentrated and purified by preparative HPLC to afford 38. MS (m / z) 619.2 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ9.30(d,J=8.1Hz,1H),8.85(dd,J=8.9,0.8Hz,1H),7.95(d,J=8.8Hz,1H ),7.68(d,J=7.5Hz,1H),7.61(d,J=7.3Hz,1H),7.48(tt,J=8.4,6.5Hz,1H),7.11(dd,J=8.5,7.5 Hz,2H),6.72(q,J=1.3Hz,2H),4.77(ddd,J=10.1,8.0,4.5Hz,1H),4.52(d,J=0.7Hz,2H),3.76( dd,J=14.7,4.5Hz,1H),3.64-3.50(m,8H),3.44(dd,J=14.8,10.1Hz,1H),1.20(t,J=7.0Hz,3H).

[0863] Example 39

[0864]

[0865] Synthesis of 8-bromo-6-fluoro-5-methylquinoline (39A): The title compound was prepared according to the method for the synthesis of compound 1A presented in Example 1 using 2-bromo-4-fluoro-5-methylaniline. MS (m / z) 240.0 [M+H] +.

[0866] Synthesis of 8-bromo-5-(bromomethyl)-6-fluoroquinoline (39B): The title compound was prepared according to the procedure for the synthesis of compound 1B presented in Example 1 using 39A. MS (m / z) 317.9 [M+H] + .

[0867] 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 according to the presented method for the synthesis of compound 34C4 using 39B. MS (m / z) 422.1 [M+H]+.

[0868] Synthesis of (S)-methyl 2-amino-3-(8-bromo-6-fluoroquinolin-5-yl)propanoate (39D): The title compound was prepared according to the procedure presented for the synthesis of compound 34 using 39C. MS (m / z) 327.0 [M+H] + .

[0869] Synthesis of (S)-methyl 3-(8-bromo-6-fluoroquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (39E): The title compound was prepared according to the procedure for the synthesis of compound 16A presented in Example 16 using 39D. MS (m / z) 467.0 [M+H] +.

[0870] 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 according to the procedure presented for the synthesis of compound 18 using 39E. MS (m / z) 569.2 [M+H]+. 1H NMR(400MHz, DMSO-d6)δ9.30(d,J=8.3Hz,1H),8.83-8.70(m,2H),7.68(dd,J=8.8,4.3Hz,1H),7.55-7.44(m,2H),7.11( dd,J=8.5,7.6Hz,2H),6.75(s,2H),4.77(td,J=8.5,6.2Hz,1H),4.54(s,2H),3.70-3.50(m,11H),1.22(t,J=7.0Hz,3H).

[0871] Example 40

[0872]

[0873] (S)-2-(2,6-Difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-7-fluoroquinolin-5-yl)propanoic acid (40): The title compound was prepared according to the procedure presented for the synthesis of compound 18 using 34E. MS (m / z) 569.2 [M+H]+. 1H NMR (400 MHz, 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=10.6,8.1,4.1Hz,1H),4.54(s,2H),3.80(dd,J=14.6, 4.1Hz, 1H), 3.62-3.55 (m, 8H), 3.43 (dd, J = 14.8, 10.5Hz, 1H), 1.22 (t, J = 7.0Hz, 3H).

[0874] Example 41

[0875] 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 hr. The reaction mixture was concentrated under reduced pressure and purified by reverse phase preparative chromatography using 0.1% TFA / MeCN in water as eluent.

[0876] 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 presented method for the synthesis of compounds 16A and 16, starting with 41A and 1E. MS (m / z) 686.5 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ13.04(s,1H),10.76(s,1H),9.18(d,J=8.0Hz,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).

[0877]

[0878] Example 42 and Example 43

[0879]

[0880] Synthesis of (S)-3-(8-bromoquinoline-5-yl)-2-(4-cyano-2,6-difluorobenzamido)methyl propionate (42A): To a stirred solution of 4-cyano-2,6-difluorobenzoic acid (0.12 g, 0.65 mmol) in DCM was added ID (0.2 g, 0.65 mmol), HATU (0.25 g, 0.65 mmol) and TEA (1 mL). 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 eluent.

[0881] (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 G (0.043 g, 0.05 mmol) and K PO (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 Na 2 SO 4 and concentrated under reduced pressure. The mixture was purified by silica gel chromatography using MeOH and DCM as eluents to afford 42 and 43. MS (m / z) 576.2 [M+H] +. 1HNMR(400MHz,DMSO-d6)δ8.72(dd,J=4.1,1.6Hz,1H),8.60(s,1H),8.15(s,1H), 7.72(s,1H),7.57(d,J=8.1Hz,2H),7.53-7.46(m,2H),7.36(d,J=7.3Hz,1H),6.6 8(d,J=2.3Hz,2H),4.61(s,1H),4.50(s,2H),3.68(dd,J=14.0,4.7Hz,1H),3.56( d,J=7.0Hz,1H),3.52(d,J=7.1Hz,6H),3.44-3.33(m,1H),1.20(t,J=7.0Hz,3H).

[0882] (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] + . 1H NMR (400MHz, DMSO-d6) δ13.15(s,1H),9.48(d,J=8.0Hz,1H),8.74(dd,J=4.1,1.7Hz,1H),8. 53(dd,J=8.7,1.7Hz,1H),8.01-7.73(m,2H),7.53(dd,J=8.6,4.1Hz,1H),7.48(d,J=7.4Hz, 1H),7.38(d,J=7.3Hz,1H),6.76-6.63(m,2H),4.75(td,J=8.8,4.4Hz,1H),4.50(s,2H),3.9 1-3.61(m,1H),3.55(t,J=7.0Hz,2H),3.53(s,3H),3.46-3.22(m,4H),1.20(t,J=7.0Hz,3H).

[0883] Example 44

[0884] Synthesis of (S)-methyl 2-amino-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)quinolin-5-yl)propanoate (44A): The title compound was prepared according to the procedure presented for the synthesis of compound 1E starting with (4-(ethoxymethyl)-2,6-dimethoxyphenyl)boronic acid.

[0885] (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 presented method 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] + . 1H NMR (400MHz, DMSO-d6) δ8.84(s,2H),8.67(d,J=7.9Hz,1H),7.64(t,J=37.5Hz,3H),6.74(d,J=2.2Hz,2H),6.11(d,J=10.7Hz ,2H),4.75-4.62(m,1H),4.53(s,2H),3.81-3.65(m,1H),3.58(d,J=7.0Hz,2H),3.55(d,J=6.1Hz,7H),1.20(t,J=7.0Hz,3H).

[0886]

[0887] Example 45

[0888]

[0889] Synthesis of 2,6-difluoro-4-(methylsulfonylamino)benzoic acid methyl ester (45A): To a stirred solution of 4-amino-2,6-difluorobenzoic acid methyl ester (500mg, 0.3mmol) in DCM, methylsulfonyl chloride (0.31ml, 0.4mmol) and pyridine (1.08mL, 1.3mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EA, washed with 1MHCl, bicarbonate, salt water, and dried, filtered, and concentrated. The material was recrystallized from EA / hexane to obtain the title compound.

[0890] Synthesis of 2,6-difluoro-4-(methylsulfonylamino)benzoic acid (45B): To a stirred solution of 45A (534 mg, 0.2 mmol) in THF was added an aqueous LiOH solution (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 / hexanes as eluents to obtain the title compound.

[0891] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(methylsulfonylamino)benzamido)propanoic acid (45): The title compound was prepared according to the presented method for the synthesis of compounds 16A and 16, starting with 45B. MS (m / z) 585.1 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ10.46(s,1H),9.15(d,J=8.1Hz,1H),8.85(dd,J=4.1,1.6Hz,1H),8.65(dd,J=8.7,1.7Hz,1H),8.17(dd,J=1.6,0.4Hz,1 H),7.92(dd,J=7.9,1.6Hz,1H),7.70-7.55(m,4H),6.83(d,J=9.3Hz,2H ),4.83-4.68(m,1H),3.87-3.66(m,1H),3.51-3.33(m,1H),3.14(s,3H).

[0892] Example 46

[0893]

[0894] (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(phenylsulfonylamino)benzamido)propanoic acid (46): The title compound was prepared according to the presented method 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) δ11.09(s,1H),9.12(d,J=8.1Hz,1H),8.84(dd,J=4.2,1.6Hz,1H),8.63-8.60(m,1H),8.17(d,J=1.7Hz,1H),7.92(d d,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).

[0895] Example 47

[0896]

[0897] 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 for the synthesis of compound 16 in Example 16 presented, starting with 2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzoic acid.

[0898] 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 according to the presented method for the synthesis of compounds 3B and 3, starting with 47A. MS (m / z) 742.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.21(s,1H),9.11(d,J=8.1Hz,1H),8.81(dd,J=4.1,1.6Hz,1 H),8.59(dd,J=8.6,1.7Hz,1H),8.33(d,J=5.3Hz,1H),8.14(d,J=1.6Hz,1H),8.09-8.0 3(m,2H),8.01-7.94(m,2H),7.89(dd,J=7.9,1.6Hz,1H),7.72(dt,J=5.4,1.8Hz,1H), 7.64-7.51(m,5H),6.78(d,J=9.2Hz,2H),4.83-4.59(m,1H),3.71(s,1H),3.34(s,1H).

[0899] Example 48

[0900] 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 methanesulfinate (96.28 mg, 0.94 mmol). This was heated to 65 °C and stirred for 1 h. 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 procedure presented for the synthesis of compound 1G.

[0901]

[0902] (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 presented procedure for the synthesis of compounds 16A and 16, starting with 48A. MS (m / z) 584.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ9.30(d,J=8.2Hz,1H),8.84(dd,J=4.2,1.6Hz,1H),8.65(dd,J=8.7,1.6Hz,1H),8.15(d,J=1.6Hz,1H),7.90(d d,J=7.9,1.7Hz,1H),7.68-7.53(m,4H),7.16(d,J=8.1Hz,2H),4.84-4.73(m,1H),4.55(s,2H),3.77(s,1H),3.40(s,1H),2.93(s,3H).

[0903] Example 49

[0904]

[0905] (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 according to the presented method for the synthesis of compound 48A of Example 48, which began with sodium benzenesulfinate, followed by the presented method for the synthesis of compounds 16 and 16C, which began with 49A. MS (m / z) 646.3 [M+H]. 1H NMR (400MHz, DMSO-d6) δ9.28(d,J=8.2Hz,1H),8.83(dd,J=4.1,1.6Hz,1H),8.64(dd,J=8.7,1.7Hz,1H),8.15(d,J=1.6Hz,1H),7.90(dd,J =7.9,1.7Hz,1H),7.81-7.69(m,3H),7.69-7.50(m,6H),6.88(d,J=8.1Hz,2H),4.82-4.73(m,1H),4.77(s,2H),3.76(s,1H),3.40(s,1H).

[0906] Example 50

[0907]

[0908] (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 presented method 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) δ11.24(s,1H),9.16(d,J=8.0Hz,1H),8.83(s,2H),8.35(d,J =5.3Hz,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=8.3Hz,1H),4.54(s,2H),3.73(dd,J=13.3,3.5Hz,1 H), 3.59 (d, J = 7.0Hz, 1H), 3.54 (d, J = 2.0Hz, 6H), 3.43 (s, 1H), 1.22 (t, J = 7.0Hz, 3H).

[0909] Example 51

[0910]

[0911] (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 presented method for the synthesis of compounds 3B and 3 starting with 47A and (2,3-dihydrophenylprop[b][1,4]oxin-5-yl)boronic acid. MS (m / z) 741.4 [M+H]. 1H NMR (400MHz, DMSO-d6) δ11.21(s,1H),9.12(d,J=8.1Hz,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=9.3Hz,2H),6.79(t,J=8.8Hz,2H),4.67(s,1 H), 4.20 (s, 2H), 4.05 (s, 2H), 3.71 (d, J = 14.0Hz, 1H), 3.42-3.27 (m, 1H).

[0912] Example 52

[0913]

[0914] (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 presented method 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) δ11.23(s,1H),9.11(d,J=8.1Hz,1H),8.97(dd,J=4.1,1.7Hz,1H),8.60(d d,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=7.5Hz, 1H),7.74(dt,J=5.4,1.8Hz,1H),7.69-7.59(m,4H),7.51(d,J=7.5Hz,1H),6.81(d,J=9.1Hz,2H) ,4.66(ddd,J=10.1,8.1,4.4Hz,1H), 3.69(dd,J=14.3,4.4Hz,1H), 3.31(dd,J=14.5,10.1Hz,1H).

[0915] Example 53

[0916] Synthesis of (S)-3-(8-dihydroxyborylquinolin-5-yl)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)propanoic acid (53A): The title compound was prepared according to the procedure presented for the synthesis of compound 4B starting from 47A.

[0917]

[0918] (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 presented method 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) δ11.19(s,1H),9.10(d,J=8.1Hz,1H),8.81(dd,J=4.1,1.6 Hz,1H),8.58(dd,J=8.7,1.7Hz,1H),8.33(dt,J=5.3,0.6Hz,1H),8.09-8.02(m,2 H),8.01-7.94(m,2H),7.72(dt,J=5.4,1.8Hz,1H),7.62-7.49(m,5H),7.43-7.32 (m, 2H), 6.79 (d, J = 9.1Hz, 2H), 4.67 (d, J = 11.2Hz, 1H), 4.14 (s, 2H), 3.36 (s, 2H).

[0919] Example 54

[0920]

[0921] (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 according to the presented method for the synthesis of compounds 3B and 3, starting with 47A and (2-chloro-4-cyclopropylphenyl)boronic acid. MS (m / z) 757.2 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ11.23(s,1H),9.12(d,J=8.1Hz,1H),8.82(d,J=4.3Hz,1H),8.61(d,J=8.7Hz,1H),8. 35(d,J=5.3Hz,1H),8.13-8.05(m,2H),8.03-7.95(m,2H),7.74(dt,J=5.3,1.8Hz,1H),7.66-7.52(m,4H),7. 25(d,J=1.8Hz,1H),7.21(d,J=7.9Hz,1H),7.11(dd,J=8.1,1.8Hz,1H),6.80(d,J=9.1Hz,2H),4.76-4.64(m, 1H),3.82-3.62(m,1H),3.45-3.25(m,1H),2.02(tt,J=8.4,5.1Hz,1H),1.07-0.99(m,2H),0.84-0.73(m,2H).

[0922] Example 55

[0923]

[0924] (S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(3,5-dimethylisoxazol-4-yl)quinolin-5-yl)propanoic acid (55): The title compound was prepared according to the presented method 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) δ11.19(s,1H),9.07(d,J=8.2Hz,1H),8.88(dd,J=4.1,1.6Hz,1H) ,8.58(dd,J=8.7,1.6Hz,1H),8.33(d,J=5.3Hz,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=9.1Hz,2H), 4.69(s,1H),3.75-3.60(m,1H),3.30(dd,J=14.4,10.6Hz,1H),2.22(s,3H),2.01(s,3H).

[0925] Example 56

[0926] (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 presented method 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) δ11.21(s,1H),9.30(d,J=1.4Hz,1H),9.11(d,J=8.2Hz,1H),8.99(dd,J=4.2,1.6Hz ,1H),8.86(d,J=5.4Hz,1H),8.67(dd,J=8.7,1.7Hz,1H),8.42-8.25(m,2H),8.19(d,J=7.5Hz,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=7.6Hz,1H),7.59(d,J=1.5H z, 1H), 6.78 (d, J = 9.1Hz, 2H), 4.68 (ddd, J = 10.3, 8.2, 4.4Hz, 1H), 3.81-3.65 (m, 1H), 3.34 (d, J = 7.0Hz, 1H).

[0927]

[0928] Example 57

[0929]

[0930] (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 presented method 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) δ11.21 (s, 1H), 9.20-9.05 (m, 2H), 8.98 (dd, J = 4.2, 1.6Hz, 1H), 8.6 9(dd,J=8.7,1.7Hz,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=1.7Hz,1H),6.78(d,J=9 .1Hz,2H),4.78-4.62(m,1H),3.74(dd,J=14.5,4.4Hz,1H),3.36(dd,J=14.5,10.2Hz,1H).

[0931] Example 58

[0932]

[0933] (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 presented method 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) δ11.22(s,1H),9.29(d,J=4.9Hz,1H),9.23(d,J=8.7Hz,1H),9.15-9.02(m ,3H),8.76(s,1H),8.33(dd,J=5.3,0.6Hz,1H),8.10-8.00(m,2H),8.00-7.92(m,2H),7.86(d,J= 7.7Hz,1H),7.71(dt,J=5.3,1.8Hz,1H),7.67(t,J=4.9Hz,1H),7.58(p,J=0.7Hz,1H),6.76(d,J= 9.1Hz, 2H), 4.77 (ddd, J = 10.4, 8.3, 4.4Hz, 1H), 3.92-3.79 (m, 1H), 3.47 (dd, J = 14.6, 10.4Hz, 1H).

[0934] Example 59

[0935] (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 presented procedure for the synthesis of compounds 5B and 5 starting with 53A and 2-bromobenzonitrile. MS (m / z) 708.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ11.22(d,J=15.6Hz,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=10.6Hz,1H),3.30(m,1H).

[0936]

[0937] Example 60

[0938]

[0939] (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 presented method for the synthesis of compounds 3B and 3, starting with 47A and (3-fluoro-2-methoxyphenyl)boronic acid. MS (m / z) 731.2 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ11.20(s,1H),9.11(d,J=8.1Hz,1H),8.85(dd,J=4.1,1.6Hz,1H),8.61(d,J=8. 6Hz,1H),8.37-8.29(m,1H),8.11-8.02(m,2H),8.02-7.93(m,2H),7.72(dt,J=5.3,1.8Hz,1H),7.65-7. 50(m,4H),7.31(ddd,J=11.8,8.2,1.6Hz,1H),7.15(td,J=8.0,5.1Hz,1H),7.06-7.01(m,1H),6.79(d,J =9.1Hz,2H),4.74-4.62(m,1H),3.71(dd,J=14.4,4.4Hz,1H),3.48(d,J=1.4Hz,3H),3.38-3.28(m,1H).

[0940] Example 61

[0941]

[0942] (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 presented method 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]. 1HNMR (400 MHz, 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, 1.7 Hz, 1H ),7.68-7.57(m,3H),7.61-7.48(m,2H),7.41-7.32(m,1H),6.79(dd,J=9.1,1.9Hz,2H),4.76-4.61(m,1H),3.77(dd,J=14.3,4.0Hz,0 .5H), 3.62 (dd, J=14.7, 5.1Hz, 0.5H), 3.44 (dd, J=14.6, 9.6Hz, 0.5H), 3.27 (dd, J=14.5, 10.5Hz, 0.5H), 2.85 (s, 1.5H), 2.80 (s, 1.5H).

[0943] Example 62

[0944] (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 presented method 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) δ11.22(s,1H),9.12(d,J=8.1Hz,1H),8.88(s,1H),8.33(dt,J=5.4,0.6Hz,1H) ,8.10-8.01(m,2H),8.01-7.90(m,2H),7.72(dt,J=5.4,1.8Hz,1H),7.59(q,J=1.1Hz,3H),7.14(d,J= 7.8Hz,1H),7.01(d,J=7.3Hz,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=14.3Hz,1H),3.43-3.27(m,1H),2.82(t,J=6.5Hz,2H),1.87(t,J=5.6Hz,3H).

[0945]

[0946] Example 63

[0947]

[0948] (S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonylamino)benzamido)-3-(8-(o-tolyl)quinolin-5-yl)propanoic acid (63): The title compound was prepared according to the presented method 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) δ11.20(s,1H),9.09(d,J=8.2Hz,1H),8.81(dd,J=4.2,1.6Hz,1H),8.62(d, J=8.7Hz,1H),8.36-8.28(m,1H),8.11-8.01(m,2H),7.97(d,J=8.4Hz,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=7.0Hz,1H),6.78(d,J=9 .5Hz,2H),4.70(s,1H),3.72(dd,J=14.4,4.4Hz,1H),3.32(dd,J=14.4,10.3Hz,1H),1.87(s,3H).

[0949] Example 64

[0950]

[0951] (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 presented method 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) δ13.03(s,1H),11.20(s,1H),9.08(d,J=8.2Hz,1H),8.73(d,J=42 .8Hz,2H),8.33(d,J=5.3Hz,1H),8.13-7.89(m,4H),7.72(dt,J=5.3,1.7Hz,1H),7.69-7 .37(m,4H),7.28(t,J=7.9Hz,1H),6.90(t,J=8.9Hz,2H),6.83-6.71(m,2H),4.79-4.66( m, 1H), 3.77 (d, J = 14.2Hz, 1H), 3.49 (s, 3H), 3.28 (dd, J = 14.4, 10.6Hz, 1H), 1.74 (s, 3H).

[0952] Example 65

[0953]

[0954] (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 according to the presented method for the synthesis of compounds 3B and 3, starting with 47A and (2-(trifluoromethyl)phenyl)boronic acid. MS (m / z) 751.5 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ11.20(d,J=2.3Hz,1H),9.10(dd,J=8.2,6.2Hz,1H),8.77(dt,J=4.0,1.9Hz,1H),8 .59(d,J=8.5Hz,1H),8.33(d,J=5.3Hz,1H),8.10-8.02(m,2H),8.01-7.93(m,2H),7.82(dt,J=7.9,1.9Hz,1 H),7.75-7.54(m,6H),7.51(d,J=1.9Hz,2H),7.32(dd,J=7.7,4.4Hz,1H),6.78(dd,J=9.0,3.5Hz,2H),4.6 9(ddd,J=10.2,8.1,4.6Hz,1H), 3.71(ddd,J=29.9,14.4,4.4Hz,1H), 3.34(ddd,J=25.9,14.5,10.2Hz,1H).

[0955] Example 66

[0956]

[0957] (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 presented method 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=8.4,6.5Hz,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=14.5,4.5Hz,1H),3.68(s,3H),3.44(dd,J=14.5,9.9Hz,1H).

[0958] Example 67

[0959]

[0960] (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 presented method 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 (400MHz, DMSO-d6) δ9.41(d,J=0.8Hz,1H),9.31(d,J=8.1Hz,1H),8.81(dd,J=4.2,1.6Hz,1H),8.72(dd, J=8.7,1.7Hz,1H),8.38-8.29(m,1H),8.24(dq,J=8.5,0.9Hz,1H),8.02(ddd,J=8.4,6.9,1.3Hz,1H),7.87( ddd,J=8.1,7.0,1.1Hz,1H),7.78(d,J=7.3Hz,1H),7.72-7.64(m,2H),7.48(tt,J=8.5,6.6Hz,1H),7.16-7. 07 (m, 2H), 4.80 (ddd, J = 10.1, 8.1, 4.4Hz, 1H), 3.81 (dd, J = 14.5, 4.4Hz, 1H), 3.46 (dd, J = 14.5, 10.1Hz, 1H).

[0961] Example 68

[0962]

[0963] (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 presented method 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) δ9.31(d,J=8.3Hz,1H),8.81(dd,J=4.2,1.6Hz,1H),8.69(dd,J=8.7,1.7Hz,1H),8.20(d,J=8.3Hz,1H),7.70-7 .52(m,4H),7.48-7.35(m,3H),4.84(td,J=9.3,4.3Hz,1H),3.75(dd,J=14.6,4.4Hz,1H),3.44(dd,J=14.6,10.1Hz,1H),2.58(s,3H).

[0964] Example 69

[0965]

[0966] (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 presented method 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) δ9.28(s,1H),8.83(dd,J=4.2,1.6Hz,1H),8.68(dd,J=8.7,1.7Hz,1H),8.16(d,J=8.9Hz,1H),7 .70-7.58(m,3H),7.47-7.34(m,3H),7.06(dt,J=8.7,0.8Hz,1H),4.86(m,1H),3.81(s,3H),3.78(m,1H),3.43(m,1H).

[0967] Example 70

[0968]

[0969] (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 presented procedure 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 (400MHz, DMSO-d6) δ9.30(d,J=7.6Hz,1H),8.88(d,J=4.4Hz,1H),8.75(d,J=8.6Hz,1H),8.27(s,1H),7.77-7.65(m,1H),7.59( d,J=7.8Hz,2H),7.48(tt,J=8.5,6.6Hz,1H),7.12(dd,J=8.4,7.6Hz,2H),4.74(s,1H),3.86-3.63(m,7H),3.43(q,J=13.6Hz,1H).

[0970] Example 71

[0971]

[0972] Synthesis of 4-(trifluoromethyl)isoquinolin-3-amine (71A): To a stirred solution of 3-aminoisoquinoline (150 mg, 1.04 mmol) in MeCN was added 3,3-dimethyl-1-(trifluoromethyl)-1,2-benzoiodooxolane (412.1 mg, 1.25 mmol) and tris(trimethylsilyl)chlorosilane (0.35 ml, 1.25 mmol). The mixture was heated to 80° C. for 1 h. The reaction mixture was filtered through celite, rinsed with EA and purified by silica gel chromatography using EA in hexanes as eluent to give the title compound.

[0973]

[0266] 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 minutes, at which point NaNO (147.96 mg, 2.14 mmol) was added as a pre-formed solution in water (5 mL). The reaction mixture was stirred at 0°C for 30 minutes, then allowed to warm to room temperature for 60 minutes. The reaction mixture was quenched with saturated sodium bicarbonate, extracted with DCM, concentrated, and purified by silica gel chromatography eluting with Hex / EA to give the title compound.

[0974] (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 presented method for the synthesis of compounds 5B and 5, starting with 4B and 71B. MS (m / z) 552.2 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ9.60(d,J=3.3Hz,1H),9.29(t,J=7.6Hz,1H),8.75(dt,J=3.9,1.8Hz,1H),8.65( ddd,J=8.7,5.6,1.7Hz,1H),8.38(d,J=8.2Hz,1H),8.18(d,J=8.7Hz,1H),8.05(ddd,J=8.6,6.9,1.4Hz, 1H),7.90(t,J=7.6Hz,1H),7.70(dd,J=7.3,4.7Hz,1H),7.66-7.58(m,2H),7.55-7.41(m,1H),7.12(q,J =8.2Hz,2H),4.77(dtd,J=18.5,8.8,4.4Hz,1H),3.77(ddd,J=25.7,14.5,4.5Hz,1H),3.49-3.34(m,1H).

[0975] Example 72

[0976]

[0977] (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 presented method 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) δ9.33(d,J=8.3Hz,1H),8.89(dd,J=4.1,1.6Hz,1H),8.70(dd,J=8.7,1.6Hz,1H),7.97(d,J=9.1Hz,1H),7.74-7.63 (m,3H),7.49-7.36(m,3H),6.81(d,J=9.1Hz,1H),4.80(td,J=9.2,4.4Hz,1H),3.74(dd,J=14.5,4.4Hz,1H),3.43(dd,J=14.6,9.9Hz,1H).

[0978] Example 73

[0979]

[0980] (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 presented method 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) δ13.00 (s, 1H), 9.27 (dd, J = 27.2, 8.3Hz, 1H), 8.83 (d t,J=4.2,2.0Hz,1H),8.69(d,J=8.6Hz,1H),7.72-7.59(m,2H),7.49-7.31(m ,4H),6.55(d,J=4.7Hz,1H),4.90-4.71(m,1H),3.73(td,J=14.4,4.0Hz,1H ), 3.47 (d, J = 4.2Hz, 3H), 3.38 (ddd, J = 24.5, 14.7, 10.5Hz, 1H), 2.52 (m, 3H).

[0981] Example 74

[0982] 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-butanol (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 h. 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 Na2SO4 and concentrated under reduced pressure to obtain the substance. The substance was suspended in hexane, the solid was filtered off and the filtrate was evaporated under reduced pressure to obtain compound 74A. MS (m / z) 236.6 [M+H-C4H8] + . 1 H NMR (400MHz, DMSO-d6) δ7.69-7.56 (m, 2H), 1.50 (s, 9H).

[0983] 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 h. The mixture was cooled to room temperature and diluted with ethyl acetate (50 mL). The obtained suspension was filtered through a pad of celite and the filtrate was evaporated under reduced pressure to afford compound 74B. MS (m / z) 284.1 [M+H-C4H8] + .

[0984]

[0985] Synthesis of (R)-2,6-difluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoic acid (74C): To a stirred solution of tert-butyl (R)-2,6-difluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoate (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 mins. The reaction mixture was concentrated under reduced pressure to obtain the material, which was purified by silica gel column chromatography and eluted with ethyl acetate in hexanes to obtain compound 74C. MS (m / z) 338.1 [M+H] + .

[0986] (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 presented method for the synthesis of compounds 16A and 16, starting with 74C. MS (m / z) 617.2 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ8.87-8.77(m,2H),8.64(dd,J=8.7,1.7Hz,1H),8.15(dd,J=1.7,0 .4Hz,1H),7.90(dd,J=7.9,1.7Hz,1H),7.73-7.44(m,4H),6.76(d,J=9.4Hz,1H),6.43(d, J=11.6Hz,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=10.1,7.5,3.8Hz,1H), 1.51(ddt,J=17.6,14.4,7.3Hz,1H), 0.90(t,J=7.3Hz,3H).

[0987] Example 75

[0988]

[0989] Synthesis of (R)-2,6-difluoro-4-(2-(trifluoromethyl)piperidin-1-yl)benzoic acid (75A): To a 150 mL pressure vessel containing a stirrer 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 to 90°C overnight. The reaction mixture was cooled to room temperature and filtered through a pad of celite, rinsed with EA and the filtrate evaporated to dryness under reduced pressure. The material was purified by silica gel chromatography using EA in hexanes as eluent. To this material was added THF (6 mL) and a 1.0 M aqueous LiOH solution (6.2 mL). 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 before extraction with EA. The organic layers were combined and dried over Na2SO4. The solvent was removed under reduced pressure to obtain 75A.

[0990] (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 presented method for the synthesis of compounds 16A and 16, starting with 75A. MS (m / z) 645.2 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ8.90(d,J=8.1Hz,1H),8.83(dd,J=4.2,1.6Hz,1H),8.64(dd,J=8.6,1.7Hz ,1H),8.15(dd,J=1.7,0.4Hz,1H),7.90(dd,J=7.9,1.7Hz,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=9.7,4.9Hz,1H),3.74(s,1H),3.59(d,J=12.9Hz,1H),3 .41(s,1H),2.99(t,J=12.2Hz,1H),1.94(d,J=14.4Hz,1H),1.85-1.67(m,2H),1.67-1.42(m,3H).

[0991] Example 76

[0992] Synthesis of (R)-2,6-difluoro-4-(2-(trifluoromethyl)pyrrolidin-1-yl)benzoic acid (76A): The title compound was prepared according to the procedure presented for the synthesis of compound 75A starting with (R)-2-(trifluoromethyl)pyrrolidine.

[0993] (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 presented procedure for the synthesis of compounds 16A and 16, starting with 76A. MS (m / z) 629.5 [M+H]+. 1H NMR (400 MHz, 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=7.9,0.6Hz,1H),6.48(d,J=11.5Hz,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=8.7Hz,1H),2.16-1.91(m,4H).

[0994]

[0995] Example 77

[0996]

[0997] Synthesis of (R)-2,6-difluoro-4-(2-(trifluoromethyl)piperazin-1-yl)benzoic acid (77A): The title compound was prepared according to the procedure presented for the synthesis of compound 75A starting with (R)-2-(trifluoromethyl)piperazine.

[0998] (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 presented method for the synthesis of compounds 16A and 16, starting with 77A. MS (m / z) 644.1 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ8.94(d,J=8.1Hz,1H),8.83(dd,J=4.1,1.6Hz,1H),8.63(dd,J=8.7,1.7H z,1H),8.15(dd,J=1.6,0.4Hz,1H),7.90(dd,J=7.9,1.6Hz,1H),7.67-7.57(m,3H),7.58-7.53(m ,1H),6.79(d,J=11.5Hz,2H),4.71(td,J=9.2,8.2,4.3Hz,1H),4.26(br,1H),4.05(d,J=13.2Hz, 1H), 3.84 (d, J = 10.9Hz, 1H), 3.75 (s, 1H), 3.42 (s, 1H), 3.29 (d, J = 10.7Hz, 1H), 3.12-2.96 (m, 3H).

[0999] Example 78

[1000]

[1001] Synthesis of 2,6-difluoro-4-(2-(trifluoromethyl)azetidin-1-yl)benzoic acid (78A): The title compound was prepared according to the procedure presented for the synthesis of compound 75A starting with 2-(trifluoromethyl)azetidine hydrochloride.

[1002] (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 presented method for the synthesis of compounds 16A and 16, starting with 78A. MS (m / z) 617.1 [M+H]+. 1H NMR (400 MHz, 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=9.9Hz,2H),4.91(q,J=6.3Hz,1H),4.71(d,J=9.6Hz,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).

[1003] Example 79

[1004]

[1005] Synthesis of 2,6-difluoro-4-morpholinobenzoic acid (79A): The title compound was prepared according to the procedure presented for the synthesis of compound 75A starting with morpholine.

[1006] (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 presented procedure for the synthesis of compounds 16A and 16, starting with 79A. MS (m / z) 577.3 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ8.87(d,J=8.0Hz,1H),8.83(dd,J=4.1,1.6Hz,1H),8.64(dd,J=8.7,1.7Hz,1H),8.15(d,J=1.6Hz,1H),7.96-7.84(m,1H),7.67- 7.58(m,3H),7.56(d,J=7.9Hz,1H),6.61(d,J=11.8Hz,2H),4.69(q,J=5.9, 4.3Hz,1H),3.74(s,1H),3.70-3.61(m,4H),3.42(s,1H),3.22-3.12(m,4H).

[1007] Example 80

[1008]

[1009] Synthesis of 4-(1,1-dioxythiomorpholino)-2,6-difluorobenzoic acid (80A): The title compound was prepared according to the procedure presented for the synthesis of compound 75A starting with thiomorpholine 1,1-dioxide.

[1010] (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 presented procedure for the synthesis of compounds 16A and 16, starting with 80A. MS (m / z) 625.5 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ8.90(d,J=8.1Hz,1H),8.84(dd,J=4.1,1.6Hz,1H),8.64(dd,J=8.6,1.7Hz,1H),8.15(dd,J=1.7,0.4Hz,1H),7.90(dd,J=7.9,1. 7Hz,1H),7.67-7.58(m,3H),7.56(dd,J=7.9,0.4Hz,1H),6.76(d,J=11.7Hz, 2H),4.78-4.64(m,1H),3.85(s,4H),3.75(s,1H),3.42(s,1H),3.06(s,4H).

[1011] Example 81

[1012] Synthesis of 2,6-difluoro-4-morpholinobenzoic acid (81A): The title compound was prepared according to the procedure presented for the synthesis of compound 75A starting with 3-(trifluoromethyl)morpholine hydrochloride.

[1013]

[1014] 2,6-Difluoro-4-(3-(trifluoromethyl)morpholino)benzoic acid (81): The title compound was prepared according to the presented method for the synthesis of compounds 16A and 16, starting with 81A. MS (m / z) 645.1 [M+H]+. 1H NMR (400 MHz, 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=11.7Hz,2H),4.89(dd,J=8.7,3.6Hz,1H),4.71(d,J=6.2Hz,1H),4.14(d,J=12.7Hz,1H),3.93(dd,J= 11.5, 3.8Hz, 1H), 3.72 (d, J = 13.0Hz, 2H), 3.59-3.45 (m, 1H), 3.40 (d, J = 12.7Hz, 2H), 3.21 (t, J = 12.2Hz, 1H).

[1015] Examples 82 and 83

[1016]

[1017] 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 by supercritical fluid chromatography using 25% MeOH / DEA cosolvent at a flow rate of 50 mL / min on a Chiralpak AD-H 5 μm 21 x 250 mm column. The title compound was identified as the first eluting peak. MS (m / z) 645.1 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ8.78(dd,J=4.2,1.6Hz,1H),8.74(s,1H),8.14(dd,J=1.6,0.4Hz,1 H),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=11.9Hz,2H ),4.88(d,J=9.0Hz,1H),4.43(s,1H),4.14(d,J=12.7Hz,1H),3.93(dd,J=11.5,3.7Hz,1H) ,3.72(d,J=12.6Hz,2H),3.60-3.48(m,1H),3.41(d,J=12.9Hz,1H),3.21(t,J=13.1Hz,2H).

[1018] 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 by supercritical fluid chromatography using 25% EtOH / TFA cosolvent at a flow rate of 50 mL / min on a Chiralpak AD-H 5 μm 21 x 250 mm column. The title compound was identified as the second eluting peak. MS (m / z) 645.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.77(dd,J=4.1,1.5Hz,2H),8.13(dd,J=1.7,0.4Hz,1H),8.08(s, 1H),7.88(dd,J=7.9,1.7Hz,1H),7.65-7.42(m,4H),6.74(d,J=11.9Hz,2H),4.88(dt,J=9. 4,4.7Hz,1H),4.40(d,J=6.6Hz,1H),4.14(d,J=12.7Hz,1H),3.93(dd,J=11.5,3.7Hz,1H), 3.71(d,J=13.0Hz,2H), 3.60-3.46(m,1H), 3.41(d,J=13.0Hz,2H), 3.23(d,J=11.8Hz,1H).

[1019] Example 84

[1020]

[1021] Synthesis of (S)-2,6-difluoro-4-(2-methylmorpholino)benzoic acid (84A): The title compound was prepared according to the procedure presented for the synthesis of compound 75A starting with (S)-2-methylmorpholine.

[1022] (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 presented method for the synthesis of compounds 16A and 16, starting with 84A. MS (m / z) 591.8 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ8.88(d,J=8.1Hz,1H),8.85(dd,J=4.2,1.5Hz,1H),8.65(d,J=8.6Hz,1H ),8.17(d,J=1.6Hz,1H),7.91(dd,J=7.9,1.6Hz,1H),7.69-7.55(m,4H),6.62(d,J=11.9Hz,2H), 4.71(t,J=11.2Hz,1H),3.87(dd,J=11.2,3.4Hz,1H),3.71(d,J=12.4Hz,2H),3.66-3.50(m,3H), 3.44(s,1H),2.70(td,J=11.8,3.6Hz,1H),2.38(dd,J=12.3,10.4Hz,1H),1.13(d,J=6.2Hz,3H).

[1023] Example 85

[1024] Synthesis of (S)-2,6-difluoro-4-(2-methylmorpholino)benzoic acid (85A): The title compound was prepared according to the procedure presented for the synthesis of compound 75A starting with (S)-2-(trifluoromethyl)morpholine.

[1025] (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 presented method for the synthesis of compounds 16A and 16, starting with 85A. MS (m / z) 645.1 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ8.93(d,J=8.1Hz,1H),8.83(dd,J=4.1,1.6Hz,1H),8.64(dd,J=8.7,1.7Hz ,1H),8.16(d,J=1.6Hz,1H),7.90(dd,J=7.9,1.7Hz,1H),7.67-7.57(m,3H),7.56(d,J=7.9Hz,1H) ,6.75(d,J=11.6Hz,2H),4.77-4.66(m,1H),4.29(dq,J=6.7,3.3Hz,1H),4.03(dd,J=10.9,3.3Hz, 1H), 3.86 (d, J = 12.2Hz, 1H), 3.75 (m, 1H), 3.69 (t, J = 10.4Hz, 2H), 3.41 (s, 1H), 2.92-2.72 (m, 2H).

[1026]

[1027] Example 86

[1028]

[1029] Synthesis of (R)-2,6-difluoro-4-((2,2,2-trifluoro-1-phenylethyl)amino)benzoic acid (86A): The title compound was prepared according to the procedure presented for the synthesis of compound 75A starting with (R)-2,2,2-trifluoro-1-phenylethan-1-amine.

[1030] (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 presented procedure for the synthesis of compounds 16A and 16, starting with 86A. MS (m / z) 665.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ8.85-8.77(m,2H),8.61(dd,J=8.8,1.7Hz,1H),8.15(dd,J=1.6,0.4Hz,1H),7.89(dd,J=7.9,1.6Hz,1H),7. 66-7.48(m,7H),7.46-7.32(m,3H),6.53(d,J=11.6Hz,2H),5.67(q,J=8.7Hz,1H),4.64(d,J=11.6Hz,1H),3.71(s,1H),3.37(s,1H).

[1031] Example 87

[1032]

[1033] Synthesis of (R)-2,6-difluoro-4-(methyl(1,1,1-trifluoropropan-2-yl)amino)benzoic acid (87A): The title compound was prepared according to the procedure presented for the synthesis of compound 75A starting with (R)-1,1,1-trifluoro-N-methylpropan-2-amine.

[1034] (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 presented procedure for the synthesis of compounds 16A and 16, starting with 87A. MS (m / z) 617.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ8.92-8.81(m,2H),8.65(dd,J=8.7,1.7Hz,1H),8.16(dd,J=1.7,0.4Hz,1H),7.90(dd,J=7.9,1.6Hz,1H),7.68-7. 53(m,4H),6.63(d,J=12.0Hz,2H),4.93(p,J=7.4Hz,1H),4.70(s,1H),3.74(s,1H),3.41(s,1H),2.83-2.77(m,3H),1.36(d,J=6.8Hz,3H).

[1035] Example 88

[1036]

[1037] 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 procedure presented for the synthesis of compound 75A starting with 1,1,1,3,3,3-hexafluoropropan-2-amine.

[1038] (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 according to the presented procedure for the synthesis of compounds 16A and 16, starting with 88A. MS (m / z) 657.1 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ8.93(d,J=8.0Hz,1H),8.83(dd,J=4.1,1.6Hz,1H),8.66-8.59(m,1H),8.15(d,J=1.7Hz,1H),7.9 0(dd,J=7.8,1.6Hz,1H),7.67-7.53(m,5H),6.69(d,J=11.1Hz,2H),5.93(s,1H),4.70(s,1H),3.62(s,1H),3.40(s,1H).

[1039] Example 89

[1040]

[1041] Synthesis of 4-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)-2,6-difluorobenzoic acid (89A): The title compound was prepared according to the procedure presented for the synthesis of compound 75A starting with 1-cyclopropyl-2,2,2-trifluoroethane-1-amine.

[1042] (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 presented method for the synthesis of compounds 16A and 16, starting with 89A. MS (m / z) 629.2 [M+H] +. 1H NMR(400MHz,DMSO-d6)δ8.86-8.75(m,2H),8.63(dd,J=8.7,1.6Hz,1H),8.15(dd,J=1.7,0 .4Hz,1H),7.90(dd,J=7.9,1.6Hz,1H),7.67-7.53(m,4H),6.93(d,J=9.5Hz,1H),6.40(d, J=11.8Hz,2H),4.67(s,1H),3.91(q,J=8.1Hz,1H),3.72(s,1H),3.40(s,1H),1.08-0.96( m,1H),0.60(dq,J=8.5,4.1,3.3Hz,1H),0.49(dd,J=11.1,5.8Hz,2H),0.34-0.23(m,1H).

[1043] Example 90

[1044]

[1045] Preparation of (S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)propanoic acid (90): 89 was separated into its two stereoisomers by supercritical fluid chromatography using 30% EtOH / TFA cosolvent at a flow rate of 45 mL / min on an IE 5 μm 21x250 mm column. The title compound was identified as the first eluting peak. MS (m / z) 629.2 [M+H] + 1H NMR(400MHz,DMSO-d6)δ8.86-8.75(m,2H),8.66-8.59(m,1H),8.15(dd,J=1.7,0 .4Hz,1H),7.90(dd,J=7.9,1.7Hz,1H),7.67-7.49(m,4H),6.92(d,J=9.5Hz,1H), 6.40(d,J=11.8Hz,2H),4.67(s,1H),3.91(d,J=7.8Hz,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).

[1046] Example 91

[1047]

[1048] Synthesis of (S)-methyl 3-(8-bromoquinolin-5-yl)-2-(tritylamino)propanoate (91A): To a stirred solution of ID (15 g, 43.4 mmol) in DCM was added TEA (15.12 mL, 108.5 mmol) and triphenylmethyl chloride (12.7 g, 45.57 mmol). The reaction mixture was stirred for 2 hours, then filtered through celite and washed 3 times (3x) with EA. The filtrate was concentrated and purified by silica gel chromatography eluting with EA / hexanes to give the title compound.

[1049] Synthesis of (S)-(5-(3-methoxy-3-oxo-2-(tritylamino)propyl)quinolin-8-yl)boronic acid (91B): The title compound was prepared according to the procedure presented for the synthesis of compound 4B starting from 91A.

[1050] 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 presented method for the synthesis of compound 11A starting with 91B and 3-iodo-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one.

[1051] 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 h and then concentrated under reduced pressure to afford the material, which was used without further purification.

[1052] (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 presented procedure for the synthesis of compound 74 starting with 91D. MS (m / z) 671.2 [M+H]. 1H NMR(400MHz,DMSO-d6)δ8.84-8.70(m,2H),8.62(s,1H),7.55(s,2H),7.42(s,1 H),6.75(dd,J=9.4,5.5Hz,1H),6.54(s,1H),6.42(dd,J=11.4,4.2Hz,2H),4.6 6(s,1H),4.29(s,1H),3.66(d,J=13.6Hz,1H),3.59-3.21(m,5H),2.51(s,2H), 1.79-1.70(m,1H),1.51(ddd,J=13.7,10.4,7.1Hz,1H),0.91(t,J=7.3Hz,3H).

[1053] Example 92

[1054] 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 was added sodium methoxide powder (118.19 mg, 2.188 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 hours. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel chromatography using EA in hexanes as eluent to obtain the title compound.

[1055] Synthesis of (S)-methyl 2-amino-3-(8-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoate (92B): The title compound was prepared according to the procedure presented for the synthesis of compounds 91C and 91D starting from 92A.

[1056] (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 procedure presented for the synthesis of compound 74, starting with 92B. MS (m / z) 657.8 [M+H]+. 1H NMR (400 MHz, 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 = 6.0 Hz, 1H), 6.76 (t, J = 8.2 Hz, 1H), 6.45 ( dd,J=11.7,7.2Hz,2H),4.68(d,J=19.6Hz,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=7.4Hz,3H).

[1057]

[1058] Synthesis of (R)-2,6-difluoro-4-(3-(trifluoromethyl)morpholino)benzoic acid (93A): The title compound was prepared according to the procedure presented for the synthesis of compound 75A starting with (R)-3-(trifluoromethyl)morpholine.

[1059] (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 presented method for the synthesis of compounds 16A and 16, starting with 92B and 93A. MS (m / z) 685.9 [M+H] +. 1H NMR(500MHz,DMSO-d6)δ8.95(dd,J=11.7,8.0Hz,1H),8.80(d,J=3.7Hz,1H),8.74(d,J=6.0Hz,1 H),8.63(t,J=8.7Hz,1H),7.61(dd,J=13.0,5.4Hz,3H),7.46(d,J=6.1Hz,1H),6.76(t,J=11.2H z,2H),4.91(d,J=9.3Hz,1H),4.77-4.64(m,1H),4.19-4.13(m,1H),4.08(s,3H),3.95(d,J=11. 7Hz, 1H), 3.80-3.66 (m, 2H), 3.55 (t, J = 11.8Hz, 1H), 3.51-3.36 (m, 2H), 3.23 (t, J = 12.5Hz, 1H).

[1060] Example 94

[1061]

[1062] Synthesis of (S)-methyl 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 procedure for the synthesis of compound 16A presented in Example 16 starting with 93A.

[1063] 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 according to the procedure presented for the synthesis of compound 4B starting from 94A.

[1064] (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 presented procedure 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)δ8.96(d,J=8.0Hz,1H),8.77(dd,J=4.0,1.5Hz,1H),8. 67-8.59(m,1H),8.03(s,1H),7.68-7.47(m,3H),6.74(d,J=11.7Hz,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),3.7 2(d,J=13.1Hz,2H),3.58-3.30(m,3H),3.21(s,1H),2.50(s,3H),2.41(s,3H).

[1065] Example 95

[1066]

[1067] (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 presented method 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) δ8.99-8.81(m,3H),7.76(s,1H),7.65(dd,J=13.5,7.3Hz,1H),7.53(t,J= 8.1Hz,1H),6.72(dd,J=11.5,2.7Hz,2H),6.20(s,1H),4.88(d,J=9.4Hz,1H),4.74-4.69(m,1H), 4.14(d,J=12.7Hz,1H),3.93(dd,J=11.5,3.8Hz,1H),3.79(s,1H),3.70(t,J=9.9Hz,1H),3.51(d ,J=10.7Hz,2H),3.46-3.34(m,4H),3.21(t,J=12.3Hz,1H),2.40(s,3H),1.73(d,J=10.6Hz,3H).

[1068] Example 96

[1069]

[1070] (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 presented method 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)δ8.96(dd,J=7.9,4.2Hz,1H),8.86-8.79(m,1H),8.67(s,1H),7.6 0(dt,J=25.1,8.5Hz,2H),7.48-7.39(m,1H),6.74(dd,J=11.6,4.3Hz,2H),6.54(s,1H), 4.90(dd,J=8.7,3.6Hz,1H),4.72-4.63(m,1H),4.14(d,J=12.7Hz,1H),3.93(dd,J=11.5 ,3.8Hz,1H),3.75-3.62(m,2H),3.60-3.32(m,6H),3.23(d,J=12.4Hz,1H),2.52(s,3H).

[1071] Example 97

[1072]

[1073] (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 presented method 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) δ9.37 (s, 1H), 9.31 (s, 1H), 8.94 (d, J = 8.3Hz, 1H), 8.78 (s, 2H), 8.1 1(s,1H),7.93(d,J=7.7Hz,1H),6.77(dd,J=37.8,12.3Hz,2H),4.97-4.75(m,2H),4.16(d d,J=12.9,8.0Hz,1H),3.91(ddd,J=25.2,12.9,4.2Hz,2H),3.72(d,J=13.1Hz,1H),3.59- 3.53(m,2H),3.41-3.36(m,1H),3.22(dd,J=14.4,11.1Hz,1H),2.66(s,3H),2.39(s,3H).

[1074] Example 98

[1075] (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 presented method 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 (400MHz, DMSO-d6) δ12.96(s,1H),8.96(d,J=8.0Hz,1H),8.89(d,J=4.2Hz,1H),8.71( d,J=8.6Hz,1H),8.50(s,1H),7.73-7.64(m,3H),7.61(d,J=7.3Hz,1H),6.76(d,J=11.8Hz ,2H),4.91(d,J=9.7Hz,1H),4.68(s,1H),4.16(d,J=12.7Hz,1H),3.95(d,J=11.4Hz,1H), 3.73(d,J=13.4Hz,2H), 3.57(s,4H), 3.44(dd,J=14.0,9.3Hz,2H), 3.24(t,J=12.5Hz,1H).

[1076]

[1077] Example 99

[1078]

[1079] (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 presented method 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) δ9.49(d,J=4.9Hz,1H),9.39(d,J=8.7Hz,1H),9.04(d,J=7.5Hz,1H ),8.95(d,J=8.4Hz,1H),8.18(dd,J=8.7,5.0Hz,1H),8.00(d,J=7.8Hz,1H),7.10(s,1H), 6.72(d,J=12.2Hz,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 = 12.8Hz, 1H), 3.21 (t, J = 12.5Hz, 1H), 2.70 (s, 3H).

[1080] Example 100

[1081]

[1082] Synthesis of (S)-methyl 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 presented method for the synthesis of compounds 91C and 91D starting with 4-chloro-3-iodo-1,6-dimethylpyridin-2(1H)-one.

[1083] (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 presented method for the synthesis of compound 93, starting with 100A. MS (m / z) 665.7 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ8.98(d,J=7.9Hz,1H),8.87(d,J=4.3Hz,1H),8.73(s,1H),7.67(d,J=9.1Hz,1H),7.63( dd,J=7.6,4.2Hz,1H),7.54(d,J=7.3Hz,1H),6.76(dd,J=11.7,3.9Hz,2H),6.49(d,J=2.8Hz,1H),4.91(dd,J=8. 9,3.6Hz,1H),4.70(dd,J=12.5,7.4Hz,1H),4.16(d,J=12.7Hz,1H),3.97-3.93(m,2H),3.73(dd,J=12.0,8.5Hz ,2H),3.52(d,J=22.8Hz,1H),3.45(d,J=1.9Hz,3H),3.41(d,J=3.5Hz,1H),3.24(t,J=12.4Hz,1H),2.46(s,3H).

[1084] Example 101

[1085] Synthesis of (S)-methyl 2-amino-3-(8-(3-(dimethylamino)pyridin-2-yl)quinolin-5-yl)propanoate (101A): The title compound was prepared according to the procedure presented for the synthesis of compounds 91C and 91D starting with 2-bromo-N,N-dimethylpyridin-3-amine.

[1086] (S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(3-(dimethylamino)pyridin-2-yl)quinolin-5-yl)propanoic acid (101): The title ...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in: L is selected from a bond, -O-, -OC(O)-*, -NH-, -C(O)-N(H)-*, and -N(H)-C(O)-*; wherein * indicates L to R 1 The connection point; R 1 Selected from A 1 , A 2 , A 3 and A 4 ; A 1 is a 5-10 membered heteroaryl group containing one to five heteroatoms independently selected from S, N and O; wherein A 1 optionally containing one to three C(O); and wherein A 1 Optionally substituted with one to six R a ; A 2 C 6-10 Aryl, optionally substituted with one to six R a ; A 3 C 5-10 Cycloalkyl or 5-14 membered heterocyclic group; wherein A 3 Optionally substituted with one to four independently selected from oxo and R a and A 4 For-NR a1 R a2 ; Each of the R a are independently selected from halogen, cyano, hydroxyl, -NR a1 R a2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -S(O) m -C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -OC 3-8 Cycloalkyl, -O-(3-6 membered heterocyclic group), -OC 1-4 Alkylene-C 3-8 Cycloalkyl and -O-phenyl; Where R a Every C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -OC 3-8 Cycloalkyl, -O-(3-6 membered heterocyclic group), -OC 1-4 Alkylene-C 3-8 Cycloalkyl and -O-phenyl are independently optionally substituted with one to three groups independently selected from the following: halogen, cyano, hydroxy, -NR a1 R a2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy; and Where R a Every C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O) m -C 1-6 The alkyl group is optionally substituted with one to three R a3 , where each R a3 are independently selected from halogen, cyano, hydroxyl, -NR a1 R a2 , C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-6 membered heterocyclic group; Where R a3 Every C 3-8 Cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with one to three R a4 ; and each R a4 are independently selected from halogen, cyano, hydroxyl, -NR a1 R a2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl and 3-6 membered heterocyclic group; each R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from H, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, -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 Aryl, 5-6 membered heteroaryl and 3-12 membered heterocyclyl; Where R 2 , R 3 , R 4 , R 5 and R 6 Every C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-8 Haloalkyl and C 1-8 The haloalkoxy group is optionally substituted with one to two R c ; Each of the R c are independently selected from azido, oxo, cyano, halogen, hydroxyl, -NR a1 R a2 , C 1-4 Alkoxy, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclic group; wherein R c Every C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are optionally substituted with one to three groups independently selected from the following: halogen, cyano, hydroxyl, -NR a1 R a2 , C 1-4 Alkyl, C 1-6 Haloalkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl; Where R 2 , R 3 , R 4 , R 5 and R 6 Every C 6-10 Aryl and 5-6 membered heteroaryl are independently optionally substituted with one to five R b ;and Where R 2 , R 3 , R 4 , R 5 and R 6 Every C 3-12 Cycloalkyl and 3-12 membered heterocyclyl are independently optionally substituted with one to six groups independently selected from the following: =CR b1 R b2 and R b ; Each of the R b are independently selected from azido, cyano, halogen, hydroxyl, -NR a1 R a2 , C 1-6 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclic group; wherein R b Every C 3-6 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are independently optionally substituted with one to three groups independently selected from the following: halogen, cyano, hydroxyl, -NR a1 R a2 , C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 Alkoxy; Each of the R b1 and R b2 Independently selected from H, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 3-8 membered heterocyclyl; Where R b1 and R b2 Every C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are independently optionally substituted with one to three groups independently selected from the following: halogen, cyano, hydroxyl, -NR a1 R a2 , C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl; and Where R b1 With R b2 Every C 1-8 Alkyl and C 1-8 The haloalkyl group is optionally substituted with one to two R b5 ; Where R b3 C 1-4 Alkylene; Where R b4 Selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclic group; wherein R b4 Every C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are optionally substituted with one to three R b6 ; Each of the R b5 are independently selected from cyano, hydroxyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl; and R b5 Every C 1-4 Alkoxy, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are optionally substituted with one to three groups independently selected from the following: halogen, cyano, hydroxyl, -NR a1 R a2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 alkoxy and phenyl; and Each of the R b6 are independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, phenyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl; wherein R b6 Every C 3-6 Cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl are independently optionally substituted with one to three groups independently selected from the following: halogen, cyano, -NR a1 R a2 , C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 alkoxy; or R 2 With R 3 , R 3 With R 4 , or R 5 With R 6 Together with the atoms it is bonded to, it forms C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl or 5-6 membered heterocyclic group; wherein each C 6-10 Aryl, 5-6 Heteroaryl, C 3-6 Cycloalkyl and 5-6 membered heterocyclyl are independently optionally substituted with one to three groups independently selected from the following: halogen, cyano, -NR a1 R a2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, C 1-4 Alkylene-C 3-8 Cycloalkyl, C 1-4 Alkylene-C 6-10 Aryl and C 1-4 Alkylene-(5-6 membered heteroaryl); each R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -NR a1 R a2 ; R 13 Selected from H, C 1-4 Alkyl and C 1-4 haloalkyl; and R 14 Selected from 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, 4-6 membered heterocyclic group and -C 1-4 Alkylene-(4-6 membered heterocyclyl); Where R 14 Every C 3-8 Cycloalkyl, -C 1-4 Alkylene-C 3-8 Cycloalkyl, 4-6 membered heterocyclic group and -C 1-4 Alkylene-(4-6 membered heterocyclyl) is optionally substituted with one to three groups independently selected from the following: halogen, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 haloalkyl; or R 14 Combined with R 13 The N on the 5-membered heterocyclic group together form a 5-membered heterocyclic group; wherein the 5-membered heterocyclic group is optionally substituted with one to two groups independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 6-10 Aryl; wherein C 6-10 Aryl is optionally substituted with one to three groups independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl; Every R a1 and R a2 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl; m is selected from 0, 1 and 2; and n is selected from 1 and 2.

2. The compound of claim 1, wherein the compound is of formula (II) or a pharmaceutically acceptable salt thereof: in: L is selected from a bond, -O-, -OC(O)-*, -NH-, -C(O)-N(H)-*, and -N(H)-C(O)-*; wherein * indicates L to R 1 The connection point; R 1 Selected from A 1 , A 2 and A 3 ; A 1 is a 5-10 membered heteroaryl group containing one to five heteroatoms independently selected from S, N and O; wherein A 1 optionally containing one to three C(O); and wherein A 1 Optionally substituted with one to six R a ; A 2 C 6-10 Aryl, optionally substituted with one to six R a ;and A 3 C 5-10 Cycloalkyl or 5-14 membered heterocyclic group; wherein A 3 Optionally substituted with one to four independently selected from oxo and R a Groups; Each of the R a are independently selected from halogen, cyano, hydroxyl, -NR a1 R a2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -S(O) m -C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -OC 3-8 Cycloalkyl, -O-(3-6 membered heterocyclic group), -OC 1-4 Alkylene-C 3-8 Cycloalkyl and -O-phenyl; Where R a Every C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -OC 3-8 Cycloalkyl, -O-(3-6 membered heterocyclic group), -OC 1-4 Alkylene-C 3-8 Cycloalkyl and -O-phenyl are independently optionally substituted with one to three groups independently selected from the following: halogen, cyano, hydroxy, -NR a1 R a2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy; and Where R a Every C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -S(O) m -C 1-6 The alkyl group is optionally substituted with one to three R a3 , where each R a3 are independently selected from halogen, cyano, hydroxyl, -NR a1 R a2 , C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-6 membered heterocyclic group; Where R a3 Every C 3-8 Cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with one to three R a4 ; and each R a4 are independently selected from halogen, cyano, hydroxyl, -NR a1 R a2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl and 3-6 membered heterocyclic group; each R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from H, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, -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 Aryl, 5-6 membered heteroaryl and 3-12 membered heterocyclyl; Where R 2 , R 3 , R 4 , R 5 and R 6 Every C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-8 Haloalkyl and C 1-8 The haloalkoxy group is optionally substituted with one to two R c ; Each of the R c are independently selected from azido, oxo, cyano, halogen, hydroxyl, -NR a1 R a2 , C 1-4 Alkoxy, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclic group; wherein R c Every C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are optionally substituted with one to three groups independently selected from the following: halogen, cyano, hydroxyl, -NR a1 R a2 , C 1-4 Alkyl, C 1-6 Haloalkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl; Where R 2 , R 3 , R 4 , R 5 and R 6 Every C 6-10 Aryl and 5-6 membered heteroaryl are independently optionally substituted with one to five R b ;and Where R 2 , R 3 , R 4 , R 5 and R 6 Every C 3-12 Cycloalkyl and 3-12 membered heterocyclyl are independently optionally substituted with one to six groups independently selected from the following: =CR b1 R b2 and R b ; Each of the R b are independently selected from azido, cyano, halogen, hydroxyl, -NR a1 R a2 , C 1-6 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclic group; wherein R b Every C 3-6 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are independently optionally substituted with one to three groups independently selected from the following: halogen, cyano, hydroxyl, -NR a1 R a2 , C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 Alkoxy; Each of the R b1 and R b2 Independently selected from H, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 3-8 membered heterocyclyl; Where R b1 and R b2 Every C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are independently optionally substituted with one to three groups independently selected from the following: halogen, cyano, hydroxyl, -NR a1 R a2 , C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl; and Where R b1 and R b2 Every C 1-8 Alkyl and C 1-8 The haloalkyl group is optionally substituted with one to two R b5 ; Where R b3 C 1-4 Alkylene; Where R b4 Selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclic group; wherein R b4 Every C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are optionally substituted with one to three R b6 ; Each of the R b5 are independently selected from cyano, hydroxyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl; and R b5 Every C 1-4 Alkoxy, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are optionally substituted with one to three groups independently selected from the following: halogen, cyano, hydroxyl, -NR a1 R a2 , C 1-4 alkyl, C 1-4 Haloalkyl, C 1-4 alkoxy and phenyl; and Each of the R b6 are independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, phenyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl; wherein R b6 Every C 3-6 Cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl are independently optionally substituted with one to three groups independently selected from the following: halogen, cyano, -NR a1 R a2 , C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 Alkoxy; or R 2 With R 3 , R 3 With R 4 , or R 5 With R 6 Together with the atoms it is bonded to, it forms C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl or 5-6 membered heterocyclic group; wherein each C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 5-6 membered heterocyclyl are independently optionally substituted with one to three groups independently selected from the following: halogen, cyano, -NR a1 R a2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, C 1-4 Alkylene-C 3-8 Cycloalkyl, C 1-4 Alkylene-C 6-10 Aryl and C 1-4 Alkylene-(5-6 membered heteroaryl); each R 7 , R 8 , R 9 , R 10 and R 11 are independently selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -NR a1 R a2 ; R 13 Selected from H, C 1-4 Alkyl and C 1-4 haloalkyl; and R 14 Selected from 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, 4-6 membered heterocyclic group and -C 1-4 Alkylene-(4-6 membered heterocyclyl); Where R 14 Every C 3-8 Cycloalkyl, -C 1-4 Alkylene-C 3-8 Cycloalkyl, 4-6 membered heterocyclic group and -C 1-4 Alkylene-(4-6 membered heterocyclyl) is optionally substituted with one to three groups independently selected from the following: halogen, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 haloalkyl; or R 14 Combined with R 13 The N on the 5-membered heterocyclic group together form a 5-membered heterocyclic group; wherein the 5-membered heterocyclic group is optionally substituted with one to two groups independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 6-10 Aryl; wherein the C 6-10 Aryl is optionally substituted with one to three groups independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl; Every R a1 and R a2 Independently selected from 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.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (IIa):

4. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (IIb): Where X 1 Selected from CR x1 and N; X 2 Selected from CR x1 R x2 NR x2 , O and S(O)2; Where R x1 Selected from H and R b ;and R x2 Selected from H, C 1-4 Alkyl and C 1-4 Haloalkyl; p is selected from 0, 1 and 2; and q is selected from 0, 1, 2, 3 and 4.

5. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound is of formula (IIc):

6. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (IId): Each of the Y 1 , Y 2 , Y 3 , Y 4 and Y 5 Independently selected from CR y and N; where each R y Independently selected from H and R a .

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (IIe): wherein u is selected from 0, 1, 2, 3, 4 and 5.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1, 2 and 6, wherein the compound is of formula (IIf): Each of the R y Independently selected from H and R a .

9. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (IIg): where Y 3 , Y 4 and Y 5 Independently selected from CR y and N; where each R y Independently selected from H and R a .

10. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound is of formula (IIh): Each of the R y Independently selected from H and R a .

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