Compounds for inhibition of α4β7 integrin

Abstract

To provide compounds useful in treating diseases, disorders or conditions that are mediated by α4β7 integrin.SOLUTION: The present disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The present disclosure also provides pharmaceutical compositions comprising a compound of Formula (I), processes for preparing compounds of Formula (I), therapeutic methods for treating inflammatory disease.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 886,798, filed August 14, 2019, the entire contents of which are incorporated herein by reference.

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

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

[0004] Integrins are heterodimeric proteins consisting of α and β subunits. There are 18 known α subunits and 8 known β subunits. The α4β7 integrin is expressed on the surface of lymphocytes and recognizes the extracellular ligand mucosal addressing cell adhesion molecule-1 (MAdCAM-1). The α4β7 integrin is expressed on the intestinal mucosa in gut-associated lymphoid tissues (GALT) and on veins within high endothelial venules (HEV), and regulates lymphocyte trafficking and retention in intestinal tissues through its interaction with MAdCAM-1. Inhibition of integrin interaction with its respective ligands has been proposed as an effective method for treating various autoimmune and inflammatory diseases, and blocking the α4β7-MAdCAM-1 interaction has shown therapeutic benefit in inflammatory bowel diseases (Crohn's disease and ulcerative colitis).

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

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

[0007] In one aspect, a compound having the structure of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: [ka] is a single bond or a double bond, A is an aromatic ring, each Z 1 , Z 2 , Z 3 , and Z 4 are independently N, N(CR c ), C(O), and CR c Each R c are independently H, halo, cyano, hydroxyl, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, and C 1~4 haloalkoxyl; R 1 is a 5- to 10-membered heteroaryl or a 6- to 10-membered heterocyclyl, R 1 each 5-10 membered heteroaryl and 6-10 membered heterocyclyl contains 1-4 N and optionally 1-3 C(O) as ring member(s); R 1 Each 5- to 10-membered heteroaryl and 6- to 10-membered heterocyclyl is selected from 1 to 4 R a and each R a are independently halo, cyano, hydroxyl, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, C 1~4 Haloalkoxyl, -C 1~4 Alkylene-OC 1~4 Alkyl, and C 3~10 cycloalkyl; Each R 2 , R 3 , R 5 , and R 6 are independently H, halo, cyano, hydroxyl, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4Haloalkyl, and C 1~4 haloalkoxyl; R 4 is 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, and —NR b1 R b2 is selected from R 4 The 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are each 1 to 6 R b and each R b are independently halo, cyano, hydroxyl, -NR a1 R a2 , C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~8 Haloalkyl, and C 1~8 haloalkoxyl, and Each R b1 and R b2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, -C 1~6 Alkylene-phenyl, and -C 1~6 haloalkylene-phenyl; R 7 is H, C 1~10 Alkyl, C 1~10 Haloalkyl, C 3~10 Cycloalkyl, 3-14 membered heterocyclyl, 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 , -C 1~4 Alkylene-C 3~10 Cycloalkyl, -C 1~4 alkylene-3 to 14-membered heterocyclyl, -C 1~4 Alkylene-C 6~10 Aryl, -C 1~4 alkylene-5 to 10-membered heteroaryl, and -L 1 -R 9 is selected from L 1 -C 1~4 Alkylene -O-, -C 1~4 Alkylene-C(O)-, -C 1~4 Alkylene-OC(O)-, -C 1~4 Alkylene-OC(O)-C 1~4 Alkylene-, -C 1~4 Alkylene-C(O)-O-, -C 1~4 Alkylene-C(O)-OC 1~4 Alkylene-, -C 1~4 Alkylene-OC(O)-O-, -C 1~4 Alkylene-OC(O)-OC 1~4 Alkylene-, -C 1~4 Alkylene-NR a1 C (O)-O- and -C 1~4 Alkylene-OC(O)-NR a1 - selected from R 9 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 3-14 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl; R 7 and R 9 Each C 3~10 Cycloalkyl, 3-14 membered heterocyclyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are independently selected from halo, hydroxyl, C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, C 1~4 Haloalkoxyl, -NR a1 R a2 , and -C 1~4 Alkylene-NR a1 R a2 optionally substituted with 1 to 4 groups selected from R 8 is H, C 1~6 Alkyl, and C 1~6 haloalkyl; Each R a1and R a2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 3~10 cycloalkyl. DETAILED DESCRIPTION OF THE INVENTION

[0008] Definitions and general parameters The following description sets forth example methods, parameters, etc. However, it should be recognized that such description is not intended to limit the scope of the present disclosure, but is instead provided as a description of example embodiments.

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

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

[0011] For example, a wavy line over a chemical group, such as: [ka] indicates a point of attachment, i.e., it indicates a broken bond where a group is attached to another described group.

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

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

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

[0015] "Alkylene" (including those that are part of other groups) refers to branched and unbranched divalent "alkyl" groups. As used herein, alkylene has 1 to 20 carbon atoms (i.e., C 1~20 alkylene), having 1 to 8 carbon atoms (i.e., C 1~8 alkylene), having 1 to 6 carbon atoms (i.e., C 1~6 alkylene), or having 1 to 4 carbon atoms (i.e., 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 groups in question having the same number of carbons. Thus, for example, propylene also includes 1-methylethylene, and butylene includes 1-methylpropylene, 1,1-dimethylethylene, and 1,2-dimethylethylene.

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

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

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

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

[0020] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl refers to a group having 6 to 20 ring carbon atoms (i.e., C6~20 aryl), having 6 to 12 carbon ring atoms (i.e., C 6~12 aryl), or having 6 to 10 carbon ring atoms (i.e., C 6~10 (aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or overlap in any way with heteroaryl, as defined below. When one or more aryl groups are fused to a heteroaryl ring, the resulting ring system is heteroaryl.

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

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

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

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

[0025] The term "fused" refers to rings that are joined to adjacent rings.

[0026] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodo.

[0027] "Haloalkyl" refers to an unbranched or branched alkyl group, as defined above, in which one or more hydrogen atoms are replaced by halogen. For example, if a residue is substituted with two or more halogens, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, which may, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0028] "Haloalkylene" refers to an unbranched or branched alkylene group, as defined above, in which one or more hydrogen atoms has been replaced by a halogen.

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

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

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

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

[0033] Whenever the graphical representation of a group terminates in a singly bonded nitrogen atom, that group represents an —NH group unless otherwise indicated. Similarly, unless otherwise stated, hydrogen atom(s) are assumed to be implied and present when needed to complete valence or provide stability, given the knowledge of those skilled in the art.

[0034] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may also be referred to as "alkylene" groups or "alkylenyl" groups, "arylene" groups, or "arylenyl" groups, respectively. Also, unless expressly indicated otherwise, combinations of groups are referred to herein as one moiety; for example, the last-mentioned group, arylalkyl, contains the atom by which the moiety is attached to the remainder of the molecule.

[0035] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where the event or circumstance does not occur. Also, the term "optionally substituted" refers to any one or more hydrogen atoms on a specified atom or group that may or may not be replaced by a non-hydrogen moiety.

[0036] The term "substituted" means that any one or more hydrogen atoms on the specified atom or group are replaced with one or more 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, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanato, thiol, thione, or combinations thereof. Polymers or similar amorphous structures resulting from defining the substituents with an infinite number of additional substituents (e.g., substituted aryls with substituted alkyls, which themselves are substituted with substituted aryl groups, which are further substituted with substituted heteroalkyl groups, etc.) are not intended to be included herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluorines or a heteroaryl group having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those of ordinary skill 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, "alkylaryl." Unless otherwise specified, if a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.

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

[0038] Some of the compounds exist as tautomeric isomers. Tautomeric isomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that the compound includes both the amide and imidic acid tautomers. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0039] Any formula or structure given herein is also intended to represent unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present disclosure include: 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 Isotopically labeled compounds of the present disclosure include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as I. 3 H, 13 C, and 14 C. Such isotopically labeled compounds may be useful in detection or imaging techniques such as metabolism studies, reaction kinetic studies, positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or It may be useful in the radioactive treatment of patients.

[0040] The present disclosure also includes compounds of the present disclosure in which one to n hydrogens bonded to a carbon atom have been replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of any compound of the present disclosure when administered to a mammal, particularly a human. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci., Vol. 5, No. 12, pp. 524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0041] The deuterium-labeled or deuterium-substituted therapeutic compounds of the present disclosure exhibit improved drug kinetics (DMPK) with respect to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life, reduced dosing requirements, and / or improved therapeutic index. 18 F-labeled compounds can be useful in PET or SPECT studies.The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by replacing readily available isotopically labeled reagents with non-isotopically labeled reagents, and carrying out the procedures disclosed in the schemes or in the examples and preparations described below.In this context, it is understood that deuterium is considered to be a substituent in the compounds of the present disclosure.

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

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

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

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

[0046] As used herein, "pharmaceutically acceptable carriers" or "pharmaceutically acceptable excipients" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents. The use of such media and agents for pharmaceutically active substances is well known in the art. Except as far as any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0047] "Treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition and / or attenuating the severity of the disease or condition), b) slowing or arresting the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition), and / or c) palliating the disease, i.e., causing regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or complete remission of the disease or condition, enhancing the effect of another drug, slowing the progression of the disease, improving quality of life, and / or prolonging survival).

[0048] "Prevention" or "preventing" means treating either a disease or condition such that the clinical symptoms of the disease or condition do not develop. In some embodiments, the compounds may be administered to subjects (including humans) who are at risk or have a family history of the disease or condition.

[0049] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation, or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0050] 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 and provide a therapeutic benefit, such as amelioration of symptoms or slowing of disease progression, when administered to a subject. For example, a therapeutically effective amount may be an amount sufficient to reduce symptoms of a disease or condition in response to inhibition of α4β7 integrin activity. A therapeutically effective amount may vary depending on the subject, the disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the mode of administration, and can be readily determined by one of ordinary skill in the art.

[0051] The term "inhibition" refers to a decrease in baseline activity of a biological activity or process. "Inhibition of the activity of α4β7 integrin" or variations thereof refers to a decrease in the activity of α4β7 integrin as a direct or indirect response to the presence of a compound described herein relative to the activity of α4β7 integrin in the absence of a compound described herein. "Inhibition of α4β7" refers to a decrease in α4β7 integrin activity as a direct or indirect response to the presence of a compound described herein relative to the activity of α4β7 integrin in the absence of a compound described herein. In some embodiments, the inhibition of α4β7 integrin activity may be compared in the same subject prior to treatment or in another subject not receiving treatment. compound

[0052] Provided herein are compounds that function as inhibitors of α4β7 integrin. In one aspect, a compound having the structure of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: [ka] is a single bond or a double bond, A is an aromatic ring, each Z 1 , Z 2 , Z 3 , and Z 4 are independently N, N(CR c ), C(O), and CR c Each R c are independently H, halo, cyano, hydroxyl, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, and C 1~4 haloalkoxyl; R 1 is a 5- to 10-membered heteroaryl or a 6- to 10-membered heterocyclyl, R 1 Each 5-10 membered heteroaryl and 6-10 membered heterocyclyl of the formula (I) contains 1-4 N and optionally 1-3 C(O) as ring member(s), and R 1 Each 5- to 10-membered heteroaryl and 6- to 10-membered heterocyclyl is selected from 1 to 4 R a and each R a are independently halo, cyano, hydroxyl, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, C 1~4 Haloalkoxyl, -C 1~4 Alkylene-OC 1~4 Alkyl, and C 3-10 cycloalkyl; Each R 2 , R 3 , R 5 , and R 6 are independently H, halo, cyano, hydroxyl, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, and C 1~4 haloalkoxyl; R 4 is 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, and —NR b1 R b2 is selected from R 4 The 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are each 1 to 6 R b and each R b are independently halo, cyano, hydroxyl, -NR a1 R a2 , C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~8 Haloalkyl, and C 1~8 haloalkoxyl, and Each R b1 and R b2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, -C 1~6 Alkylene-phenyl, and -C 1~6 haloalkylene-phenyl; R 7 is H, C 1~10 Alkyl, C 1~10 Haloalkyl, C 3~10 Cycloalkyl, 3-14 membered heterocyclyl, 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 , -C 1~4Alkylene-C 3~10 Cycloalkyl, -C 1~4 alkylene-3 to 14-membered heterocyclyl, -C 1~4 Alkylene-C 6~10 Aryl, -C 1~4 alkylene-5 to 10-membered heteroaryl, and -L 1 -R 9 is selected from L 1 -C 1~4 Alkylene -O-, -C 1~4 Alkylene-C(O)-, -C 1~4 Alkylene-OC(O)-, -C 1~4 Alkylene-OC(O)-C 1~4 Alkylene-, -C 1~4 Alkylene-C(O)-O-, -C 1~4 Alkylene-C(O)-OC 1~4 Alkylene-, -C 1~4 Alkylene-OC(O)-O-, -C 1~4 Alkylene-OC(O)-OC 1~4 Alkylene-, -C 1~4 Alkylene-NR a1 C (O)-O- and -C 1~4 Alkylene-OC(O)-NR a1 - selected from R 9 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 3-14 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl; R 7 and R 9 Each C 3~0 Cycloalkyl, 3-14 membered heterocyclyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are independently selected from halo, hydroxyl, C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, C 1~4 Haloalkoxyl, -NR a1 R a2 , and -C1~4 Alkylene-NR a1 R a2 optionally substituted with 1 to 4 groups selected from R 8 is H, C 1~6 Alkyl, and C 1~6 haloalkyl, and Each R a1 and R a2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 3~10 cycloalkyl.

[0053] In another aspect, there is provided a compound of formula (II), or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 , R 2 , R 4 , R 6 , and R 7 is as defined above in formula (I) or as defined elsewhere in this disclosure.

[0054] In another aspect, there is provided a compound of formula (IIa), or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 2 , R 4 , R 6 , R 7 , and R a is as defined above in Formula (I), Formula (II), or as defined elsewhere in this disclosure. 1 is N or CH. d is H, C 1~4 Alkyl, and C 1~4 haloalkyl; and r is selected from 0, 1, 2, and 3.

[0055] In another aspect, there is provided a compound of formula (IIb), or a pharmaceutically acceptable salt thereof: [ka] In the formula, R a , R 2 , R 6 , R 7 , and R b is as defined above in formula (I), formula (II), or as defined elsewhere in this disclosure. 1 is CR x1 and N. 2 is CR x1 R x2 , N.R. x2 and O. x1 is H and R b and R x2 is H, C 1~4 Alkyl, and C 1~4 haloalkyl. d is H, C 1~4 Alkyl, and C 1~4 haloalkyl, r is selected from 0, 1, 2, and 3, and m is selected from 0, 1, 2, 3, and 4.

[0056] In another aspect, there is provided a compound of formula (IIc), or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 2 , R 6 , and R 7 is as defined above in Formula (I), Formula (II), or as defined elsewhere in this disclosure. b is C 1~4 Alkyl or C 1~6 haloalkyl. R d is H, C 1~4 Alkyl, and C 1~4 haloalkyl.

[0057] In another aspect, there is provided a compound of formula (IId), or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 7 is as defined above in formula (I), formula (II), or As defined elsewhere in the disclosure. 2 and R 6 independently, halo, C 1~4 Alkyl, and C 1~4 haloalkyl. b is C 1~4 Alkyl or C 1~6 haloalkyl. R d is H, C 1~4 Alkyl or C 1~4 It is haloalkyl.

[0058] In another aspect, there is provided a compound of formula (III), or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 , R 2 , R 4 , R 6 , R 7 , and R c is as defined above in formula (I) or as defined elsewhere in this disclosure.

[0059] In another aspect, there is provided a compound of formula (IIIa), or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 , R 2 , R 6 , R 7 , R b , and R c is as defined above in formula (I) or as defined elsewhere in this disclosure. 1 is CRx1 and N. 2 is CR x1 R x2 , N.R. x2 and O. x1 is H and R b Selected from: R x2 is H, C 1~4 Alkyl, and C 1~4 haloalkyl; m is selected from 0, 1, and 2.

[0060] In another aspect, there is provided a compound of formula (IIIb), or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 , R 2 , R 6 , R 7 , and R c is as defined above in formula (I) or as defined elsewhere in this disclosure. 7 , R b is C 1~4 Alkyl, or C 1~6 It is haloalkyl.

[0061] In another aspect, there is provided a compound of formula (IV), or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 , R 2 , R 4 , R 6 , R 7 , and R c is as defined above in formula (I) or as defined elsewhere in this disclosure.

[0062] In some embodiments of Formula (I), (II), (III), (IIIa), or (IIIb), R 1are pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, isoxazolyl, triazolyl, pyrazolyl, benzothiazolyl, pyridinonyl, quinolinonyl, isoquinolinonyl, quinazolinedionyl, pyrazinonyl, pyrimidinonyl, pyrimidinedionyl, pyridazinonyl, and quinazolinedionyl. Each R is selected from the group consisting of azolinonyl, ... 1 are independently 1 to 4 R a is optionally replaced by

[0063] In some embodiments of Formula (I), (II), (III), (IIIa), or (IIIb), R 1 teeth, [ka] wherein each R 1 are independently 1 to 3 R a In some embodiments, R 1 teeth, [ka] wherein each R 1 are independently 1 to 3 R a In some embodiments, each R a are independently halo, CN, -OH, NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, and C 1~4 In some embodiments, each R is selected from haloalkoxyl. a are independently selected from F, Cl, OH, CN, —NH 2 , —N(CH 3 ) 2 , —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCH 3 , and —OCF 3 .

[0064] In some embodiments of Formula (I), (II), (III), (IIIa), or (IIIb), R 1 teeth, [ka] and R d is C 1~4 In some embodiments, R d is methyl or ethyl. In some embodiments, R d is methyl. In some embodiments, R 1 teeth, [ka] is.

[0065] In some embodiments of Formula (I), (II), (III), (IIIa), or (IIIb), R 1 is 1 to 3 R a optionally replaced with [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0066] In some embodiments of Formula (I), (II), (III), (IIIa), or (IIIb), R 1 is a 10-membered heterocyclyl containing two N and two C(O) ring members, and R 1 is 1 to 3 R a In some embodiments, each R a is independently selected from F, Cl, OH, CN, —NH, —N(CH), —CH, —CHF, —CHF, —CF, —OCH, and —OCF. 1and [ka] each of which is selected from 1 to 3 R a In some embodiments, R d is -CH3. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0067] In some embodiments of Formula (I), (II), (III), (IIIa), or (IIIb), R 1 teeth, [ka] is.

[0068] In some embodiments of Formula (I), (II), (III), (IIIa), or (IIIb), R 1 teeth, [ka] In some embodiments, R d is -CH3. In some embodiments, R 1 teeth, [ka] is.

[0069] In some embodiments of Formula (I), Z 1 is N. Z 2 , Z 3 , and Z 4 is CR c In some embodiments, Z 1is N, and Z 2 , Z 3 , and Z 4 is CH. In some embodiments, Z 3 is N, and Z 1 , Z 2 , and Z 4 is CR c In some embodiments, Z 1 and Z 2 is N. In some embodiments, Z 1 and Z 3 is N. In some embodiments, Z 1 is CR c and R c is C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, and C 1~4 In some embodiments, Z is selected from haloalkoxyl. 1 is CR c and R c is selected from —CH 3 , —OCH 3 , and —CF 3 . In some embodiments, Z 1 is C-OCH3.

[0070] In some embodiments of Formula (I), each R 3 and R 5 is independently selected from H and halo. In some embodiments, each R 3 and R 5 is H.

[0071] Formulas (I), (II), (IIa), (IIb), (IIc), (IId), (III) In some embodiments of (IIIa), (IIIb), or (IIIc), each R 2 and R 6 are independently H, halo, and C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, and C 1~4 In some embodiments, each R is selected from haloalkoxyl. 2 and R6 is independently selected from F and —CH. In some embodiments, R 2 is F and R 6 is -CH3.

[0072] In some embodiments of Formula (I), (II), (IIa), or (III), R 4 is 1 to 3 R b In some embodiments, R is a 3- to 8-membered heterocyclyl optionally substituted with 4 The 3- to 8-membered heterocyclyl of R contains 1 to 2 heteroatoms or groups independently selected from S, N, O, and S(O)2. In some embodiments, each R b are independently halo, hydroxyl, cyano, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl and C 1~4 In some embodiments, each R b are independently selected from F, Cl, CN, —OH, —CH 3 , —CH(CH 3 ) 2 , —CF 3 , and —CH 2 CF 3 .

[0073] In some embodiments of Formula (I), (II), (IIa), or (III), R 4 is 1 to 3 R b In some embodiments, R is a 6-membered heterocyclyl optionally substituted with 4 teeth, [ka] and each of which is selected from 1 to 3 R b In some embodiments, each R b independently, halo, C 1~4 Alkyl, and C 1~4 In some embodiments, R is selected from haloalkyl. 4 is R b optionally replaced with [ka] and R b is selected from -CH, -CHF, -CF, and -CHCF. In some embodiments, R b is selected from -CH3, -CHF2, and -CF3. In some embodiments, R b is selected from -CH2CHF2, and -CH2CF3. In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] is.

[0074] In some embodiments of Formula (I), (II), (IIa), or (III), R 4 teeth, [ka] In some embodiments, [ka]

[0075] In some embodiments of Formula (I), (II), (IIa), or (III), R 4 is -NR b1 R b2 In some embodiments, each R b1 and R b2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 3~6 In some embodiments, R b1 is H and R b2 is C 1~6 In some embodiments, R 4 teeth, [ka] is. In some embodiments, R4 is [ka] is.

[0076] In some embodiments of Formula (I), (II), (IIa), or (III), R 4 is 1 to 3 R b and each R b independently, halo, C 1~4 Alkyl, and C 1~4 In some embodiments, R is selected from haloalkyl. 4 is 1 to 3 R b In some embodiments, R 4 is 1 to 3 R b In some embodiments, R 4 is 1 to 3 R b In some embodiments, each R b is independently selected from -CH, -CHF, -CF, and -CHCF. In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R b is selected from —CH 3 , —CHF 2 , —CF 3 , and —CH 2 CF 3 .

[0077] In some embodiments of Formula (IIb) or Formula (IIIa), X 1 is N and X 2 is O. In some embodiments, X 1 is N. In some embodiments, X 1 and X 2 is N. In some embodiments, X 2 is O. In some embodiments, X 2 is CR x1 R x2 and R x1 is H and C 1~4 alkyl, and R x2 is H. In some embodiments, X 2 is -CH2-.

[0078] In some embodiments of Formula (III), (IIIa), or (IIIb), R c Ha, Halo, C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, and C 1~4 In some embodiments, R is selected from haloalkoxyl. c is selected from F, Cl, CH, —OCH, —OCF, and —CF. In some embodiments, R c is -OCH3.

[0079] In some embodiments of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (III), (IIIa), or (IIIb), R 7 is H, C 1~6 Alkyl, and C 3~6 In some embodiments, R 7 is H, C 1~6 Alkyl, and C 3~6 cycloalkyl. R 7 is selected from H, methyl, ethyl, propyl, butyl, cyclopropyl, —CH—OC(O)C(CH) and phenyl. In some embodiments, R 7 is selected from H, methyl, ethyl, propyl, and cyclopropyl. In some embodiments, R 7 is H, methyl, ethyl, propyl, butyl, -CH2C(O)N(CH3)2, -(CH2 )2N(CH2CH3)2, —CH2-OC(O)CH3, —(CH2)2-OC(O)CH3, —CH2-OC(O)C(CH)3, —(CH2)2-OC(O)C(CH)3, —CH2-OC(O)-O-CH3, —CH(CH3)-OC(O)-O-CH3, —CH2-OC(O)-O-CH2CH3, —CH2-OC(O)-O-CH(CH3), —CH2-OC(O)-OC(CH3), and —(CH2)2C(O)CH3. In some embodiments, R 7 is H. In some embodiments, R 7 is methyl. In some embodiments, R 7 is ethyl. In some embodiments, R 7 is cyclopropyl. In some embodiments, R 7 is phenyl.

[0080] In some embodiments of Formula (I), R 8 is H.

[0081] In some embodiments, the compound of the present disclosure is selected from Examples 1-53.

[0082] In some embodiments, the compound of the present disclosure is selected from Examples 54-93.

[0083] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, in which 1 to n hydrogen atoms bonded to a carbon atom may be replaced with deuterium atoms or D, where n is the number of hydrogen atoms in the molecule. As known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds may increase resistance to metabolism and therefore may be useful for increasing the half-life of the compounds described herein, or their pharmaceutically acceptable salts, isomers, or mixtures, when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci., Vol. 5, No. 12, pp. 524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0084] In some embodiments, compounds of the present disclosure contain 1 to 6 deuterium ( 2 In some embodiments, R 2 , R 3 , R 4 , R 5 , and R 6 In some embodiments, one of R 6 contains 1 to 6 D. In some embodiments, R 6 is CD3.

[0085] Pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that are useful in preparing pharmaceutical compositions suitable for veterinary or human medicine. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. In addition, if a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, addition salts, particularly pharmaceutically acceptable addition salts, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts.

[0086] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0087] "Prodrugs" are compounds that, upon administration to the human body, undergo some chemical or enzymatic pathway. It is therefore a biologically inactive derivative of a drug that is converted into the biologically active parent drug.

[0088] In certain embodiments, optical isomers, racemates, or other mixtures or mixtures thereof of the compounds described herein or pharmaceutically acceptable salts thereof are provided. In these situations, single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by the ability to resolve a racemate. The ability to resolve a racemate can be achieved by conventional methods, such as, for example, crystallization in the presence of a resolving agent, or chromatography, for example, using a chiral high-performance liquid chromatography (HPLC) column. In addition, Z- and E-forms (or cis- and trans-forms) of the compounds described herein are also provided. Specifically, Z- and E-forms are included even when only one name is designated for both carbon-carbon double bonds.

[0089] Where chirality is not specified, it is understood that the embodiment is directed to either a particular diastereomerically or enantiomerically enriched form, or a racemic or scalenic mixture of such compound(s).

[0090] "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 in a ratio other than 1:1 is a "scalemic" mixture.

[0091] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0092] "Atropisomers" are stereoisomers that arise due to hindered rotation about a single bond, where the barrier to rotation about the bond is high enough to allow for the isolation of individual stereoisomers. Provided are atropisomers of the compounds described herein.

[0093] Compositions provided herein that contain a compound described herein or a pharmaceutically acceptable salt, isomer, or mixture thereof may include a racemic mixture, or a mixture containing an enantiomeric excess of one enantiomer or a single diastereomer, or a diastereomeric mixture. All such isomeric forms of these compounds are expressly included herein as if each and every isomeric form were specifically and individually listed.

[0094] In certain embodiments, chelates, noncovalent complexes, and mixtures, isomers, or mixtures thereof of the compounds described herein or pharmaceutically acceptable salts thereof are also provided. A "chelate" is formed by coordinating a compound to a metal ion at two (or more) points. A "noncovalent complex" is formed by the interaction of a compound with another molecule where no covalent bond is formed between the compound and the molecule. For example, complex formation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding). Therapeutic Uses of the Compounds

[0095] The methods described herein may be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, such as inside an animal or human. In this context, the methods described herein may 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. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and their biopsies. In this context, the present invention relates to the treatment of various cell populations, including therapeutic and experimental purposes. The present invention can be used for a variety of purposes. For example, the present invention can be used ex vivo to determine the optimal schedule and / or dosing of α4β7 integrin inhibitor administration for a given indication, cell type, individual, and other parameters. Information gleaned from such use can be used for experimental purposes or to design protocols for in vivo treatment in the clinic. Other ex vivo uses for which the present invention may be suitable are described below or will become apparent to those skilled in the art. Selected compounds can be further characterized to determine safety or tolerated dosage in human or non-human subjects. Such properties can be determined using methods commonly known to those skilled in the art.

[0096] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, or deuterated analogs thereof, may be used to treat subjects having or suspected of having disease states, disorders, and conditions (collectively referred to as "indications") that are responsive or thought to be responsive to inhibition of α4β7 integrin activity. In some embodiments, the compounds described herein may be used to inhibit the activity of α4β7 integrin. In some embodiments, the compounds described herein may be used to inhibit excessive or destructive immune responses or growth or proliferation of cells, such as cancer cells, or to inhibit immunosuppression.

[0097] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, or deuterated analogs thereof, may be used to treat subjects having or suspected of having disease states, disorders, and conditions (collectively referred to as "indications") that are responsive or thought to be responsive to inhibition of α4β7 integrin activity. In some embodiments, the compounds described herein may be used to inhibit the activity of α4β7 integrin. In some embodiments, the compounds described herein may be used to inhibit excessive or destructive immune responses or growth or proliferation of cells, such as cancer cells, or to inhibit immunosuppression. method

[0098] In some embodiments, the present disclosure provides compounds described herein that are useful as inhibitors of α4β7 integrin. In some embodiments, the present disclosure provides methods of treating an inflammatory disease or condition, comprising administering a compound described herein.

[0099] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier.

[0100] In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound described herein, as well as at least one additional therapeutic agent and at least one pharmaceutically acceptable excipient.

[0101] The present disclosure provides compounds described herein for use in therapy.

[0102] In another embodiment, the present disclosure provides a compound described herein for use in the manufacture of a medicament for treating a disease or condition provided herein.

[0103] In some embodiments, compounds described herein are provided that are useful for treating a disease or condition in a patient suitable for treatment by inhibiting α4β7 integrin. Diseases or conditions that can be treated with 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, fatty liver, nonalcoholic fatty liver disease (NAFLD), nonalcoholic fatty liver disease nonalcoholic steatohepatitis (NASH), systemic lupus erythematosus lupus erythematosus (SLE), and lupus nephritis.

[0104] In some embodiments, there are provided compounds described herein that are useful for treating an inflammatory disease or condition in a patient that is mediated, at least in part, by α4β7 integrin.

[0105] "Administering" or "administration" refers to the delivery of one or more therapeutic agents to a patient. In some embodiments, the administration is monotherapy, where a compound described herein is the only active ingredient administered to a patient in need of treatment. In another embodiment, the administration is simultaneous administration, where two or more therapeutic agents are delivered together during the course of treatment. In some embodiments, the two or more therapeutic agents are co-formulated into a single dosage form or "combination dosage unit," or can be formulated separately and then combined into a combination dosage unit, as in the case of intravenous or oral administration, typically as a monolayer or bilayer tablet or capsule.

[0106] In some embodiments, the compounds described herein are administered to a human patient in need thereof in an effective amount, such as about 0.1 mg to about 1000 mg of the compound per dose. In some embodiments, the effective amount is about 0.1 mg to about 400 mg per dose. In some embodiments, the effective amount is about 0.1 mg to about 300 mg per dose. In some embodiments, the effective amount is about 0.1 mg to about 200 mg per dose. In some embodiments, the effective amount is about 1 mg to about 100 mg per dose. In other embodiments, the effective amount is about 1 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 18 mg, about 20 mg, about 30 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 200 mg, or about 300 mg per dose.

[0107] In some embodiments, a compound described herein and at least one additional therapeutic agent are administered to a human patient in need thereof in a formulation with an effective amount of each agent, independently, from about 0.1 mg to about 1000 mg per dose of compound or per dose of compound. In some embodiments, an effective amount of a combination treatment of a compound described herein and an additional compound is independently from about 0.1 mg to about 200 mg per dose of compound. In some embodiments, an effective amount of a combination treatment of a compound described herein and an additional compound is independently from about 1 mg to about 100 mg per dose of compound. In other embodiments, an effective amount of a combination treatment of a compound described herein and an additional compound is independently from about 1 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 18 mg, about 20 mg, about 30 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 200 mg, or about 500 mg per dose of each component, respectively.

[0108] In some embodiments, the dose of a compound described herein and / or the combination of a dose of a compound described herein and / or a dose of an additional therapeutic agent is administered once daily, twice daily, or three times daily. In yet another embodiment, the dose of a compound described herein and / or a dose of an additional therapeutic agent is administered as a loading dose of about 0.1 mg to about 1000 mg per compound on day 1 and daily, or every other day or weekly for up to one month, followed by the usual regimen of a compound described herein and / or one or more additional therapeutic agents or therapies. Maintenance doses can be about 0.1 mg to about 1000 mg once daily, twice daily, three times daily, or weekly for each component of a multi-component drug regimen. A competent treating physician will recognize the optimal dosage regimen for a particular patient or particular presenting condition and will make the appropriate treatment regimen determination for that patient. Thus, in another embodiment, appropriate The appropriate treating physician may adjust the dosage regimen of the compounds described herein and / or the additional therapeutic agent(s) disclosed herein to suit the particular needs of the patient. Accordingly, it will be understood that the amount of the dose of the compounds described herein and the amount of the dose of the additional therapeutic agent actually administered will typically be determined by the physician in view of the relevant circumstances, including the condition(s) to be treated, the selected route of administration, the actual compound (e.g., salt or free base) administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0109] Coadministration can also include administering component drugs, e.g., one or more compounds described herein, and one or more additional (e.g., second, third, fourth, or fifth) therapeutic agent(s). Such combinations of one or more compounds described herein with one or more additional therapeutic agent(s) can be administered simultaneously or sequentially (alternating) within a reasonable time period (e.g., about 1 minute to 24 hours) between administrations, depending on the pharmacokinetic and / or pharmacodynamic properties of each agent or combination. Coadministration can also include fixed combination treatment, where the agents of the treatment regimen can be combined in a fixed dosage or a combined dosage vehicle, e.g., solid, liquid, or aerosol. In some embodiments, kits can be used to administer the drugs or drug components.

[0110] Accordingly, some embodiments of the present disclosure are methods of treating a disease or condition mediated, at least in part, by α4β7 integrin, comprising administering, e.g., via a kit, a therapeutically effective amount of a formulation of one or more compounds described herein and one or more additional therapeutic agents to a patient in need thereof. It will be understood that a competent treating physician will administer or prescribe the administration of a therapeutically effective amount of any of the disclosed compound(s) or combinations of compounds.

[0111] "Intravenous administration" is the administration of a substance into a vein or "into a vein." Compared to other routes of administration, the intravenous (IV) route is a more common method for delivering fluids and medications throughout the body. It is a faster method. Infusion pumps can allow precise control over the flow rate and total amount of medication delivered. However, if changes in flow rate do not have serious consequences or a pump is not available, the drip is often left to flow by simply placing the bag above the patient's level and adjusting the rate with a clamp. Alternatively, if the patient requires a high flow rate and the IV access device is large enough in diameter to accommodate it, a rapid infuser can be used. This is either an inflatable cuff placed around the fluid bag to force the fluid into the patient, or a similar electrical device that can also heat the fluid being infused. If the patient only needs medication at a specific time, an intermittent infusion is used, which does not require additional fluid. This can use the same technique as an intravenous drip (pump or gravity drip), but after the full dose of medication is given, the tubing is disconnected from the IV access device. Some medications are also given by IV push or bolus; that is, a syringe is connected to the IV access device and the medication is injected directly (or slowly, if this stimulates the vein or causes a rapid effect). When a medication is injected into the fluid stream of an IV tubing, there must be some means to ensure that it reaches the patient through the tubing. Typically, this is accomplished by allowing the fluid stream to flow normally, thereby carrying the medication into the bloodstream. However, a second fluid injection is sometimes used after the injection as a "washout" to allow the medication to flow more quickly into the bloodstream. Thus, in some embodiments, the compound(s) or combination of compounds described herein may be administered by IV administration, alone or in combination with administration of specific components of a treatment regimen by oral or parenteral routes.

[0112] "Oral administration" means a route of administration in which a substance is taken through the mouth, unless it is done so, for example, through a tube, so that the drug is not in direct contact with any of the oral mucosa, including buccal administration, Sublabial and sublingual administration, as well as enteral and respiratory administration Typical forms for oral administration of therapeutic agents include the use of tablets or capsules. Thus, in some embodiments, a compound(s) or combination of compounds described herein may be administered by the oral route, either alone or in combination with administration of certain components of the treatment regimen by IV or parenteral routes. Pharmaceutical preparations

[0113] The compounds described herein can be administered in a pharmaceutical formulation. Pharmaceutical formulations / compositions contemplated by the present disclosure include, in addition to a carrier, a compound described herein or a combination of compounds described herein, optionally in combination with an additional therapeutic agent.

[0114] Pharmaceutical formulations / compositions contemplated by the present disclosure may also be intended for administration by injection and include aqueous solutions, oily suspensions, emulsions (with sesame oil, corn oil, cottonseed oil, or peanut oil), as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and / or by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0115] Sterile injectable solutions are prepared by incorporating the required amount of the component compound(s) into an appropriate solvent with various other ingredients as listed above, or as needed, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle containing the basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred preparation methods are vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient(s) plus any additional desired ingredients from a previously sterile-filtered solution.

[0116] In preparing pharmaceutical compositions containing the compounds described herein, optionally in combination with additional drugs / therapies useful for that purpose, or with pharmaceutically acceptable salts thereof, the active ingredient is typically diluted with an excipient or carrier and / or enclosed or mixed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material (as described above) that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid vehicles), 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.

[0117] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl- and propylhydroxybenzoates, sweetening agents, and flavoring agents.

[0118] The compositions of the present disclosure can be administered to patients by employing procedures known in the art. They may be formulated to provide immediate, sustained, or delayed release of the active ingredient after administration. In some embodiments, sustained-release formulations are used. Controlled-release drug delivery systems for oral administration include osmotic pump systems and solution systems containing polymer-coated reservoirs or drug-polymer matrix formulations.

[0119] Certain compositions are preferably formulated in unit dosage form. The term "unit dosage form" or "combined dosage unit" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of one or more active ingredients (e.g., a compound described herein, optionally in combination with additional therapeutic agents calculated to produce the desired effect, along with a suitable pharmaceutical excipient in, for example, a tablet, capsule, ampoule, or injection vial. However, it will be understood that the amount of each agent actually administered will be determined by the physician in view of the relevant circumstances, including the condition to be treated, the selected route of administration, the actual compounds administered and their relative activities, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0120] To prepare solid compositions such as tablets, the primary active ingredient(s) are mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present disclosure. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient(s) are dispersed evenly throughout the composition, so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0121] Tablets or pills containing a compound described herein of the present disclosure, optionally in combination with a second agent, can be coated or otherwise compounded to provide a dosage form that can provide the benefit of prolonged action or protect from the acidic conditions of the stomach. For example, a tablet or pill can include an inner dosage element and an outer dosage element, the latter in the form of an envelope over 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 formed in which one portion or half of the tablet or capsule is filled with a formulation of a compound described herein, but the other portion or half is filled with a formulation of a compound described herein. The may be in a side-by-side configuration such as a capsule or tablet, with the other half or half of the capsule containing an additional therapeutic agent.

[0122] A variety of materials may be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate. One of ordinary skill in the art will be aware of the techniques and materials used in preparing dosage forms of the formulations disclosed herein.

[0123] A "sustained release formulation" or "sustained release formulation" is a formulation designed to slowly release a therapeutic agent into the body over an extended period of time, whereas 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 only released once it reaches its desired target in the body (e.g., the stomach). One of ordinary skill in the art can develop sustained release formulations of the compounds of the present disclosure without undue experimentation. Thus, in some embodiments, a compound(s) or combination of compounds described herein can be delivered via a sustained release formulation, either alone or in combination with administration of specific components of a treatment regimen by oral, IV, or parenteral routes.

[0124] Lyophilized formulations may also be used to administer the compounds described herein, alone or in combination with additional therapeutic agents. Those skilled in the art will recognize how to make and use lyophilized formulations of drug substances suitable for lyophilization.

[0125] 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 will recognize how to make and use spray-dried formulations of drug substances suitable for spray drying. Other known formulation techniques can also be used to formulate the compounds or combinations of compounds disclosed herein.

[0126] The compounds disclosed herein are useful for treating diseases or conditions mediated, at least in part, by α4β7 integrin. Non-limiting examples of diseases or conditions mediated, at least in part, by α4β7 integrin include acne, acid-induced lung injury, Addison's disease, adrenal hyperplasia, adrenal insufficiency, adult-onset Still's disease, adult respiratory distress syndrome, and the like. 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, allograft rejection, alopecia, alopecia areata, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, angina pectoris, angioedema, angiofibroma, anhidrotic ectodermal dysplasia, antiglomerular basement membrane disease, antigen-antibody complex-dependent disease, ankylosing spondylitis, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, ascites, asthma Pergillosis, asthma, atherosclerosis, atherosclerotic plaque, atopic dermatitis, atrophic thyroiditis, autoimmune diseases, autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria), autoimmune polyendocrine syndrome, autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia), autoimmune hepatitis, autoimmune thyroid disorders, autoinflammatory diseases, back pain, anthrax infection, Behçet's disease, bee-sting-induced inflammation, Behçet's syndrome, Bell's palsy, beryllium disease, Blau syndrome, bone pain, bronchiolitis, bullous pemphigoid (BP) asthma, burns, bursae inflammation, cardiac hypertrophy, carpal tunnel syndrome, Castleman's disease, catabolic disorder ), cataracts, celiac disease, cerebral aneurysms, chemical irritant-induced inflammation, chorioretinitis, lipodystrophy, and chronic atypical neutrophilic skin disease with fever. dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome syndrome, chronic heart failure, chronic lung disease of prematurity, chronic obstructive pulmonary disease (COPD), chronic pancreatitis, chronic prostatitis, chronic recurrent multifocal osteomyelitis, cicatricial alopecia, colitis, complex regional pain syndrome, organ transplant complications, conjunctivitis, connective tissue disease, contact dermatitis, corneal graft neovascularization, corneal ulcer, Crohn's disease, cryopyrin-associated periodic fever syndrome, cutaneous lupus erythematosus (CLE), cryptococcosis ulcerative colitis, cystic fibrosis, deficiency of the interleukin-1 receptor antagonist (DIRA), dermatitis, dermatitis endotoxemia, dermatomyositis, diabetic macular edema, diverticulitis, eczema, encephalitis, Endometriosis, endotoxemia, eosinophilic pneumonia, epicondylitis, epidermolysis bullosa, erythema multiforme, erythroblastopenia, esophagitis, familial amyloidotic polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth retardation, fibromyalgia, fistulizing Crohn's disease, food allergy, giant cell arteritis, glaucoma, glioblastoma, glomerular disease, glomerulonephritis, gluten-sensitive enteropathy, gout, gouty arthritis, graft-versus-host disease Graft-versus-host disease (GVHD), granulomatous hepatitis, Graves' disease, epiphyseal plate injury, Guillain-Barré syndrome, intestinal disease, hair loss, Hashimoto's thyroiditis, head trauma, headache, hearing loss, heart disease, hemangioma, hemolytic anemia, hemophilic arthropathy, Henoch-Schönlein purpura, hepatitis, fatty liver, nonalcoholic fatty liver disease fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hereditary periodic fever syndromes, hereditary disorders of connective tissue, shingles and herpes simplex, hidradenitis suppurativa (HS), hip replacement, hodgkin's disease Kinesiosis, Huntington's disease, hyaline membrane disease, hyperactive inflammatory response hyperammonemia, hypercalcemia, hypercholesterolemia, hypereosinophilic syndrome (HES), hyperimmunoglobulin D with relapsing fever Hyperimmunoglobulinemia D with recurrent fever (HIDS), hypersensitivity pneumonitis, hypertrophic bone formation, aplastic anemia and other anemias, aplastic anemia, ichthyosis, idiopathic demyelinating polyneuropathy, idiopathic inflammatory myopathy (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, acquired immunodeficiency syndrome (HIV infection), hepatitis A, B, C, D, and E, infectious diseases including viral diseases such as herpes, inflammation, inflammation of the central nervous system (CNS), inflammatory bowel disease Inflammatory diseases of the lower respiratory tract, including bronchitis or chronic obstructive pulmonary disease (IBD), inflammatory diseases of the upper respiratory tract, including the nose and sinuses, such as rhinitis or sinusitis, inflammatory diseases of the airways, inflammatory-ischemic events such as stroke or cardiac arrest, inflammatory lung diseases, inflammatory myopathies such as myocarditis, inflammatory liver diseases, inflammatory neuropathy, inflammatory pain, insect sting-induced inflammation, interstitial cystitis, interstitial lung disease, iritis, irritant-induced inflammation, ischemia / reperfusion, joint replacement surgery, juvenile arthritis, juvenile rheumatoid arthritis (juvenile rheumatoid arthritis), keratitis, kidney damage due to parasitic infections, kidney transplant rejection, leptospirosis, leukocyte adhesion deficiency, lichen sclerosus (LS), and Lambert-Eaton myasthenic syndrome. group, Löffler syndrome, lupus, lupus nephritis, Lyme disease, Marfan syndrome (MFS), mast cell activation syndrome, mastocytosis, meningitis, meningioma, mesothelioma, mixed connective tissue disease, Muckle-Wells syndrome (urticaria deafness amyloidosis), mucositis, multisystem dysfunction syndrome, multiple sclerosis, muscle wasting, muscular dystrophy, myasthenia gravis (MG), myelodysplastic syndrome, myocarditis, myositis, rhinosinusitis, necrotizing enterocolitis, neonatal onset multisystem inflammatory disease (NO) MID), neovascular glaucoma, nephrotic syndrome, neuritis, neuropathological diseases, non-allergen-induced asthma, obesity, ocular allergy, optic neuritis, organ transplant rejection, Osler-Weber syndrome, osteoarthritis, osteogenesis imperfecta, osteonecrosis, osteoporosis, osteoarthritis, otitis, pachyonychia congenita, Paget's disease, Paget's disease of bone, pancreatitis, Parkinson's disease, childhood rheumatism, pelvic inflammatory disease, pemphigus, pemphigus vulgaris (PV), bullous pemphigoid Smallpox (bullous pemphigoid: BP), pericarditis, periodontitis, peritoneal endometriosis, malignant Anemia (Addison's disease), whooping cough, PFAPA (periodic fever aphthous pharyngitis and cervical adenopathy), pharyngitis and adenitis (PFAPA syndrome), plant irritant-induced inflammation, Pneumocystis infection, pneumonia, pneumonitis, poison ivy / urushiol oil-induced inflammation, polyarteritis nodosa, polychondritis, polycystic kidney disease, polymyalgia rheumatica, giant cell arteritis, polymyositis, pouchitis, preperfusion injury and graft rejection, primary biliary cirrhosis, primary pulmonary hypertension, primary sclerosing cholangitis (PSC), proctitis, psoriasis, plaque psoriasis, psoriatic arthritis, epidermal psoriasis epidermis), psychosocial stress disorders, lung diseases, pulmonary fibrosis, pulmonary hypertension, pyoderma gangrenosum, pyogenic granulomatous retrolental fibroplasia, suppurative aseptic arthritis, Raynaud's syndrome, Reiter's disease, reactive arthritis, kidney diseases, renal transplant rejection, reperfusion injury, respiratory distress syndrome, retinal diseases, retrolental fibroplasia, Raynaud's syndrome, rheumatic carditis, rheumatic diseases, rheumatic fever, rheumatoid arthritis, rhinitis, rhinitis psoriasis, rosacea, sarcoidosis, Schnitzler's syndrome, scleritis, sclerosis, scleroderma, spinal scoliosis, seborrhea, sepsis, septic shock, severe pain, Sezary syndrome, sickle cell anemia, silica-induced disease (silicosis), Sjogren's syndrome, skin diseases, skin irritation, skin rash, skin sensitization (contact dermatitis or allergic contact dermatitis), sleep apnea, spinal cord injury, spinal stenosis, spondyloarthropathy, sports injuries, sprains and strains, Stevens-Johnson syndrome (SJS), stroke, subarachnoid hemorrhage, sunburn, synovial inflammation, Systemic inflammatory response syndrome (SIRS), systemic lupus erythematosus, systemic mast cell disease (SMCD) , systemic vasculitis, systemic-onset juvenile idiopathic arthritis, temporal arteritis, tendonitis, tenosynovitis, thrombocytopenia, thyroiditis, Tissue transplantation, toxoplasmosis, trachoma, transplant rejection, traumatic brain injury, tuberculosis, renal tubules Interstitial nephritis, tumor necrosis factor (TNF) receptor-associated periodic syndrome These conditions include, but are not limited to, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), type 1 diabetes, type 2 diabetes, complications of type 1 or type 2 diabetes, ulcerative colitis, urticaria, uterine fibroids, uveitis, vascular restenosis, vasculitis, vasculitis (NHLBI), vitiligo, Wegener's granulomatosis, and Whipple's disease.

[0127] In further embodiments, methods are provided for alleviating symptoms of a disease or disorder mediated, at least in part, by α4β7 integrin. In some embodiments, the methods include identifying a mammal having symptoms of a disease or disorder mediated, at least in part, by α4β7 integrin, and providing the mammal with a compound described herein in an amount effective to ameliorate the symptoms (i.e., reduce the severity of the symptoms).

[0128] In some embodiments, the disease or condition mediated, at least in part, by α4β7 integrin is an inflammatory disease or LPS-induced endotoxic shock. In some embodiments, the disease is an autoimmune disease. In particular embodiments, the autoimmune disease is systemic lupus erythematosus (SLE), myasthenia gravis, rheumatoid arthritis (RA), acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis (MS), inflammatory bowel disease (IBD), sepsis, psoriasis, Sjögren's syndrome, autoimmune hemolytic anemia, asthma, or chronic obstructive pulmonary disease (COPD), ankylosing spondylitis, acute gout and ankylosing spondylitis, reactive arthritis, monoarthritis, osteoarthritis, gouty arthritis, juvenile arthritis, juvenile onset rheumatoid arthritis, juvenile rheumatoid arthritis, or psoriatic arthritis. In 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.

[0129] 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 of the disclosure include diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autistic enterocolitis, and indeterminate colitis. ), Behcet's disease, gastroduodenal Crohn's disease, jejunoileitis, ileitis, ileocolitis, colonic Crohn's disease (granulomatous colitis), irritable bowel syndrome, mucositis, radiation-induced enteritis, short bowel syndrome, celiac disease, gastric ulcer, diverticulitis, pouchitis, proctitis, and chronic diarrhea.

[0130] Treating or preventing IBD may also include improving or reducing one or more symptoms of IBD. As used herein, the term "symptoms of irritable bowel syndrome (IBD)" 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. Some such symptoms are subject to quantitative analysis (e.g., weight loss, fever, anemia, etc.). Some symptoms are easily determined from blood tests (e.g., anemia) or tests that detect the presence of blood (e.g., rectal bleeding). The term "reducing the symptom" refers to a qualitative or quantitative reduction in a detectable symptom, including, but not limited to, a detectable effect on the rate of recovery from the disease (e.g., weight gain rate). Diagnosis is typically determined by endoscopic observation of the mucosa and pathological examination of an endoscopic biopsy sample.

[0131] The course of IBD is variable and can often be associated with intermittent periods of disease remission and disease exacerbation. The disease activity and severity of IBD, as well as the risk of developing IBD, can be significantly affected by IBD. Various methods have been described for characterizing response to treatment in subjects. Treatment by this method is generally applicable to subjects suffering from IBD with any level or degree of disease activity.

[0132] In some embodiments, diseases or conditions that may be treated by administration of the compounds of the compositions described herein include acute gout and ankylosing spondylitis, allergic disorders, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis (ALS), and rheumatoid arthritis. sclerosis and multiple sclerosis, atherosclerosis, bacterial infections, bone cancer pain and pain due to endometriosis, BRAF-resistant melanoma, brainstem glioma or pituitary adenoma, burns, bursitis, cancer of the anal region, cancer of the endocrine system, kidney or ureter cancer (e.g., renal cell carcinoma and renal pelvis cancer), penile cancer, small intestine cancer, thyroid cancer, urethral cancer, blood cancers such as acute myeloid leukemia, tongue cancer, cervical cancer, endometrial cancer , fallopian tube cancer, renal pelvis cancer, vaginal or vulvar cancer, chronic myeloid leukemia, chronic or acute leukemia, chronic pain, classic Bartter's syndrome, cold conjunctivitis, coronary heart disease, cutaneous or intraocular melanoma, dermatitis, dysmenorrhea, eczema, endometriosis, familial adenomatous polyposis, fibromyalgia, fungal infection, gout, gynecological tumors, uterine sarcoma, fallopian tube cancer, headache, hemophilic arthropathy, Parkinson's disease, acquired immune deficiency syndrome, These include shingles, Hodgkin's disease, Huntington's disease, hyperprostaglandin E syndrome, influenza, iritis, juvenile arthritis, juvenile-onset rheumatoid arthritis, juvenile rheumatoid arthritis, low back and neck pain, lymphocytic lymphoma, myofascial disorders, myositis, neuralgia, neurodegenerative disorders such as Alzheimer's disease, neuroinflammatory disorders, neuropathic pain, vulvar cancer, Parkinson's disease, pediatric malignancies, pulmonary fibrosis, rectal cancer, rhinitis, sarcoidosis, soft tissue sarcoma, scleritis, skin cancer, pediatric solid tumors, spinal axis tumors, sprains and strains, gastric cancer, stroke, subacute and chronic musculoskeletal pain syndromes such as bursitis, symptoms associated with surgical or dental procedures, influenza or other viral infections, synovitis, toothache, ulcers, uterine cancer, uterine sarcoma, uveitis, vasculitis, viral infections, viral infections (e.g., influenza), and wound healing.

[0133] Criteria useful for assessing disease activity in subjects with ulcerative colitis can be found, for example, in Truelove et al. ((1955) Br Med J Vol. 2, pp. 1041-1048). Using these criteria, disease activity can be characterized as mild or severe in subjects with IBD. Subjects who do not meet all the criteria for severe disease activity and subjects who exceed the criteria for mild disease activity are classified as having moderate disease activity.

[0134] The treatment methods disclosed herein can also be applied at any point in the course of the disease. In some embodiments, the methods are applied to subjects suffering from IBD in remission (i.e., inactive disease). In such embodiments, the methods provide benefit by extending the period of remission (e.g., extending the period of inactive disease) or by preventing, reducing, or delaying the onset of active disease. In other embodiments, the methods may be applied to subjects suffering from IBD during the active disease stage. Such methods provide benefit by shortening the duration of the active disease stage, reducing or ameliorating one or more symptoms of IBD, or treating IBD.

[0135] Measures for determining the effectiveness of IBD treatment in clinical practice have been described, including, for example, symptom control, fistula closure, required level of corticosteroid therapy, and improvement in quality of life. Heath-related quality of life (HRQL) can be assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ), which is widely used in clinical practice to assess quality of life in subjects suffering from IBD. (Guyatt et al. (1989) Gastroen (See, Interology 96:804-810.) In some embodiments, the disease or condition is an immune-mediated liver injury, disease or condition.

[0136] 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." (April-June 2016), Vol. 29, No. 2, pp. 236-237.) Alcoholic hepatitis can lead to liver cirrhosis and hepatocellular fibrosis. Glucocorticoids (e.g., prednisolone) and phosphodiesterase inhibitors (e.g., pentoxifylline) can be used to treat alcoholic hepatitis. The compounds herein can be used as an independent treatment or in combination with existing treatments for alcoholic hepatitis.

[0137] In some embodiments, the disease or condition mediated, at least in part, by α4β7 integrin is fatty liver disease. In some embodiments, the disease is fatty liver, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH). The compounds herein can be used as an independent treatment or in combination with existing treatments for fatty liver disease.

[0138] In one aspect, the present disclosure provides a method of treating or preventing human immunodeficiency virus (HIV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0139] In some embodiments, the disease or condition mediated, at least in part, by α4β7 integrin is systemic lupus erythematosus (SLE), lupus nephritis, a lupus-related disorder, or other autoimmune disorder or symptoms of SLE. Symptoms of systemic lupus erythematosus include joint pain, joint swelling, arthritis, fatigue, hair loss, mouth sores, swollen lymph nodes, photosensitivity, skin rash, headache, numbness, tingling, seizures, vision problems, personality changes, abdominal pain, nausea, vomiting, irregular heartbeat, vomiting blood and difficulty breathing, mottled skin color, and Raynaud's phenomenon. Combination therapy

[0140] Also provided are methods of treatment in which a compound described herein is administered to a patient in combination with one or more additional agents or therapies.

[0141] Thus, in some embodiments, a method of treating a disease or condition at least partially mediated by α4β7 integrin, and / or a disease or symptom that coexists with, or is exacerbated or caused by, a disease or condition at least partially mediated by α4β7 integrin, e.g., an allergic disorder, 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 agent), which may be useful in treating the disease or condition at least partially mediated by α4β7, the allergic disorder and / or an autoimmune disease and / or an inflammatory disease, and / or an acute inflammatory response that coexists with or coexists with the disease or condition at least partially mediated by α4β7 integrin. Treatment with the second, third, fourth, or fifth agent may occur prior to, concurrently with, or after treatment with a compound described herein. In some embodiments, the compounds described herein are combined with another agent in a single dosage form. Suitable therapeutic agents that may be used in combination with the compounds described herein include any of the therapeutic agents provided herein, or at least one of the therapeutic agents provided herein. Combinations include, but are not limited to, combinations comprising at least one therapeutic agent.

[0142] Included herein are methods of treatment in which the compounds described herein are administered in combination with agents for the treatment of inflammatory diseases or conditions. Examples of agents for the treatment of inflammatory diseases or conditions that can be used in combination with the compounds described herein include alpha-fetoprotein modulators, adenosine A3 receptor antagonists, adrenomedullin ligands, AKT1 gene inhibitors, antibiotics, antifungals, ASK1 inhibitors, ATPase inhibitors, beta-adrenergic receptor antagonists, BTK inhibitors, calcineurin inhibitors, carbohydrate metabolism modulators, cathepsin S inhibitors, CCR9 chemokine antagonists, CD233 modulators, CD29 modulators, CD3 antagonists, CD40 ligand inhibitors, CD40 ligand receptor antagonists, chemokine CXC ligand inhibitors, CHST15 gene inhibitors, collagen modulators, CSF-1 antagonists, CX3CR1 chemokine modulators, ecobiotics, eotaxin ligand inhibitors, EP4 prostanoid receptor agonists, F1F0 ATP synthase modulator, farnesoid X receptor agonist, fecal microbiota transplant transplantation (FMT), fructanoalkyne ligand inhibitor, free fatty acid receptor 2 antagonists, GATA3 transcription factor inhibitors, glucagon-like peptide 2 agonists, glucocorticoid agonists, glucocorticoid receptor modulators, guanylate cyclase receptor agonists, HIF prolyl hydroxylase inhibitors, histone deacetylase inhibitors, HLA class II antigen modulators, hypoxia-inducible factor-1 stimulators, ICAM1 gene 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, 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, lactate kinase inhibitors, Antiferroferrin stimulators, LanC-like protein 2 modulators, leukocyte elastate inhibitors, leukocyte proteinase-3 inhibitors, MAdCAM inhibitors, melanin-concentrating hormone (MCH-1) antagonists, melanocortin agonists, metalloproteinase 9 inhibitors, microbiome-targeted therapeutics, natriuretic peptide receptor C agonists, neuregulin 4 ligands, NLPR3 inhibitors, NKG2D-activating NK receptor antagonists, NR1H4 receptor (FXR) agonists or modulators, nuclear factor kappa B inhibitors, and Pyroid 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, 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, vanilloid VR1 agonists, and zonulin inhibitors, and combinations thereof.

[0143] Adenosine A3 receptor antagonists include PBF-677.

[0144] Adrenomedullin ligands include adrenomedullin.

[0145] Antibiotics include ciprofloxacin, metronidazole, vancomycin, and rifaximin.

[0146] ASK1 inhibitors include GS-4997.

[0147] Alpha-fetoprotein modulators include ACT-101.

[0148] Anti-CD28 inhibitors include JNJ-3133.

[0149] Beta-adrenergic receptor antagonists include NM-001.

[0150] BTK inhibitors include GS-4059.

[0151] Calcineurin inhibitors include tacrolimus and cyclosporine.

[0152] Carbohydrate metabolism modulators include ASD-003.

[0153] Cathepsin S inhibitors include VBY-129.

[0154] CCR9 chemokine antagonists include CCX-507.

[0155] CD233 modulators include GSK-2831781.

[0156] CD29 modulators include PF-06687234.

[0157] CD3 antagonists include NI-0401.

[0158] CD4 antagonists include IT-1208.

[0159] CD40 ligand inhibitors include SAR-441344 and ritolizumab.

[0160] CD40 gene inhibitors include NJA-730.

[0161] CD40 ligand receptor antagonists include FFP-104 and BI-655064.

[0162] Chemokine CXC ligand inhibitors include LY-3041658.

[0163] CHST15 gene inhibitors include STNM-01.

[0164] Collagen modulators include ECCS-50 (DCCT-10).

[0165] COT protein kinase inhibitors include GS-4875.

[0166] CSF-1 antagonists include JNJ-40346527 (PRV-6527) and SNDX-6352.

[0167] CX3CR1 chemokine modulators include E-6130.

[0168] Ecobiotics include SER-287.

[0169] Eotaxin ligand inhibitors include bertilimumab.

[0170] EP4 prostanoid receptor agonists include KAG-308.

[0171] F1F0 ATP synthase modulators include LYC-30937 EC.

[0172] Fructalkyne ligand inhibitors include E-6011.

[0173] Free fatty acid receptor 2 antagonists include GLP-0974.

[0174] GATA3 transcription factor inhibitors include SB-012.

[0175] Glucagon-like peptide 2 agonists include teduglutide.

[0176] Glucocorticoid agonists include budesonide, beclomethasone dipropionate, and dexamethasone sodium phosphate.

[0177] Glucocorticoid receptor modulators / TNF ligand inhibitors include ABBV-3373.

[0178] Guanylate cyclase receptor agonists include dolucatide.

[0179] HIF prolyl hydroxylase inhibitors include DS-1093 and AKB-4924.

[0180] HIF prolyl hydroxylase-2 inhibitors / hypoxia inducible factor-1 stimulators include GB-004.

[0181] Histone deacetylase inhibitors include givinostat.

[0182] Histone deacetylase-6 inhibitors include CKD-506.

[0183] HLA class II antigen modulators include HLA class II protein modulators.

[0184] ICAM1 gene inhibitors include alicaforsen.

[0185] IL-12 antagonists include ustekinumab (IL12 / IL23).

[0186] IL-13 antagonists include tralokinumab.

[0187] IL-18 antagonists include GSK-1070806.

[0188] IL-22 agonists include RG-7880.

[0189] IL-23 antagonists include tildrakizumab, risankizumab (BI-655066), mirikizumab (LY-3074828), brazikumab (AMG-139), and PTG-200.

[0190] IL-23A inhibitors include guselkumab.

[0191] IL-6 antagonists include olokizumab.

[0192] IL-7 receptor antagonists include OSE-127.

[0193] IL-8 receptor antagonists include clotrimazole.

[0194] Integrin alpha-4 / beta-1 antagonists include natalizumab.

[0195] Integrin alpha-4 / beta-7 antagonists include etrolizumab (alpha4beta7 / aEb7), vedolizumab, carotegast methyl, TRK-170 (alpha4beta7 / alpha4beta1), PN-10943, and PTG-100.

[0196] Integrin antagonists include E-6007.

[0197] Interleukin ligand inhibitors include bimekizumab (IL-17A / IL-17F).

[0198] Interleukin receptor 17A antagonists include brodalumab.

[0199] Interleukin-1β ligands include K(D)PT.

[0200] Interleukin-1-like receptor 2 inhibitors include BI-655130.

[0201] IL-6 receptor modulators include olamuxcept.

[0202] JAK tyrosine kinase inhibitors include tofacitinib(1 / 3), peficitinib(1 / 3), TD-3504, and TD-1473. Jak1 tyrosine kinase inhibitors include compounds disclosed in International Publication No. WO2008 / 109943. Examples of other JAK inhibitors include, but are not limited to, AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110, lestaurtinib, momelotinib (CYT0387), NS-018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), XL019, upadacitinib (ABT-494), filgotinib, GLPG-0555, SHR-0302, and PF-06700841 (JAK1 / Tyk2).

[0203] Jak3 tyrosine kinase inhibitors include PF-06651600.

[0204] Lactoferrin stimulators include recombinant human lactoferrin (VEN-100).

[0205] LanC-like protein 2 modulators include BT-11.

[0206] Leukocyte elastase inhibitors / leukocyte proteinase-3 inhibitors include tiprelestat.

[0207] MAdCAM inhibitors include SHP-647 (PF-547659).

[0208] Melanin-concentrating hormone (MCH-1) antagonists include CSTI-100.

[0209] Melanocortin agonists include ASP-3291 and PL-8177.

[0210] Metalloproteinase 9 inhibitors include GS-5745.

[0211] Natriuretic peptide receptor C agonists include plecanatide.

[0212] Neuregulin-4 ligands include NRG-4.

[0213] NKG2D-activating NK receptor antagonists include JNJ-4500.

[0214] NLPR3 inhibitors include dapanastril, BMS-986299, SB-414, MCC-950, IFM-514, JT-194, PELA-167, and NBC-6.

[0215] NR1H4 receptor (FXR) agonists or modulators include tropifexor and GS-9674.

[0216] Nuclear factor kappa B inhibitors include Thetanix.

[0217] Opioid receptor antagonists include naltrexone and IRT-103.

[0218] OX40 ligand inhibitors include KHK-4083.

[0219] Oxidoreductase inhibitors include olsalazine.

[0220] Pellino homolog 1 inhibitors include BBT-401.

[0221] P2X7 purinergic receptor modulators include SGM-1019.

[0222] PDE4 inhibitors include apremilast.

[0223] PPARα / δ agonists include elafibranor (GFT-1007).

[0224] PPARγ agonists include GED-0507-34-Levo.

[0225] Protein fimH inhibitors include EB-8018.

[0226] P-selectin glycoprotein ligand 1 inhibitors include SEL-K2, AbGn-168H, and neihulizumab.

[0227] Ret tyrosine kinase receptor inhibitors include GSK-3179106.

[0228] RIP-1 kinase inhibitors include GSK-2982772.

[0229] RIP-2 kinase inhibitors include GSK-2983559.

[0230] Sphingosine-1-phosphate phosphatase 1 stimulators include etrasimod.

[0231] Sphingosine-1-phosphate receptor 1 agonists include moclavimod (KRP-203) and BMS-986166.

[0232] Sphingosine-1-phosphate receptor-1 agonists / sphingosine-1-phosphate receptor-5 agonists include ozanimod.

[0233] Sphingosine-1-phosphate receptor 1 antagonists include amiselimod (MT-1303).

[0234] Sphingosine-1-phosphate receptor-1 modulators include OPL-002.

[0235] Stem cell antigen 1 inhibitors include Ampion (DMI-9523).

[0236] Superoxide dismutase modulators include midismase.

[0237] Syk inhibitors include GS-9876.

[0238] TLR-3 antagonists include PRV-300.

[0239] TLR-4 antagonists include JKB-122.

[0240] 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.

[0241] TLR-9 agonists include cobitolimod, IMO-2055, IMO-2125, lefitolimod, litenimod, MGN-1601, and PUL-042.

[0242] TNFα ligand inhibitors include adalimumab, ceratolizumab pegol, infliximab, golimumab, DLX-105, Debio-0512, HMPL-004, CYT-020-TNFQb, Hemay-007, and V-565.

[0243] TNF antagonists include AVX-470, tulinercept, and This includes etanercept.

[0244] TPL-2 inhibitors include GS-4875.

[0245] Tumor necrosis factor 14 ligand modulators include AEVI-002.

[0246] Tumor necrosis factor 15 ligand inhibitors include PF-06480605.

[0247] Tyk2 tyrosine kinase inhibitors include PF-06826647 and BMS-986165.

[0248] Type I IL-1 receptor antagonists include anakinra.

[0249] Zonulin inhibitors include larazotide acetate.

[0250] Included herein are methods of treatment in which the compounds described herein are administered in combination with anti-inflammatory agents, including, but not limited to, NSAIDs, nonspecific and COX-2 specific cyclooxgenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptor antagonists, immunosuppressants, and methotrexate.

[0251] Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, a combination of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, nabumetone sodium, sulfasalazine, tolmetin sodium, and hydroxychloroquine. Examples of NSAIDs also include COX-2 specific inhibitors (i.e., inhibitors of COX-1 activity), such as celecoxib, valdecoxib, lumiracoxib, etoricoxib, and / or rofecoxib. 50 IC at least 50-fold lower than 50 This also includes compounds that inhibit COX-2.

[0252] In a further embodiment, the anti-inflammatory agent is a salicylate, including but not limited to acetylsalicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylates.

[0253] The anti-inflammatory agent may also be a corticosteroid, for example, the corticosteroid may be selected from cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, and prednisone.

[0254] In some embodiments, the anti-inflammatory therapeutic agent is a gold compound such as gold sodium thiomalate or auranofin.

[0255] In some embodiments, the anti-inflammatory agent is a metabolic inhibitor, such as a dihydrofolate reductase inhibitor, such as methotrexate, or a dihydroorotate dehydrogenase inhibitor, such as leflunomide.

[0256] In some embodiments, the anti-inflammatory compound is an anti-C5 monoclonal antibody (such as eculizumab or pexelizumab), a TNF antagonist such as entanercept, or the anti-TNFα monoclonal antibody infliximab.

[0257] Included herein are methods of treatment in which a compound described herein is administered in combination with an immunosuppressant. In some embodiments, the immunosuppressant is methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, or mycophenolate mofetil.

[0258] Included herein are methods of treatment in which the compounds described herein are administered in combination with classes of drugs for the treatment of IBD. Examples of classes of drugs for the treatment of IBD that can be used in combination with the compounds described herein include ASK1 inhibitors, beta-adrenergic inhibitors, and the like. Phosphate 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 modulators, CSF-1 antagonists, cyclooxygenase inhibitors, cytochrome P4503A4 inhibitors, Otaxin ligand inhibitor, EP4 prostanoid receptor agonist, fractalkine ligand inhibitor, free fatty acid receptor 2 antagonist, GATA3 transcription factor inhibitor, glucagon-like peptide 2 agonist, glucocorticoid agonist, guanylate cyclase receptor agonist, histone deacetylase inhibitor, HLA class II antigen modulator, IL-12 antagonist, IL-13 antagonist, IL-23 antagonist, IL-6 antagonist agonists, 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 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, NKG2D-activated NK receptor antagonists, opioid receptor antagonists, opioid receptor delta antagonists, oxidoreductase inhibitors, P2X7 purinergic receptor agonists, PDE4 inhibitors, phagocytosis-stimulating peptide modulators, potassium channel inhibitors, PPARα agonists, PPARδ agonists, PPARγ agonists, fimH protein 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, thymulin agonists, TLR antagonists, TLR agonists, TNFα ligand inhibitors, TNF antagonists, tumor necrosis factor 14 ligand modulators, TNF type II receptor modulators, Tpl 2 inhibitors, and zonulin inhibitors.

[0259] Included herein are methods of treatment in which a compound described herein is administered in combination with an agent for the treatment of IBD. Examples of agents for the treatment of IBD that can be used in combination with a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analog thereof, include agents provided herein for the treatment of inflammatory diseases or conditions, as well as ABX-464, adlimumab, 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, Clostridium butyricum (Clostridium butyricum), ChAdOx2-HAV, dexamethasone sodium phosphate, DNVX-078, etanercept, ETX-201, golimumab, GS-4997, GS-9876, GS-4875, GS-4059, infliximab, mesalazine, HLD-400, LYC-30937 EC, IONIS-JBI1-2.5Rx, JNJ-64304500, JNJ-4447, naltrexone, natalizumab, neihulizumab, olsalazine, PH-46-A , propionyl-L-carnitine, PTG-100, remestemcel-L, tacrolimus, teduglutide, tofacitinib, ASP-1002, ustekinu Mab, 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, bertilimumab, DLX-105 , dolucatide, E-6011, FFP-104, filgotinib, foralumab, GED-0507-34-Levo, gibinostat, GLPG-0974, iberogast, JNJ-40346527, K(D)PT, KAG-308, KHK-4083, KRP-203, larazotide acetate, LY-3074828, mi These include Zismase, olokizumab, OvaSave, P-28-GST, PF-547659, prednisolone, QBECO, RBX-2660, JKB-122, SB-012, STNM-01, Debio-0512, TRK-170, zucapsaicin, ABT-494, Ampion, BI-655066, carotegast methyl, cobitolimod, elafibranor, etrolizumab, GS-5745, HMPL-004, LP-02, ozanimod, peficitinib, RHB-104, rifaximin, tildrakizumab, tralokinumab, brodalumab, laquinimod, plecanatide, bidofludimus, and AZD-058.

[0260] Methods of treatment are included herein in which the compounds described herein are administered in combination with an agent for the treatment of graft-versus-host disease. Examples of agents for the treatment of graft-versus-host disease that can be used in combination with the compounds described herein include the agents provided herein for the treatment of inflammatory diseases or conditions, as well as [18F]F-AraG, AM-01, AAT-IV, Allocetra, AMG-592, arsenic trioxide, ATIR-101, basiliximab, belatacept, belimumab, bortezomib, brentuximab vedotin, brimonidine, brimonidine tartrate, cannabidiol, and CE-114. 5, cyclosporine, clazakizumab, CSL-964, CYP-001, defibrotide, zilanubicel, dornase alfa, DSM-9843, eculizumab, EDP-1066, everolimus, Furestem, GSK-1070806, ibrutinib, IMSUT-CORD, IRX-4204, KD-025, MaaT-013, milatuzumab, mizoribine, mycophenolate mofetil, MSCTC-0010, nalotimagene carmaleucel, MET-2, nilotinib, OMS-721, pacritinib , PF-05285401, PLX-1, ProTmune, QPI-1002, remestemcel-L, RGI-2001, rivogenlecleucel, saratin, SCM-CGH, ​​sirolimus, T-allo10, telmisartan, T-Guard, TOP-1288, TZ-101, voclosporin, CCR5 chemokine antagonist, PRO-140, CD 40 ligand receptor antagonist, iscalimab; complement C1s small component inhibitor: stimulimab, Cinryze, BIVV-009; B lymphocyte antigen CD20 inhibitor: obinutuzumab; CASP9 gene stimulator: rivogenlecleucel; CD3 antagonist or CD7 inhibitor: T-Guard; complement C5a factor inhibitor: orentalizumab; dipeptidyl peptida and sphingosine-1-phosphate receptor-1 agonists, such as ketamine, ketase 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 alpha subunit inhibitor: inolimomab, IL-6 receptor agonist: PLX-1, IL-6 receptor antagonist: clazakizumab, OX40 ligand inhibitor, KY-1005. Examples of such OX40 inhibitors include the compounds disclosed in U.S. Pat. No. 8,450,460, the entire contents of which are incorporated herein by reference; signal transducer CD24 modulator: CD24-IgFc; somatostatin receptor agonist: thymoglobulin; and sphingosine-1-phosphate receptor-1 agonist: ponesimod.

[0261] The present invention also includes a method of treatment in which the compounds described herein are administered in combination with an agent for treating primary sclerosing cholangitis. Examples of agents for treating primary sclerosing cholangitis that can be used in combination with the compounds described herein include the agents provided herein for treating inflammatory diseases or conditions, as well as BTT-1023, CM-101, Doconexent, GRI-0124, HTD-1801, HTD-2802, hymecromone, IDN-7314, NGM-282, norursodeoxycholic acid, ORBCEL-C, SCT-5-27, STP-705, farnesoid X receptor agonists: obeticholic acid, GS-9674, and MET-409, liver X receptor antagonists: DUR-928, and CCR5 / CCR2 chemokine antagonists: cenicriviroc.

[0262] In some embodiments, the one or more additional therapeutic agents are combination drugs for HIV, other drugs treating HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reactivators, compounds targeting the HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

[0263] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of HIV protease inhibitor compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs that treat HIV, or pharmaceutically acceptable salts of any of the foregoing, or any combination thereof.

[0264] In some embodiments, the one or more additional therapeutic agents are immunomodulatory agents, e.g., immunostimulatory agents or immunosuppressants. In certain other embodiments, the immunomodulatory agent is an agent capable of altering immune checkpoint function, including the CTLA-4, LAG-3, B7-H3, B7-H4, Tim3, BTLA, KIR, A2aR, CD200, and / or PD-1 pathways. In other embodiments, the immunomodulatory agent is an immune checkpoint modulator. Exemplary immune checkpoint modulators include anti-CTLA-4 antibodies (e.g., ipilimumab), anti-LAG-3 antibodies, anti-B7-H3 antibodies, anti-B7-H4 antibodies, and anti-Tim3 antibodies. , anti-BTLA antibodies, anti-KIR antibodies, anti-A2aR antibodies, anti-CD200 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CD28 antibodies, anti-CD80 or anti-CD86 antibodies, anti-B7RP1 antibodies, anti-B7-H3 antibodies, anti-HVEM antibodies, anti-CD137 or anti-CD137L antibodies, anti-OX40 or anti-OX40L antibodies, anti-CD40 or anti-CD40L antibodies, anti-GAL9 antibodies, anti-IL-10 antibodies, and A2aR agents. For certain such immune pathway gene products, the use of either antagonists or agonists of such gene products is contemplated, as well as small molecule modulators of such gene products. In some embodiments, the immunomodulatory agent comprises an agent capable of altering the function of a mediator in a cytokine-mediated signaling pathway.

[0265] In some embodiments, a compound disclosed herein (e.g., a compound described herein) can be combined with one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents at any dose of a compound described herein (e.g., 10 mg to 1000 mg of a compound).

[0266] The compounds described herein can be combined with agents provided herein at any dosage of compound (e.g., 50 mg to 500 mg of compound), as if each dosage combination were specifically and individually listed.

[0267] In some embodiments, kits are provided that include a pharmaceutical composition comprising a compound described herein, or a compound described herein and at least one additional therapeutic agent, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, kits are provided that include a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analog thereof, in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, or 1 to 3, or 1 to 4) additional therapeutic agents. Any pharmaceutical composition provided in this disclosure can be used in a kit, just as if each individual composition were specifically and individually listed for use in the kit. In some embodiments, the kit includes instructions for use in treating an inflammatory disease or condition. In some embodiments, the kit instructions are directed to using the pharmaceutical composition for the treatment of IBD. [Table 1-1] [Table 1-2] [Table 1-3] synthesis

[0268] The compounds of the present disclosure may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent in light of the disclosure herein and methods well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods may be used. The synthesis of exemplary compounds of formula (I), e.g., compounds having a structure described by one or more of formulas (I), or other formulas or compounds disclosed herein, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, or deuterated analogs thereof, can be achieved as described in the following examples. General Scheme

[0269] Exemplary embodiments of the compounds according to the present disclosure may be synthesized using the general reaction schemes and / or examples set forth below. Given the description herein, it will be apparent that the general schemes can be modified by substituting other materials of similar structure to result in correspondingly different products. The synthetic description follows, providing numerous examples of how starting materials can be varied to provide the corresponding products. Starting materials are typically obtained from commercial sources or synthesized using published methods for synthesizing compounds that are embodiments of the present disclosure, and inspection of the structure of the synthesized compound will provide the identity of each substituent. The identity of the final product will generally be apparent by a simple inspection process of the identities of the necessary starting materials, given the examples herein. [ka]

[0270] General Scheme 1 illustrates the general route used to prepare compounds of formula (I). From intermediate AA1, which has a hydroxyl or halogen group as Q and a halogen group as X, amino acid ester (AA2) can be prepared under a variety of conditions (e.g., Schollkopf, Maruoka, etc.). The free amine can be protected by a protecting group. After appropriate protection with a suitable group (PG), e.g., trityl, Boc, etc., AA2 was synthesized using standard conditions. Under suitable conditions (e.g., Miyaura), the boronic acid or boronic ester (AA3) was obtained. 1 was introduced under various cross-coupling conditions to give AA4. After removal of the amine protecting group (PG) under appropriate conditions, the amine was coupled with an acid to give AA5. [ka]

[0271] In some embodiments, AA4 is prepared as outlined in General Scheme 2, which illustrates another general route for preparing compounds of Formula (I). From intermediate AA6, which bears a halogen group as Q and an amino group, R is attached to AA7 through several chemical steps, including urea formation and ring closure. 1 The amino acid ester (AA4) can be prepared from AA7 under various conditions (e.g., Schollkopf, Maruoka, etc.). After appropriate removal of the amine protecting group (PG) under appropriate conditions, the amine was coupled with an acid to give the heterocyclic compound AA5. [ka]

[0272] Synthesis of tert-butyl 4-bromo-2,6-difluorobenzoate (A1): To a stirred solution of 4-bromo-2,6-difluorobenzoic acid (5 g, 21.1 mmol) and tert-butyl alcohol (50 mL) in DCM (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 allowed to stir at room temperature for 12 hours. The mixture was concentrated under reduced pressure, dissolved in EA (100 mL), and washed with a 10% aqueous solution of citric acid (100 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain crude material. This material was suspended in hexane, the solid was filtered off, and the filtrate was evaporated under reduced pressure to obtain compound A1.

[0273] Synthesis of tert-butyl (R)-2,6-difluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoate (A2): To a stirred suspension of A1 (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 EA (50 mL). The resulting suspension was filtered through a pad of Celite, and the filtrate was evaporated under reduced pressure to give compound A2.

[0274] Synthesis of (R)-2,6-difluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoic acid (A): To a stirred solution of A2 (188 mg, 0.55 mmol) in DCM (1 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure to give the crude material. This material was purified by silica gel column chromatography, eluting with EA in hexane, to give intermediate A. MS (m / z) 284.1 [M+H] + . [ka]

[0275] Synthesis of (R)-2,6-difluoro-4-(3-(trifluoromethyl)morpholino)benzoic acid (B): To a 150 mL pressure vessel equipped with a stir bar was added methyl 4-bromo-2,6-difluorobenzoate (700 mg, 1.8 mmol), RuPhos (169 mg, 0.36 mmol), tBuBrettPhos Pd G3 (155 mg, 0.18 mmol), Cs2CO3 (2.95 g, 9.1 mmol), (R)-3-(trifluoromethyl)morpholine (416 mg, 2.7 mmol), and toluene (18 mL). The reaction vessel was then sealed and heated at 90 °C overnight. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, rinsed with EA, and the filtrate was evaporated to dryness under reduced pressure. The material was purified by silica gel chromatography using EA in hexane as the eluent. To this material was added THF (6 mL) and aqueous LiOH (6.2 mL, 1.0 M). The reaction mixture was stirred at 60° C. for 20 h. 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 give intermediate B. [ka]

[0276] Synthesis of (R)-2-fluoro-6-methyl-4-(3-(trifluoromethyl)morpholino)benzoic acid (C): The title compound was prepared according to the method presented for the synthesis of intermediate B starting from methyl 4-bromo-2-fluoro-6-methylbenzoate. [ka]

[0277] Synthesis of (R)-2-fluoro-6-methyl-4-((1,1,1-trifluorobutan-2-yl)amino)benzoic acid (D): The title compound was prepared according to the method presented for the synthesis of intermediate A starting from tert-butyl 4-bromo-2-fluoro-6-methylbenzoate. [ka]

[0278] tert-Butyl (R)-2,3,6-trifluoro-4-((1,1,1-trifluoromethyl) Synthesis of (orobutan-2-yl)amino)benzoate (E1): To a stirred suspension of tert-butyl 4-bromo-2,3,6-trifluorobenzoate (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 2 hours. The mixture was cooled to room temperature and diluted with EA (50 mL). The resulting suspension was filtered through a pad of Celite, and the filtrate was evaporated under reduced pressure to provide compound E1.

[0279] Synthesis of (R)-2,3,6-trifluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoic acid (E): To a stirred solution of E1 (188 mg, 0.55 mmol) in DCM (1 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure to give the crude material. This material was purified by silica gel column chromatography, eluting with EA in hexanes, to give intermediate E. [ka]

[0280] Synthesis of methyl (R)-2,6-difluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoate (F1): To a solution of intermediate A (300 mg, 1.06 mmol) in MeOH (3 mL) and DCM (5 mL) was added TMS diazomethane (1.06 mL, 2.12 mmol). The reaction mixture was stirred for 45 minutes at room temperature. Water was added, and the organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give F1 without further purification.

[0281] Synthesis of methyl (R)-4-(cyclopropyl(1,1,1-trifluorobutan-2-yl)amino)-2,6-difluorobenzoate (F2): To F1 (307 mg, 0.67 mmol) in dioxane was added Cs2CO3 (656 mg, 2 mmol) and Pd-176 (56 mg, 0.067 mmol). The reaction mixture was purged with N2, and then cyclopropyl bromide (406 mg, 3.36 mmol) was added. The reaction was heated to 95 °C overnight. The reaction mixture was filtered through Celite and concentrated in vacuo to give a 0-60% yield. Purification by silica gel chromatography eluting with Hex / EA gave F2.

[0282] Synthesis of (R)-4-(cyclopropyl(1,1,1-trifluorobutan-2-yl)amino)-2,6-difluorobenzoic acid (F): To F2 (360 mg, 1.07 mmol) in THF was added 1.0 M LiOH (5 mL). The reaction was stirred overnight at 40 °C. 2.0 M HCl was added (20 mL) and extracted three times with EA. The combined organics were washed with brine and concentrated in vacuo to give intermediate F without further purification. [ka]

[0283] Synthesis of 5-iodo-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one (G): A solution of 6-methyl-4-(trifluoromethyl)pyridin-2(1H)-one (1.26 g, 7.11 mmol), TFA (16.0 g, 140 mmol), and TFAA (3.2 g, 15 mmol) in DME (3.80 mL) was heated at 60° C. for 5 minutes, followed by the addition of NIS (2.04 g, 9.0 mmol). The mixture was then heated at 60° C. for an additional 12 hours, after which the solvent was removed under reduced pressure, and the residue was dissolved in EA, washed with water, and washed with saturated aqueous NaHCO. The organic layer was concentrated under reduced pressure, and the crude product was suspended in DME (3.80 mL). To this mixture was added KCO (0.98 g, 7.0 mmol) and MeI (1.0 g, 7.0 mmol), and the mixture was heated at 95 °C for 2 h. Upon completion, the reaction was diluted with EA, and the solid was filtered off and washed with EA. The filtrate was concentrated under reduced pressure, and the crude product was purified using flash chromatography eluting with EA in hexanes (25% to 100%) to give intermediate G. [ka]

[0284] Synthesis of 1,4-dimethyl-5-(trifluoromethyl)pyridin-2(1H)-one (H1): To a stirred solution of 4-methyl-5-(trifluoromethyl)pyridin-2(1H)-one (100 mg, 0.056 mmol) in DMF, NaH (25 mg, 0.62 mmol) was added, and the reaction mixture was stirred for 30 minutes, at which time bubbling was stopped. The reaction mixture was cooled to 0°C, and methyl p-toluenesulfonate (116 mg, 0.062 mmol) was added dropwise. After 4 hours, the reaction mixture was warmed to room temperature, concentrated under reduced pressure, and purified by silica gel chromatography eluting with 0-100% Hex / EA to provide the title compound.

[0285] Synthesis of 3-iodo-1,4-dimethyl-5-(trifluoromethyl)pyridin-2(1H)-one (H): To a stirred solution of H1 (0.72 g, 4 mmol) in neat TFA (16 mL) was added TFAA (1.6 g, 8 mmol). The reaction mixture was heated to 100° C. The mixture was heated in a sealed vial for 5 min at RT, followed by the addition of NIS (1.08 g, 5 mmol) and further heating at 60 °C for 3 h. The reaction mixture was cooled and the TFA was removed under reduced pressure. The residue was dissolved in EA and washed with saturated sodium bicarbonate and then brine. The organic layer was filtered and concentrated to give intermediate G without further purification. [ka]

[0286] Synthesis of (2S,5R)-2-(4-bromo-3-methylbenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (I1): To a solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1.36 g, 7.39 mmol) in THF (28.0 mL) at −78° C. was added a solution of n-BuLi in hexane (4.62 g, 7.96 mmol). The mixture was stirred at −78° C. for 20 minutes, followed by the dropwise addition of a solution of 1-bromo-4-(bromomethyl)-2-methylbenzene (1.5 g, 5.68 mmol) in THF (37 mL). The reaction was stirred at −78° C. for 40 minutes and quenched with water (10 mL). The cold bath was removed, and the reaction was allowed to warm to room temperature, extracted with EA, washed with brine, dried over NaSO, and concentrated under reduced pressure to give crude material. The crude product was purified using flash chromatography eluting with EA in hexane (10% to 100%) to give compound I1.

[0287] Synthesis of (2S,5S)-2-isopropyl-3,6-dimethoxy-5-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-2,5-dihydropyrazine (I2): To a solution of compound I1 (297 mg, 0.809 mmol) in DMA (5.40 mL), bis(pinacolato)diboron (262 mg, 1.03 mmol) and KOAc (238 mg, 2.42 mmol) were added, and the mixture was purged with nitrogen gas for 6 minutes. CataCXium A Pd G3 (29.5 mg, 0.04 mmol) was added, and the mixture was heated at 90 °C for 1 hour. Upon completion, the reaction was quenched with water, extracted with EA, washed with brine, dried over NaSO, and concentrated under reduced pressure to provide compound I2, which was used without further purification.

[0288] Synthesis of 3-(4-(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)methyl)-2-methylphenyl)-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one (I3): Compound I2 (130 mg, 0.157 mmol), 3-iodo-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one To a solution of (1H)-ethyl)pyridin-2(1H)-one (65.0 mg, 0.204 mmol) in DME (1.50 mL) was added a 1 M aqueous solution of KPO (117 mg, 0.550 mmol), and the mixture was purged with nitrogen gas for 6 minutes. XPhos Pd G (13.0 mg, 0.016 mmol) was then added, and the mixture was purged with nitrogen gas for an additional 3 minutes and thermally heated at 77 °C for 45 minutes. The solvent was then removed under reduced pressure, and the mixture was dissolved in EA, washed with HO, dried over NaSO, and concentrated under reduced pressure to give crude material. The crude material was purified using flash chromatography eluting with EA (20% to 100%) in hexanes, followed by MeOH (0% to 35%) in EA to give I3.

[0289] Synthesis of methyl (S)-2-amino-3-(4-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-3-methylphenyl)propanoate (I): To a solution of compound I3 (185 mg, 0.387 mmol) in ACN (13 mL) was added an aqueous solution of 2 M HCl (67.6 mg, 1.16 mmol), and the mixture was stirred at room temperature for 3 hours. Upon completion, the solvent was removed under reduced pressure, and the crude material was purified using flash chromatography eluting with EA (0% to 100%) in hexanes, followed by MeOH (0% to 35%) in DCM to give intermediate I. [ka]

[0290] Synthesis of (2S,5R)-2-(4-bromo-3-fluorobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (J1): The title compound was prepared according to the method presented for the synthesis of intermediate I1 starting from 1-bromo-4-(bromomethyl)-2-fluorobenzene.

[0291] Synthesis of (2S,5R)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (J2): The title compound was prepared according to the method presented for the synthesis of intermediate I2 starting from J1.

[0292] Synthesis of 3-(2-fluoro-4-(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)methyl)phenyl)-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one (J3): The title compound was prepared according to the method presented for the synthesis of intermediate I3 starting from compound J2.

[0293] Synthesis of methyl (S)-2-amino-3-(4-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-3-fluorophenyl)propanoate (J): The title compound was prepared according to the method presented for the synthesis of intermediate I starting from compound J3. [ka]

[0294] Synthesis of methyl 3-(3-(5-bromopyridin-2-yl)ureido)isonicotinate (K1): To methyl 3-aminoisonicotinate (21.5 g, 141 mmol, 1.00 equiv) in DCM (430.0 mL) was added DIEA (36.5 g, 282 mmol, 49.2 mL, 2.00 equiv). The mixture was degassed and purged with N2 three times, then cooled to 0 °C. Triphosgene (14.69 g, 49.5 mmol, 0.35 equiv) dissolved in DCM (90.0 mL) at 0 °C was added slowly. The mixture was stirred for 2 h at 0 °C and then concentrated in vacuo. MeCN (150.0 mL) and 5-bromopyridin-2-amine (24.4 g, 141 mmol, 1.00 equiv) were added to the mixture and stirred for 2 h at 65° C. After cooling to room temperature, the solid was filtered off and collected to give K1.

[0295] Synthesis of 3-(5-bromopyridin-2-yl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (K2): K1, without further purification, was dissolved in MeCN (430 mL) and stirred at 65 °C for 16 h. K2CO3 (19.5 g, 141.4 mmol, 1.00 equiv.) was added, followed by MeOTs (39.4 g, 211.7 mmol, 1.5 equiv.). The resulting mixture was stirred at 65 °C for 8 h. EA (500 mL) and water (500 mL) were added. The organic layer was removed, and the aqueous phase was extracted with additional EA (500 mL). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, and concentrated in vacuo. TBME was added to form a slurry, and the resulting solid was collected on a filter to give K2.

[0296] Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate (K3): Zn (7.85 g, 120.0 mmol, 4.00 equiv.) was added to a round-bottom flask and heated with a heat gun at 110° C. for 10 min under vacuum. After cooling to room temperature, DMA (130 mL) and TMSCl (1.63 g, 15.0 mmol, 1.90 mL, 0.50 equiv.) were added and stirred at 70° C. for 1 h. Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate (K3) was dissolved in DMA (40 mL). (-butoxycarbonyl)amino)-3-iodopropanoate (19.7 g, 60.0 mmol, 2.00 equiv) was added and stirred at 50 °C for 1 h. After cooling to 30 °C, the zinc reagent was added dropwise to a pre-degassed mixture of K2 (10.0 g, 30.0 mmol, 1.00 equiv) and Pd(PPh3)2Cl2 (6.32 g, 9.01 mmol, 0.30 equiv) in DMA (130.0 mL). The reaction mixture was stirred at 80 °C for 3 h. After cooling to room temperature, EA (200 mL) and water (500 mL) were added. The organic layer was separated, and the aqueous layer was washed with EA (200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated in vacuo. The material was purified by silica gel column chromatography using EA / hexane to give K3.

[0297] Synthesis of methyl (S)-2-amino-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate (K): The title compound was prepared according to the method presented for the synthesis of intermediate I starting from compound K3. [ka]

[0298] Synthesis of cyclopropyl O-benzyl-N-(tert-butoxycarbonyl)-L-serinate (L1): To O-benzyl-N-(tert-butoxycarbonyl)-L-serine (20 g, 68 mmol) in DCM (135 mL) was added DMAP (8.27 g, 68 mmol), EDCI (25.96 g, 135 mmol), and cyclopropanol (39 g, 677 mmol). The mixture was stirred for 4 hours, diluted with EA (500 mL), washed with water (500 mL), and washed with 0.5 N citric acid (2 × 500 mL). The organic layer was evaporated, and the residue was chromatographed on silica gel eluting with 50% EA in hexane to give L1.

[0299] Synthesis of cyclopropyl(tert-butoxycarbonyl)-L-serinate (L2): To L1 (5.5 g, 16 mmol) in EA (10 mL) was added palladium on charcoal (3.5 g, 5% Pd). The contents were agitated under 50 PSI of hydrogen gas on a Parr shaker for 3 h at room temperature. The mixture was filtered, washed with EA, and the solvent was evaporated to give L2, which was used in the next step without further purification.

[0300] Synthesis of cyclopropyl (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (L3): To L2 (2.8 g, 11.4 mmol) in DCM was added iodine (3.2 g, 13 mmol, 1.1 equiv), imidazole (0.855 g, 13 mmol, 1.1 equiv), and PPh3 (2.96 g, 12 mmol, 1.05 equiv) and the mixture was stirred for 2 h. The solvent was removed in vacuo, and the residue was chromatographed on silica gel eluting with EA (0-20%) in hexane to give L3.

[0301] Synthesis of cyclopropyl (S)-2-((tert-butoxycarbonyl)amino)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate (L4): Zinc (1.27 g, 19.5 mmol, 20-30 mesh granules) was placed in a flame-dried round-bottom flask vial equipped with a stir bar. DMF (4.2 mL) and TMSCl (0.49 mL, 3.8 mmol) were added, and the mixture was stirred for 30 min. The supernatant was decanted using a syringe, and the activated zinc was further washed with DMF (2 × 1.3 mL). L3 (2.985 g, 8.4 mmol, 2 equiv) was then added dropwise to DMF (4.9 mL) at a rate that kept the resulting exotherm below 50 °C, followed by stirring for 30 min. The zinc iodo reagent was then introduced via syringe and added to a second flask containing Intermediate K2 (1.4 g, 4.2 mmol, 1 equiv), palladium acetate (0.094 g, 0.42 mmol, 0.1 equiv), Xphos (0.24 g, 0.5 mmol, 0.12 equiv), and DMF (7.8 mL), and the reaction mixture was stirred at 45 °C for 3 days. The mixture was diluted with EA, filtered through Celite, the solvent removed in vacuo, and chromatographed on silica gel eluting with methanol in DCM (0-10% methanol) to give L4.

[0302] Synthesis of cyclopropyl (S)-2-amino-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate (L): To L4 (1.8 g, 3.7 mmol) was added DCM (12 mL) and TFA (12 mL). The reaction was stirred for 2 hours and then concentrated in vacuo to give intermediate L. [ka]

[0303] Synthesis of methyl 3-(3-(6-iodopyridin-3-yl)ureido)isonicotinate (M1): To a 500 mL RB flask was added 6-iodopyridin-3-amine (5.0 g, 22.7 mmol, 1 eq.), 4-(methoxycarbonyl)nicotinic acid (4.57 g, 29.5 mmol, 1.3 eq.), (trifluoromethyl)benzene (46.0 mL), and triethylamine (4.76 mL, 34.1 mmol, 1.5 eq.). The reaction mixture was heated to 50° C. for 10 minutes. Diphenylphosphoryl azide (6.37 mL, 29.5 mmol, 1.3 eq.) was then added dropwise to the reaction mixture. The reaction was stirred for 60 minutes. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water (200 mL each). The organics were separated, washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by column chromatography on silica gel using 0-20% methanol in DCM as eluent to afford the title compound (M1).

[0304] Synthesis of 3-(6-iodopyridin-3-yl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (M2): The title compound was prepared according to the method presented for the synthesis of intermediate K2 starting from M1.

[0305] Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(5-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-2-yl)propanoate (M3): The title compound was prepared according to the method proposed for the synthesis of intermediate K3 starting from M2.

[0306] Synthesis of methyl (S)-2-amino-3-(5-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-2-yl)propanoate (M): The title compound was prepared according to the method presented for the synthesis of intermediate K starting from M3. [ka]

[0307] Synthesis of methyl (S)-3-(3-(4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)phenyl)ureido)isonicotinate (N1): The title compound was prepared according to the method presented for the synthesis of intermediate M1 starting from methyl (S)-3-(4-aminophenyl)-2-((tert-butoxycarbonyl)amino)propanoate.

[0308] Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)phenyl)propanoate (N2): The title compound was prepared according to the method presented for the synthesis of intermediate M2 starting from N1.

[0309] Synthesis of methyl (S)-2-amino-3-(4-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)phenyl)propanoate (N): The title compound was prepared according to the method presented for the synthesis of intermediate L starting from N2. [ka]

[0310] Synthesis of methyl 3-(3-(4-iodo-2-methoxyphenyl)ureido)isonicotinate (O1): The title compound was prepared according to the method presented for the synthesis of intermediate M1 starting from 4-iodo-2-methoxyaniline.

[0311] Synthesis of 3-(4-iodo-2-methoxyphenyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (O2): The title compound was prepared according to the method presented for the synthesis of intermediate M2 starting from O1.

[0312] Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-methoxy-4-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)phenyl)propanoate (O3): The title compound was prepared according to the method proposed for the synthesis of M3 starting from O2.

[0313] Synthesis of methyl (S)-2-amino-3-(3-methoxy-4-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)phenyl)propanoate (O): The title compound was prepared according to the method presented for the synthesis of intermediate M starting from O3. [ka]

[0314] Synthesis of (R)-2-chloro-6-fluoro-4-(3-(trifluoromethyl)morpholino)benzoic acid (P): To a 150 mL pressure vessel equipped with a stir bar was added methyl 4-bromo-2,6-difluorobenzoate (200 mg, 0.52 mmol), RuPhos (48 mg, 0.10 mmol), tBuBrettPhos Pd G3 (44 mg, 0.052 mmol), Cs2CO3 (844 mg, 2.6 mmol), (R)-3-(trifluoromethyl)morpholine (198 mg, 1.0 mmol), and toluene (6 mL). The reaction vessel was then sealed and heated at 90 °C overnight. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, rinsed with EtOAc, and the filtrate was evaporated to dryness under reduced pressure. The material was purified by silica gel chromatography using EtOAc in hexanes as the eluent to give a yellow oil. To this material was added THF (2.6 mL) and aqueous LiOH (0.78 mL, 1.0 M). The reaction mixture was stirred at 40° C. for 20 hours and at 50° C. for an additional 4 hours. The reaction mixture was cooled to room temperature and acidified with 1.0 M HCl before extraction with EtOAc. The organic layers were combined and dried over Na2SO4. The solvent was removed under reduced pressure to give P. [ka]

[0315] Synthesis of (S)-4-(3-(2,2-difluoroethyl)morpholino)-2-fluoro-6-methylbenzoic acid (Q): To a pressure vessel equipped with a 150 mL stir bar was added methyl 4-bromo-2-fluoro-6-methylbenzoate (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), (S)-3-(2,2-difluoroethyl)morpholine (416 mg, 2.7 mmol), and toluene (18 mL). The reaction vessel was then sealed and heated at 90 °C overnight. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, rinsed with EA, and the filtrate was evaporated to dryness under reduced pressure. The material was purified by silica gel chromatography using EA in hexane as the eluent. This material was purified by elution with THF (6 mL) and aqueous LiOH ( 6.2 mL of 1.0 M aqueous HCl was added. The reaction mixture was stirred at 60° C. for 20 h. 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 give Q. Intermediate R

[0316] Synthesis of methyl (S)-4-(3-(4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)phenyl)ureido)-5,6-dihydro-2H-pyran-3-carboxylate (R1): To a solution of methyl 4-amino-5,6-dihydro-2H-pyran-3-carboxylate (114 mg, 0.725 mmol) in dichloromethane (4 mL) was added 20% phosgene in toluene (0.352 mL, 0.67 mmol) and the reaction was stirred at room temperature for 30 minutes. It was cooled to 0° C. and then Hunig's base (0.237 mL, 1.36 mmol) was added, followed by To the residue was added methyl (S)-3-(4-aminophenyl)-2-((tert-butoxycarbonyl)amino)propanoate (100 mg, 0.34 mmol). The reaction was allowed to warm to room temperature and stirred for 16 hours. It was diluted with ethyl acetate and washed with 10% citric acid, saturated sodium bicarbonate, and saturated sodium chloride solutions. It was dried over anhydrous sodium sulfate, filtered, and concentrated. It was purified by flash chromatography (5-100% linear gradient of ethyl acetate / hexanes) to give R1. [ka]

[0317] Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(2,4-dioxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-d]pyrimidin-3(4H)-yl)phenyl)propanoate (R2): To a solution of R1 (107 mg, 0.224 mmol) in anhydrous methanol (2.8 mL) was added anhydrous potassium carbonate (155 mg, 1.12 mmol) and the reaction was stirred for 20 minutes. It was quenched by adding 10% citric acid to water. Additional water was added to precipitate the product, which was collected via filtration to give R2.

[0318] Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-methyl-2,4-dioxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-d]pyrimidin-3(4H)-yl)phenyl)propanoate (R3): To a solution of R2 (47 mg, 0.11 mmol) in N,N-dimethylformamide (0.36 mL) was added anhydrous potassium carbonate (15 mg, 0.11 mmol) and methyl tosylate (16 μL, 0.11 mmol), and the reaction was stirred for 4 hours. Water was added to precipitate the product. The solid was collected to give R3.

[0319] Synthesis of methyl (S)-2-amino-3-(4-(1-methyl-2,4-dioxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-d]pyrimidin-3(4H)-yl)phenyl)propanoate (R): To R3 (37 mg, 0.08 mmol) in ethyl acetate (0.7 mL) was added 4 M hydrogen chloride in dioxane (0.2 mL, 0.8 mmol) and the reaction was stirred for 16 hours. It was concentrated to give R. [ka]

[0320] Synthesis of ethyl 5-amino-3,6-dihydro-2H-pyran-4-carboxylate (S1): To a solution of ethyl 3-oxotetrahydro-2H-pyran-4-carboxylate (2.0 g, 12 mmol) in methanol (71 mL), ammonium acetate (4.57 g, 59 mmol) was added and the reaction was stirred at room temperature for 3 hours. It was concentrated, dissolved in dichloromethane, and washed with water and saturated sodium chloride. It was dried over anhydrous sodium sulfate, filtered, and concentrated to give S1.

[0321] Synthesis of methyl (S)-2-amino-3-(4-(1-methyl-2,4-dioxo-1,2,4,5,6,8-hexahydro-3H-pyrano[3,4-d]pyrimidin-3-yl)phenyl)propanoate (S): The title compound was prepared according to the method presented for the synthesis of intermediate R starting from S1. [ka]

[0322] Synthesis of methyl (S)-2-amino-3-(4-(1-methyl-2,4-dioxo-1,2,4,5,6,7-hexahydro-3H-cyclopenta[d]pyrimidin-3-yl)phenyl)propanoate (T): The title compound was prepared according to the method presented for the synthesis of intermediate R starting from methyl 2-aminocyclopent-1-ene-1-carboxylate. [ka]

[0323] Synthesis of methyl (S)-2-amino-3-(4-(1-methyl-2,4-dioxo-1,2,5,7-tetrahydrofuro[3,4-d]pyrimidin-3(4H)-yl)phenyl)propanoate (U): The title compound was prepared according to the method presented for the synthesis of intermediate R starting from methyl 4-amino-2,5-dihydrofuran-3-carboxylate. [ka]

[0324] Synthesis of ethyl (S)-2-amino-3-(6-(1-methyl-2,4-dioxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-d]pyrimidin-3(4H)-yl)pyridin-3-yl)propanoate (V): The title compound was prepared according to the method proposed for the synthesis of intermediate R starting from methyl 4-amino-5,6-dihydro-2H-pyran-3-carboxylate. [ka]

[0325] Synthesis of methyl 4-amino-2,5-dihydrofuran-3-carboxylate (W1): The title compound was prepared according to the method presented for the synthesis of intermediate S1 starting from methyl 4-oxotetrahydrofuran-3-carboxylate.

[0326] Synthesis of methyl 4-(3-(4-iodophenyl)ureido)-2,5-dihydrofuran-3-carboxylate (W2): The title compound was prepared according to the method presented for the synthesis of intermediate S2 starting from W1.

[0327] Synthesis of methyl (S)-2-amino-3-(4-(1-methyl-2,4-dioxo-1,2,5,7-tetrahydrofuro[3,4-d]pyrimidin-3(4H)-yl)phenyl)propanoate (W): The title compound can be obtained by synthesis of intermediate O starting from W2 instead of O1. The composition was prepared according to the method presented. Example 1

[0328] Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)phenyl)propanoate (1A): A solution of (S)-(4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)phenyl)boronic acid (100 mg, 0.310 mmol) and 3-iodo-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one (124 mg, 0.390 mmol) in DME (1.6 mL) was purged with nitrogen gas for 5 minutes. To this mixture was added a 1 M aqueous solution of XPhos Pd G3 (26.0 mg, 0.031 mmol) and K3PO4 (230 mg, 1.00 mmol), and the reaction was purged with nitrogen gas for an additional 5 minutes. The mixture was then heated with stirring at 77 °C for 7 minutes. Upon completion, the solvent was removed under reduced pressure, and the mixture was dissolved in EA, washed with water, dried over Na2SO4, and concentrated under reduced pressure to give the crude material. The crude product was purified using flash chromatography eluting with EA (20% to 80%) in hexane to give compound 1A. [ka]

[0329] Synthesis of methyl (S)-2-amino-3-(4-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)phenyl)propanoate (1B): To a solution of compound 1A (98.0 mg, 0.210 mmol) in EA (1.1 mL) was added a 4 M solution of HCl in dioxane (76.2 mg, 2.10 mmol), and the mixture was stirred at room temperature for 2 hours. Upon completion, the solvent was removed under reduced pressure, and the crude product 1B was used in the next step without further purification.

[0330] Synthesis of (S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(4-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)phenyl)propanoic acid (1): To a solution of compound 1B (85.0 mg, 0.210 mmol), intermediate A (65.0 mg, 0.231 mmol), and DIEA (163 mg, 1.26 mmol) in DMF (2.1 mL) was added HATU (96.0 mg, 0.252 mmol), and the mixture was stirred at room temperature for 2 hours. Upon completion, the mixture was diluted with EA, washed with water, dried over NaSO, and concentrated under reduced pressure to give the crude material. The crude product was purified using flash chromatography eluting with EA (12% to 100%) in hexanes. To obtain the ester. To a solution of the ester (91.0 mg, 0.144 mmol) in THF (4.80 mL), a 1 M aqueous solution of LiOH (10.0 mg, 0.432 mmol) was added, and the mixture was stirred at room temperature for 40 minutes. Upon completion, the mixture was acidified with TFA, and the volatiles were removed under reduced pressure. The crude material was dissolved in DMSO and chromatographed on C-18 modified silica gel eluting with acetonitrile in water (0.4% TFA) to obtain compound 1. MS (m / z) 620.1 [M+H]+.1H NMR(400MHz,DMSO-d6)δ8.68(d,J=7.7Hz,1H),7.28(d,J=8.1Hz,2H),7.06(d,J=8.2H z,2H),6.76(d,J=10.4Hz,1H),6.50(s,1H),6.45(d,J=11.4Hz,2H),4.58-4.50(m,1H) ),4.37-4.26(m,1H),3.48(s,3H),3.13(dd,J=14.1,5.8Hz,1H),2.97(dd,J=13.7,10 .1Hz,1H),2.47(s,3H),1.81-1.74(m,1H),1.59-1.48(m,1H),0.93(t,J=7.5Hz,3H). Example 2 [ka]

[0331] Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1,2-dimethyl-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenyl)propanoate (2A): A solution of (S)-(4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)phenyl)boronic acid (200 mg, 0.619 mmol) and Intermediate G (247 mg, 0.780 mmol) in DME (3.0 mL) was purged with nitrogen gas for 5 minutes. To this mixture was added XPhos Pd G3 (52.0 mg, 0.062 mmol) and a 1 M aqueous solution of K3PO4 (460 mg, 2.0 mmol), and the reaction was purged with nitrogen gas for an additional 5 minutes. The mixture was then heated at 90° C. with stirring for 10 minutes, after which the solvent was removed under reduced pressure. The mixture was dissolved in EA, washed with water, dried over Na SO , and concentrated under reduced pressure to give a crude material. The crude product was purified by flash chromatography eluting with EA (20% to 80%) in hexane to give compound 2A.

[0332] Synthesis of methyl (S)-2-amino-3-(4-(1,2-dimethyl-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenyl)propanoate (2B): The title compound was prepared according to the method proposed for the synthesis of 1B starting from 2A.

[0333] Synthesis of (S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(4-(1,2-dimethyl-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenyl)propanoic acid (2): The title compound was prepared according to the method proposed for the synthesis of 1 starting from 2B and intermediate A. MS (m / z) 620.1 [M+H]+.1H NMR(400MHz,DMSO-d6)δ8.65(d,J=8.1Hz,1H),7.35-7.30(m,2H),7.09(t,J=7.4Hz ,2H),6.74(d,J=10.9Hz,1H),6.73(s,1H),6.43(d,J=11.3Hz,2H),4.66-4.57(m,1 H),4.37-4.24(m,1H),3.54(s,3H),3.18(dd,J=14.1,4.4Hz,1H),2.94(dd,J=14.3 ,10.2Hz,1H),2.03(s,3H),1.80(s,1H),1.58-1.47(m,1H),0.93(t,J=7.2Hz,3H). Example 3 [ka]

[0334] Synthesis of (S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)phenyl)propanoic acid (3): The title compound was prepared according to the method proposed for the synthesis of 1 using Intermediate 1B and Intermediate B. MS (m / z) 648.3 [M+H]+. NMR(400MHz,DMSO-d6)δ8.84(d,J=7.9Hz,1H),7.29(d,J=8.1Hz,2H),7.06(d,J=8.0Hz,2H),6.76( d,J=11.6Hz,2H),6.49(s,2H),4.91(m,1H),4.57(m,1H),4.16(d,J=12.7Hz,1H),3.96(dd,J=11.5 ,3.8Hz,1H),3.78-3.70(m,1H),3.56(td,J=11.6,2.9Hz,1H),3.48(s,3H),3.43(d,J=12.9Hz,1H) ,3.24(t,J=12.2Hz,1H),3.15(dd,J=14.2,4.7Hz,1H),2.99(dd,J=14.1,9.8Hz,1H),2.47(s,3H). Example 4

[0335] Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1,4-dimethyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)phenyl)propanoate (4A): A solution of (S)-(4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)phenyl)boronic acid (100 mg, 0.310 mmol) and Intermediate H (124 mg, 0.390 mmol) in DME (1.6 mL) was purged with nitrogen gas for 5 minutes. To this mixture was added a 1 M aqueous solution of XPhosPdG (26.0 mg, 0.031 mmol) and KPO (230 mg, 1.00 mmol), and the reaction was purged with nitrogen gas for an additional 5 minutes. The mixture was then heated with stirring at 77°C for 7 minutes. Upon completion, the solvent was removed under reduced pressure. The mixture was dissolved in EA, washed with water, dried over NaSO, and concentrated under reduced pressure to give crude material, which was purified by flash chromatography eluting with EA in hexane (20% to 100%) to give compound 4A. [ka]

[0336] Synthesis of methyl (S)-2-amino-3-(4-(1,4-dimethyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)phenyl)propanoate (4B): The title compound was prepared according to the method proposed for the synthesis of 1B starting from compound 4A.

[0337] Synthesis of (S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1,4-dimethyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)phenyl)propanoic acid (4): The title compound was prepared according to the method proposed for the synthesis of 1 starting from compound 4B and intermediate B. MS (m / z) 648.3 [M+H]+.1H NMR(400MHz,DMSO-d6)δ8.82(d,J=8.0Hz,1H),8.30(s,1H),7.32(d,J=8.1Hz,2H),7.09(d,J=8.2 Hz,2H),6.76(d,J=11.6Hz,2H),4.90(td,J=8.5,3.2Hz,1H),4.62-4.55(m,1H),4.16(d,J=12.7H) z,1H),3.98-3.91(m,1H),3.76-3.71(m,1H),3.59-3.52(m,1H),3.49(s,3H),3.42(d,J=12.3Hz, 1H),3.29-3.23(m,1H),3.17(dd,J=14.0,4.6Hz,1H),2.98(dd,J=13.9,10.1Hz,1H),2.00(s,3H). Example 5 [ka]

[0338] Synthesis of (S)-3-(4-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-3-methylphenyl)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)propanoic acid (5): The title compound was prepared according to the method proposed for the synthesis of 1 starting from intermediate I and intermediate C. MS (m / z) 658.3 [M+H]+.1H NMR(400MHz,DMSO-d6)δ8.71(dd,J=8.0,4.0Hz,1H),7.17(d,J=12.1Hz,1H),7.10(t,J=8.5Hz,1H),6.89-6.83(m,1H) ,6.69(d,J=14.1Hz,1H),6.65(s,1H),6.51(s,1H),4.90-4.79(m,1H),4.68-4.55(m,1H),4.14(d,J=12.6Hz,1H),3.94 (dd,J=11.2,3.2Hz,1H),3.73(d,J=11.9Hz,1H),3.59-3.51(m,1H),3.50(s,3H),3.35(d,J=11.5Hz,1H),3.27(d,J=12 .8Hz,1H),3.13(dd,J=14.2,3.9Hz,1H),2.97-2.89(m,1H),2.49(s,3H),2.04(d,J=1.6Hz,3H),1.97(d,J=4.0Hz,3H). Example 6 [ka]

[0339] Synthesis of (S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-3-fluorophenyl)propanoic acid (6): The title compound was prepared according to the method presented for the synthesis of 1 starting from intermediate J and intermediate B. MS(m / z)666.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.87(dd,J=7.9,2.4Hz,1H),7.19-7.03(m,2H),6.77(d,J=8.1Hz,2H),6. 54(s,1H),4.97-4.86(m,1H),4.63-4.54(m,1H),4.16(d,J=12.7Hz,1H),3.95(dd,J=11.3,3.5Hz ,1H),3.74(d,J=14.9Hz,1H),3.56(td,J=11.9,2.8Hz,1H),3.50(s,3H),3.43( d,J=13.9Hz,1H),3.22(ddd,J=31.6,12.8,4.0Hz,2H),3.00(t,J=13.3Hz,1H). Example 7 [ka]

[0340] Synthesis of (2S,5R)-2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (7A): To a solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (361 mg, 1.96 mmol) in THF (9.80 mL) at −78° C. was added a solution of n-BuLi in hexane (2.11 g, 2.11 mmol). The mixture was stirred at −78° C. for 20 minutes, followed by the dropwise addition of a solution of 2-(4-(bromomethyl)-2-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg, 1.51 mmol) in THF (7.50 mL). The reaction was stirred for 40 minutes at -78 °C and quenched with water. The cold bath was removed, and the reaction was allowed to warm to room temperature, extracted with EA, washed with brine, dried over NaSO, and concentrated under reduced pressure to give compound 7A, which was used without further purification.

[0341] Synthesis of 3-(2-chloro-4-(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)methyl)phenyl)-1,5,6-trimethylpyrazin-2(1H)-one (7B): To a solution of compound 7A (200 mg, 0.276 mmol), 3-chloro-1,5,6-trimethylpyrazin-2(1H)-one (47.6 mg, 0.276 mmol) in DME (2.3 mL) was added a 1 M aqueous solution of KPO (342 mg, 0.1.61 mmol), and the mixture was purged with nitrogen gas for 6 minutes. XPhosPdG (11.7 mg, 0.014 mmol) was then added, and the mixture was purged with nitrogen gas for an additional 4 minutes and heated at 90 °C for 30 minutes. The solvent was then removed under reduced pressure, and the mixture was dissolved in EA, washed with water, dried over NaSO, and concentrated under reduced pressure to give crude material. The crude product was purified using flash chromatography eluting with EA in hexane (20% to 100%), then MeOH in EA (0% to 25%) to give compound 7B.

[0342] Methyl (S)-2-amino-3-(3-chloro-4-(4,5,6-trimethyl-3- Synthesis of oxo-3,4-dihydropyrazin-2-yl)phenyl)propanoate (7C): The title compound was prepared according to the method presented for the synthesis of intermediate J starting from compound 7B.

[0343] Synthesis of (S)-3-(3-chloro-4-(4,5,6-trimethyl-3-oxo-3,4-dihydropyrazin-2-yl)phenyl)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)propanoic acid (7): The title compound was prepared according to the method proposed for the synthesis of 1 using 7C and intermediate C. MS (m / z) 625.2 [M+H]+. NMR(400MHz,DMSO-d6)δ8.73(d,J=7.8Hz,1H),7.42(s,1H),7.29(s,2H),6.73-6.63(m,2H), 4.90-4.79(m,1H),4.64-4.56(m,1H),4.14(d,J=7.9Hz,1H),3.95(d,J=11.7Hz,1H),3.73(d ,J=13.9Hz,1H),3.56(d,J=12.2Hz,1H),3.52(s,3H),3.36(d,J=11.3Hz,1H),3.27(d,J=11. 9Hz,1H),3.18(d,J=11.2Hz,1H),3.03-2.93(m,1H),2.37(s,3H),2.30(s,3H),2.09(s,3H). Example 8 [ka]

[0344] Synthesis of methyl (S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate (8): The title compound was prepared according to the method proposed for the synthesis of 1 using intermediate K and intermediate A. MS (m / z) 621.1 [M+H]+.1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.93(d,J=7.6Hz,1H),8.56(d,J=5.0Hz,1H),8.47(d,J=2.3Hz,1H),7.96- 7.85(m,2H),7.40(d,J=8.1Hz,1H),6.81(d,J=9.4Hz,1H),6.46(d,J=11.6Hz,2H),4.72-4.56(m,1H),4.31(d,J =10.0Hz,1H),3.20(dd,J=14.2,5.1Hz,1H),3.16-2.99(m,2H),2.67(d,J=0.7Hz,2H),1.76(ddd,J=13.7,7.3,3 .3Hz,1H),1.52(ddd,J=13.8,10.5,7.2Hz,1H),1.32-1.21(m,6H),1.09(d,J=0.7Hz,2H),0.91(t,J=7.3Hz,3H). Example 9 [ka]

[0345] Synthesis of (S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoic acid (9): To 8 (12.5 mg, 0.02 mmol) dissolved in THF, 1.0 M LiOH (0.04 mL, 0.04 mmol) was added, and the mixture was stirred at room temperature for 1 h. Then, 4.0 M LiOH in dioxane (0.1 mL, 0.4 mmol) was added. HCl was added and the mixture was stirred overnight. The reaction mixture was concentrated, filtered, and purified via reverse phase HPLC (MeCN / HO) to give 9. Example 10 [ka]

[0346] Synthesis of methyl (S)-2-(2-fluoro-6-methyl-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate (10): The title compound was prepared according to the method proposed for the synthesis of 1 using intermediate K and intermediate D. MS (m / z) 617.3 [M+H]+. NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.81(d,J=7.8Hz,1H),8.57(dd,J=5.1,1.8Hz,1H),8.49(s,1H),8.16 (s,2H),7.92(dd,J=12.9,6.5Hz,2H),7.42(d,J=8.1Hz,1H),6.40(d,J=7.4Hz,2H),6.32(d,J=9.3Hz,1H), 4.72(d,J=6.2Hz,1H),4.20(s,1H),3.68(d,J=2.0Hz,3H),3.32(d,J=1.9Hz,4H),3.24(dd,J=14.9,4.6Hz, 1H),3.19-3.01(m,4H),2.00(s,3H),1.75(d,J=10.1Hz,1H),1.55(d,J=15.8Hz,1H),0.93(t,J=7.3Hz,3H). Example 11 [ka]

[0347] Synthesis of (S)-2-(2-fluoro-6-methyl-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoic acid (11): The title compound was prepared according to the method proposed for the synthesis of Example 9 starting from 10. MS (m / z) 603.2 [M+H]+.1H NMR(400MHz,DMSO-d6)δ9.00(d,J=1.9Hz,1H),8.67(d,J=8.1Hz,1H),8.62-8.52(m,1H),8.50(s,1H),8. 02-7.80(m,2H),7.41(dd,J=8.2,2.0Hz,1H),6.53-6.34(m,3H),6.30(d,J=9.2Hz,1H),5.76(d,J=1.8Hz ,1H),4.65(d,J=11.1Hz,1H),4.03(d,J=7.0Hz,1H),3.61(s,3H),3.26(d,J=13.9Hz,1H),3.03(t,J=12. 6Hz,1H), 2.00(d,J=2.3Hz,4H),1.89-1.63(m,2H),1.52(dd,J=14.8,8.1Hz,1H),0.93(t,J=7.4Hz,3H). Example 12 [ka]

[0348] Synthesis of methyl (S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate (12): The title compound was prepared according to the method proposed for the synthesis of 1 using intermediate K and intermediate B. MS (m / z) 649.5 [M+H]+. NMR (400 MHz, DMSO-d6) δ 9.09 (d, J = 7.6 Hz, 1H), 9.00 (s, 1H), 8.57 (dd, J = 5.0, 1.5 Hz, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.01 - 7.80 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 11.8 Hz, 2H), 5.09 - 4.81 (m , 1H), 4.70 (td, J = 9.0, 5.7 Hz, 1H), 4.17 (d, J = 12.7 Hz, 1H), 4.07 - 3.88 (m, 1H), 3.75 (d, J = 12.9 Hz, 1H), 3.67 (d, J = 1.6 Hz, 3H), 3.61 (d, J = 1.6 Hz, 3H), 3.58 - 3.51 (m, 1H), 3.44 (d, J = 12.7 Hz, 1H), 3.29 - 3.19 (m, 2H), 3.12 (dd, J = 14.2, 9.9 Hz, 1H). Example 13

Chemical Structure

[0349] Synthesis of (S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoic acid (13): The title compound was prepared according to the method proposed for the synthesis of Example 9 starting from 12. MS (m / z) 635.2 [M+H]+.1H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.95(d,J=7.9Hz,1H),8.57(d,J=5.0Hz,1H),8.50(d,J=2.3Hz, 1H),7.96-7.85(m,2H),7.41(d,J=8.1Hz,1H),6.78(d,J=11.6Hz,2H),4.92(s,1H),4.70-4.55(m,1H) ),4.16(d,J=12.7Hz,1H),3.96(dd,J=11.3,3.9Hz,1H),3.74(d,J=12.6Hz,1H),3.61(s,3H),3.55(d ,J=10.6Hz,1H),3.44(d,J=12.5Hz,1H),3.25(dd,J=14.3,4.6Hz,2H),3.08(dd,J=14.3,10.0Hz,1H). Example 14 [ka]

[0350] Synthesis of methyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate (14): The title compound was prepared by the reaction of 1 with intermediates K and C. Prepared according to the proposed synthesis method. MS (m / z) 644.8 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.93 (d, J = 7.9 Hz, 1H), 8.57 (dd, J = 5.0, 1.6 Hz, 1H), 8.50 (s, 1H), 7.93 (dd, J = 16.9, 6.6 Hz, 2H), 7.42 (d, J = 8.1 Hz, 1H), 6.87-6.48 (m, 2H), 4.93-4.69 (m, 2H), 4.15 (d ,J=12.7Hz,2H),3.97(s,12H),3.77-3.71(m,1H),3.69(d,J=1.7Hz,3H),3.61(d,J=1.7Hz,3H),3.59 -3.48(m,1H),3.36(d,J=12.4Hz,1H),3.26(dd,J=14.1,4.9Hz,2H),3.14-3.01(m,1H),2.06(s,3H). Example 15 [ka]

[0351] Synthesis of (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoic acid (15): The title compound was prepared according to the method proposed for the synthesis of Example 9 starting from 14. MS (m / z) 631.2 [M+H]+.1H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.79(d,J=8.1Hz,1H),8.57(d,J=5.0Hz,1H),8.50(s,1H) ,7.95(d,J=8.3Hz,1H),7.90(d,J=5.1Hz,1H),7.42(d,J=8.0Hz,1H),6.75-6.61(m,2H),4.85( d,J=9.6Hz,1H),4.69(d,J=8.4Hz,1H),4.15(d,J=12.6Hz,1H),4.07-3.90(m,1H),3.73(d,J=1 2.6Hz,1H),3.61(s,3H),3.59-3.49(m,1H),3.43-3.19(m,3H),3.13-2.95(m,1H),2.04(s,3H). Example 16 [ka]

[0352] Synthesis of methyl (S)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)-2-(2,3,6-trifluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)propanoate (16): The title compound was prepared according to the method proposed for the synthesis of 1 using intermediate K and intermediate E. MS (m / z) 639.2 [M+H]+.1H NMR(400MHz,DMSO-d6)δ9.10(d,J=7.8Hz,1H),9.00(s,1H),8.60-8.54(m,1H),8 .49(s,1H),7.92(d,J=8.3Hz,2H),7.48-7.35(m,1H),6.99-6.78(m,1H),6.73(d, J=9.3Hz,1H),4.77-4.66(m,1H),4.44-4.34(m,1H),3.67(s,3H),3.61(s,3H),3. 29-3.19(m,1H),3.16-3.04(m,1H),1.77(q,J=7.3Hz,2H),0.93(t,J=6.8Hz,3H). Example 17 [ka]

[0353] Synthesis of (S)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)-2-(2,3,6-trifluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)propanoic acid (17): The title compound was prepared according to the method proposed for the synthesis of Example 9 starting from 16. MS (m / z) 625.2 [M+H]+. 1H NMR(400MHz,DMSO-d6)δ9.02-8.91(m,2H),8.57(d,J=5.4Hz,1H),8.49(s,1H),7.98-7.87(m,2H),7.44-7.36(m,1H),6.94-6.80(m,1H), 6.71(d,J=9.2Hz,1H),4.64(s,1H),3.61(s,3H),3.26(d,J=14.1Hz,1H),3.15-2.95(m,1H),1.77(d,J=8.4Hz,2H),0.93(t,J=7.1Hz,3H). Example 18 [ka]

[0354] Synthesis of methyl (S)-2-(4-(cyclopropyl((R)-1,1,1-trifluorobutan-2-yl)amino)-2,6-difluorobenzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate (18): The title compound was prepared according to the method proposed for the synthesis of 1 using intermediate K and intermediate F. MS (m / z) 661.3 [M+H]+.1H NMR(400MHz,DMSO-d6)δ9.05(d,J=7.6Hz,1H),9.00(s,1H),8.57(d,J=5.0Hz,1H),8.52-8.45(m,1H),7.96-7.87(m,2H) ),7.42(dd,J=8.1,0.7Hz,1H),6.68(d,J=12.1Hz,2H),5.68(ddd,J=22.3,10.1,4.9Hz,1H),5.25-5.15(m,2H),4.81(s ,1H),4.69(ddd,J=10.1,7.6,5.1Hz,1H),4.01(s,2H),3.67(s,3H),3.61(s,3H),3.23(dd,J=14.2,5.1Hz,1H),3.09(d d,J=14.2,10.0Hz,1H),1.92(ddd,J=14.3,10.4,7.1Hz,1H),1.78(dtd,J=13.8,7.0,3.8Hz,1H),0.87(t,J=7.3Hz,3H). Example 19 [ka]

[0355] Synthesis of (S)-2-(4-(cyclopropyl((R)-1,1,1-trifluorobutan-2-yl)amino)-2,6-difluorobenzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoic acid (19): The title compound was prepared according to the method proposed for the synthesis of Example 9 starting from 18. MS (m / z) 647.2 [M+H]+. 1H NMR(400MHz,DMSO-d6)δ13.23-12.44(s,1H),9.00(s,1H),8.91(d,J=7.9Hz,1H),8.57(d,J=4.9Hz,1H),8 .50(d,J=2.3Hz,1H),7.97-7.86(m,2H),7.45-7.38(m,1H),6.67(d,J=12.0Hz,2H),5.78-5.59(m,1H),5.2 8-5.12(m,2H),4.81(s,1H),4.61(ddd,J=10.1,7.8,4.5Hz,1H),4.01(s,2H),3.61(s,3H),3.24(dd,J=14. 2,4.5Hz,1H),3.06(dd,J=14.2,10.2Hz,1H),1.99-1.85(m,1H),1.85-1.73(m,1H),0.86(t,J=7.3Hz,3H). Example 20

[0356] Synthesis of cyclopropyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate (20): The title compound was prepared according to the method proposed for the synthesis of 1 using intermediate L and intermediate C. MS (m / z) 671.2 [M +H]+. 1H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.92(d,J=7.7Hz,1H),8.57(d,J=4.9Hz,1H),8.49(d,J=2.3Hz,1 H),8.00-7.86(m,2H),7.42(d,J=8.1Hz,1H),6.82-6.60(m,2H),4.85(d,J=9.7Hz,1H),4.71(ddd,J=10 .3,7.6,5.2Hz,1H),4.14(ddd,J=9.3,4.7,2.3Hz,2H),3.99-3.92(m,1H),3.61(s,3H),3.36(d,J=12. 4Hz,1H),3.23(dd,J=14.2,5.3Hz,1H),3.08(dd,J=14.2,10.3Hz,1H),2.06(s,3H),0.77-0.52(m,3H).

change

change

[0357] Synthesis of ethyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate (21): To 15 (600 mg, 0.8 mmol) in DCM (13 mL), DIAD (1.15 mL, 8.0 mmol), EtOH (0.47 mL, 8.0 mmol), and PPh (1.27 g, 4.83 mmol) were added, and the mixture was stirred for 10 min. The reaction mixture was concentrated in vacuo and then purified by column chromatography on silica gel eluting with 0-100% EA in hexane to give 21. MS (m / z) 659.2 [M+H]. 1H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.92(d,J=7.7Hz,1H),8.57(d,J=4.9Hz,1H),8.50(d,J=2.3Hz,1H),7.95(dd,J=8. 2,2.4Hz,1H),7.91(dd,J=5.0,0.8Hz,1H),7.47-7.35(m,1H),6.77-6.59(m,2H),4.85(dd,J=8.8,3.5Hz,1H),4.74(ddd ,J=10.4,7.8,5.2Hz,1H),4.20-4.08(m,3H),3.95(dd,J=11.4,3.6Hz,1H),3.79-3.72(m,1H),3.61(s,3H),3.58-3.50( m,1H),3.43(s,1H),3.35(s,1H),3.31-3.21(m,2H),3.09(dd,J=14.2,10.4Hz,1H),2.07(s,3H),1.20(t,J=7.1Hz,3H). Example 22 [ka]

[0358] Synthesis of methyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(5-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-2-yl)propanoate (22): The title compound was prepared according to the method proposed for the synthesis of 1 using intermediate M and intermediate C. MS (m / z) 645.2 [M+H]+. 1H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.86(d,J=7.7Hz,1H),8.58(d,J=5.0Hz,1H),8.48(d,J=2.5Hz,1H),7.92( d,J=4.9Hz,1H),7.74(dd,J=8.2,2.5Hz,1H),7.48(d,J=8.3Hz,1H),6.77-6.61(m,2H),4.97(ddd,J=9.8,7.7,5. 2Hz,1H),4.85(dd,J=8.9,3.6Hz,1H),4.15(d,J=12.6Hz,1H),3.95(dd,J=11.5,3.6Hz,1H),3.74(d,J=12.7Hz, 1H),3.67(s,3H),3.62(s,3H),3.59-3.47(m,1H),3.41-3.29(m,2H),3.23(dd,J=14.3,9.8Hz,2H),2.06(s,3H). Example 23 [ka]

[0359] Synthesis of (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(5-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-2-yl)propanoic acid (23): The title compound was prepared according to the method proposed for the synthesis of Example 9 starting from 22. MS(m / z)631.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.71(d,J=8.0Hz,1H),8.58(d,J=4.9Hz,1H),8.48(d,J=2.5H) z,1H),7.92(d,J=4.9Hz,1H),7.74(dd,J=8.2,2.5Hz,1H),7.47(d,J=8.3Hz,1H),6.74-6.61(m,2H ),4.98-4.78(m,2H),4.14(d,J=12.6Hz,1H),3.95(dd,J=11.6,3.6Hz,1H),3.73(d,J=12.8 Hz,1H),3.62(s,3H),3.60-3.49(m,1H),3.42-3.29(m,2H),3.31-3.09(m,2H),2.05(s,3H). Example 24 [ka]

[0360] Synthesis of methyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)phenyl)propanoate (24): The title compound was prepared according to the method proposed for the synthesis of 1 using intermediates N and C. MS (m / z) 644.2 [M+H]+. 1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.89(d,J=7.7Hz,1H),8.55(d,J=5.0Hz,1H),7.90(d,J=5.0Hz,1H),7.39(d,J=8.1Hz,2H),7 .23(d,J=8.2Hz,2H),6.70(dd,J=12.9,2.3Hz,1H),6.67(d,J=2.3Hz,1H),4.84(dt,J=9.8,5.1Hz,1H),4.70(ddd,J=10.4,7.7,4.8 Hz,1H),4.15(d,J=12.6Hz,1H),3.95(dd,J=11.5,3.7Hz,1H),3.74(dd,J=12.1,3.4Hz,1H),3.67(s,3H),3.60(s,3H),3.59-3.50 (m,1H),3.36(d,J=11.8Hz,1H),3.27(d,J=12.2Hz,1H),3.19(dd,J=14.2,5.0Hz,1H),3.05(dd,J=14.1,10.4Hz,1H),2.07(s,3H). Example 25 [ka]

[0361] Synthesis of (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)phenyl)propanoic acid (25): The title compound was prepared according to the method proposed for the synthesis of Example 9 starting from 24. MS (m / z) 630.2 [M+H]+. 1H NMR (400 M H z, DMSO-d6) δ 8.97 (s, 1H), 8.74 (d, J = 8.0 Hz, 1H), 8.55 (d, J = 5.0 Hz, 1H), 7.90 (d, J = 5.0 Hz, 1H), 7.40 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 6.69 (dd, J = 13.0, 2.2 Hz, 1H), 6.65 (d, J = 2.3 Hz, 1H), 4.90 - 4.78 (m, 1H), 4.65 (tt, J = 8.0, 4.3 Hz, 1H), 4.15 (d, J = 12.5 Hz, 1H), 3.95 (dd, J = 11.5, 3.6 Hz, 1H), 3.73 (d, J = 12.6 Hz, 1H), 3.60 (s, 3H), 3.55 (td, J = 11.8, 11.3, 3.0 Hz, 1H), 3.36 (d, J = 11.5 Hz, 1H), 3.27 (d, J = 12.4 Hz, 1H), 3.21 (dd, J = 14.1, 4.2 Hz, 1H), 3.01 (dd, J = 14.2, 10.7 Hz, 1H), 2.05 (s, 3H). Example 26 [Chemical formula]

[0362] Synthesis of methyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(3-methoxy-4-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)phenyl)propanoate (26): The title compound was prepared according to the method proposed for the synthesis of 1 using intermediate O and intermediate C. MS (m / z) 674.2 [M+H]+. 1H NMR(400MHz,DMSO-d6)δ8.97(s,1H),8.91(d,J=7.7Hz,1H),8.56(d,J=4.9Hz,1H),7.94-7.84( m,1H),7.21-7.09(m,2H),6.96(dd,J=8.0,1.7Hz,1H),6.77-6.63(m,2H),4.84(td,J=8.8,3.5H z,1H),4.72(ddd,J=10.6,7.7,4.7Hz,1H),4.15(d,J=12.6Hz,1H),3.95(dd,J=11.4,3.6Hz,1H ),3.84-3.72(m,1H),3.69(d,J=3.9Hz,6H),3.64-3.58(m,4H),3.31-3.00(m,6H),2.09(s,3H). Example 27 [ka]

[0363] (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl Synthesis of )morpholino)benzamido)-3-(3-methoxy-4-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)phenyl)propanoic acid (27): The title compound was prepared according to the method proposed for the synthesis of Example 9 starting from 26. MS (m / z) 660.2 [M+H]+. 1H NMR(400MHz,DMSO-d6)δ8.97(s,1H),8.76(d,J=8.0Hz,1H),8.56(d,J=5.0Hz,1H),7.89(dd,J=5.0,1 .4Hz,1H),7.20-7.12(m,2H),6.97(dd,J=8.0,1.6Hz,1H),6.74-6.61(m,2H),4.84(dd,J=8.9,3.5Hz, 1H),4.67(ddd,J=11.6,7.9,4.1Hz,1H),4.15(d,J=12.6Hz,1H),3.95(dd,J=11.5,3.7Hz,1H),3.71(s ,5H),3.69(s,3H),3.40-3.31(m,1H),3.31-3.17(m,2H),3.01(dd,J=14.2,10.8Hz,1H),2.08(s,3H). Example 54 [ka]

[0364] Synthesis of ethyl (S)-2-(2-chloro-6-fluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate (54): The title compound was prepared according to the method proposed for the synthesis of 8 using the ethyl ester of intermediate K and intermediate P. MS (m / z) 679.2 [M+H]+.1H NMR(400MHz,DMSO-d6)δ9.16(d,J=7.9Hz,1H),9.00(s,1H),8.57(d,J=5.0Hz,1H),8.50(d,J=2.3Hz,1H),7.94(dd,J =8.1,2.4Hz,1H),7.90(d,J=5.0Hz,1H),7.41(d,J=8.1Hz,1H),6.98-6.88(m,2H),4.93(dd,J=8.9,3.5Hz,1H),4.74 (ddd,J=10.3,7.9,5.1Hz,1H),4.20-4.08(m,3H),3.95(dd,J=11.6,3.7Hz,1H),3.74(d,J=12.7Hz,1H),3.61(s,3H) ,3.54(t,J=9.14Hz,1H),3.41(d,J=12.5Hz,1H),3.25(m,2H),3.09(dd,J=14.2,10.2Hz,1H),1.20(t,J=7.1Hz,3H). Example 55 [ka]

[0365] Synthesis of (S)-2-(2-chloro-6-fluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoic acid (55): The title compound was prepared according to the method proposed for the synthesis of Example 9 starting from 54. MS (m / z) 651.1 [M+H]+. 1H NMR(400MHz,DMSO-d6)δ13.32-12.45(s,1H),9.04(d,J=8.2Hz,1H),9.00(s,1H),8.57(d,J=5.0Hz,1H),8.50 (d,J=2.3Hz,1H),7.94(dd,J=8.1,2.4Hz,1H),7.90(d,J=5.0Hz,1H),7.41(d,J=8.1Hz,1H),6.96-6.87(m,2H) ),5.00-4.84(m,1H),4.76-4.63(m,1H),4.15(d,J=12.7Hz,1H),3.95(dd,J=11.5,3.7Hz,1H),3.74(d,J=12. 7Hz,1H),3.61(s,3H),3.60-3.49(m,1H),3.40(d,J=12.7Hz,1H),3.27(m,2H),3.04(dd,J=14.3,10.6Hz,1H). Example 56 [ka]

[0366] Synthesis of methyl (S)-2-(4-((S)-3-(2,2-difluoroethyl)morpholino)-2-fluoro-6-methylbenzamido)-3-(4-(1-methyl-2,4-dioxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-d]pyrimidin-3(4H)-yl)phenyl)propanoate (56): The title compound was prepared according to the method presented for the synthesis of 8 using the ethyl ester of intermediate R and intermediate Q. MS(m / z)645.4[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.83(d,J=7.7Hz,1H),7.40-7.29(m,2H),7.14-7.05(m,2H),6.61-6.48(m,2H),6.3 6-5.97(m,1H),4.67(ddd,J=10.4,7.7,4.9Hz,1H),4.28(d,J=1.8Hz,2H),4.02(d,J=9.3Hz,1H),3.93-3.80 (m,4H),3.66(s,3H),3.63(s,1H),3.52(td,J=11.7,3.2Hz,1H),3.34(s,1H),3.16(dd,J=14.1,4.9Hz,1H ),3.09-2.95(m,2H),2.72(d,J=5.8Hz,2H),2.37(d,J=14.0Hz,1H),2.05(s,3H),1.77(q,J=17.5Hz,1H). Example 57 [ka]

[0367] Synthesis of (S)-2-(4-((S)-3-(2,2-difluoroethyl)morpholino)-2-fluoro-6-methylbenzamido)-3-(4-(1-methyl-2,4-dioxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-d]pyrimidin-3(4H)-yl)phenyl)propanoic acid (57): The title compound was prepared according to the method proposed for the synthesis of Example 9 starting from 56. MS (m / z) 631.4 [M+H]+. 1H NMR(400MHz,DMSO-d6)δ12.87-12.58(s,1H),8.68(d,J=8.1Hz,1H),7.36(d,J=8.2Hz,2H),7. 10(d,J=8.2Hz,2H),6.53(d,J=8.7Hz,2H),6.34-5.94(m,1H),4.70-4.54(m,1H),4.28(s,2H), 4.01(s,1H)394-379(m4H)364(dJ=112Hz1H)352(d,J=3.3Hz,1H),3.33(s,1H),3.31(s,3H),3. 22-3.14(m,1H),3.09-2.93(m,2H),2.71(s,2H),2.43-2.34(m,1H),2.04(s,3H),1.79(s,1H). Example 58 [ka]

[0368] Synthesis of methyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1-methyl-2,4-dioxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-d]pyrimidin-3(4H)-yl)phenyl)propanoate (58): The title compound was prepared according to the method proposed for the synthesis of 8 using the ethyl ester of intermediate R and intermediate C. MS (m / z)649.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.87(d,J=7.7Hz,1H),7.35(d,J=8.3Hz,2H),7.14-7.07(m,2H),6.69(d,J=13.5Hz,1H),6 .66(d,J=2.3Hz,1H),4.84(d,J=9.0Hz,1H),4.68(ddd,J=12.4,7.8,4.9Hz,1H),4.29(s,2H),4.15(d,J=12.6Hz,1H ),4.00-3.92(m,1H),3.88(t,J=5.6Hz,2H),3.73(d,J=12.6Hz,1H),3.66(s,3H),3.54(t,J=10.2Hz,1H),3.35(d,J =13.3Hz,2H),3.31(s,2H),3.16(dd,J=14.2,5.0Hz,1H),3.02(dd,J=14.1,10.2Hz,1H),2.71(m,2H),2.05(s,3H). Example 59 [ka]

[0369] Synthesis of (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1-methyl-2,4-dioxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-d]pyrimidin-3(4H)-yl)phenyl)propanoic acid (59): The title compound was prepared according to the method proposed for the synthesis of Example 9 starting from 58. MS (m / z) 635.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 8.0 Hz, 1H), 7.41 - 7.30 (m, 2H), 7.13 - 7.05 (m, 2H), 6.68 (dd, J = 12.9, 2.3 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H), 4.84 (dd, J = 8.9, 3.5 Hz, 1H), 4.63 (ddd, J = 12.0, 8.0, 4.4 Hz, 1H), 4.28 (d, J = 1.8 Hz, 2H), 4.14 (d, J = 12.6 Hz, 1H), 3.95 (dd, J = 11.3, 3.7 Hz, 1H), 3.88 (t, J = 5.6 Hz, 2H), 3.73 (d, J = 12.7 Hz, 1H), 3.62 - 3.49 (m, 1H), 3.31 (s, 5H), 3.18 (dd, J = 14.2, 4.3 Hz, 1H), 2.99 (dd, J = 14.2, 10.6 Hz, 1H), 2.71 (s, 1H), 2.04 (s, 3H). Example 60 [Chemical formula]

[0370] Synthesis of methyl (S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1-methyl-2,4-dioxo-1,2,4,5,6,8-hexahydro-3H-pyrano[3,4-d]pyrimidin-3-yl)phenyl)propanoate (60): The title compound was prepared following the procedure proposed for the synthesis of 8 using the ethyl ester of intermediate S and intermediate B. MS (m / z) 653.2 [M+H]+.1H NMR(400MHz,DMSO-d6)δ9.03(d,J=7.5Hz,1H),7.34(d,J=8.4Hz,2H),7.11(d,J=8.3Hz,2H),6.79( d,J=11.6Hz,2H),4.91(dt,J=12.0,6.0Hz,1H),4.68-4.56(m,3H),4.17(d,J=12.7Hz,1H),3.96(d d,J=11.4,3.8Hz,1H),3.84-3.70(m,3H),3.64(s,3H),3.61-3.51(m,1H),3.44(d,J=12.7Hz,1H), 3.26(d,J=13.2Hz,1H),3.21(s,3H),3.17(d,J=5.3Hz,1H),3.15-3.01(m,2H),2.39-2.24(m,2H). Example 61 [ka]

[0371] Synthesis of (S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1-methyl-2,4-dioxo-1,2,4,5,6,8-hexahydro-3H-pyrano[3,4-d]pyrimidin-3-yl)phenyl)propanoic acid (61): The title compound was prepared according to the method proposed for the synthesis of Example 9 starting from 60. MS (m / z) 639.2 [M+H]+. 1H NMR(400MHz,DMSO-d6)δ8.88(d,J=7.8Hz,1H),7.35(dd,J=8.5,2.0Hz,2H),7.16-7.00(m,2H),6.78( d,J=11.6Hz,2H),5.04-4.82(m,1H),4.64-4.49(m,3H),4.16(d,J=12.7Hz,1H),3.96(dd,J=11.5,3. 7Hz,1H),3.83-3.70(m,3H),3.62-3.49(m,1H),3.43(d,J=12.7Hz,1H),3.26(d,J=12.5Hz,1H),3.21 (s,3H),3.16(dd,J=14.2,4.8Hz,1H),3.02(dd,J=14.2,9.7Hz,1H),2.33(qd,J=4.3,3.0,2.4Hz,2H). Example 62 [ka]

[0372] Synthesis of methyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1-methyl-2,4-dioxo-1,2,4,5,6,8-hexahydro-3H-pyrano[3,4-d]pyrimidin-3-yl)phenyl)propanoate (62): The title compound was prepared according to the method proposed for the synthesis of 8 using the ethyl esters of intermediate S and intermediate C. MS (m / z) 671.2 [M+Na]. NMR(400MHz,DMSO-d6)δ8.87(d,J=7.7Hz,1H),7.35(d,J=8.2Hz,2H),7.10(d,J=8.2Hz,2H) ,6.70(d,J=13.5Hz,1H),6.66(s,1H),4.84(d,J=7.7Hz,1H),4.76-4.64(m,1H),4.60(s,2H) ),4.15(d,J=12.6Hz,1H),4.03-3.90(m,1H),3.86-3.70(m,3H),3.66(s,3H),3.55(t,J=10 .7Hz,1H),3.21(s,4H),3.03(dd,J=14.1,10.3Hz,1H),2.33(d,J=2.5Hz,3H),2.06(s,3H). Example 63 [ka]

[0373] Synthesis of (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1-methyl-2,4-dioxo-1,2,4,5,6,8-hexahydro-3H-pyrano[3,4-d]pyrimidin-3-yl)phenyl)propanoic acid (63): The title compound was prepared according to the method proposed for the synthesis of Example 9 starting from 62. MS (m / z) 635.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 8.0 Hz, 1H), 7.41 - 7.33 (m, 2H), 7.15 - 7.03 (m, 2H), 6.68 (dd, J = 12.9, 2.3 Hz, 1H), 6.64 (d, J = 2.3 Hz, 1H), 4.84 (dd, J = 9.0, 3.6 Hz, 1H), 4.69 - 4.56 (m, 3H), 4.14 (d, J = 12.6 Hz, 1H), 3.95 (dd, J = 11.4, 3.6 Hz, 1H), 3.79 (t, J = 5.5 Hz, 2H), 3.76 - 3.68 (m, 1H), 3.61 -3.49 (m, 1H), 3.35 (d, J = 12.3 Hz, 1H), 3.27 (d, J = 12.5 Hz, 1H), 3.21 (s, 4H), 2.99 (dd, J = 14.2, 10.6 Hz, 1H), 2.40 - 2.25 (m, 2H), 2.04 (s, 3H). Example 64 [Chemical formula]

[0374] Synthesis of (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1-methyl-2,4-dioxo-1,2,4,5,6,7-hexahydro-3H-cyclopenta[d]pyrimidin-3-yl)phenyl)propanoic acid (64): The title compound was prepared according to the method proposed for the synthesis of 1 using the ethyl ester of intermediate T and intermediate C. MS (m / z) 619.2 [M+H]+. 1H NMR(400MHz,DMSO-d6)δ8.72(d,J=8.0Hz,1H),7.35(dd,J=8.5,2.0Hz,2H),7.11-7.00(m,2H),6.68(dd,J=12. 9,2.4Hz,1H),6.64(d,J=2.4Hz,1H),4.84(dd,J=8.8,3.5Hz,1H),4.63(ddd,J=10.6,8.0,4.2Hz,1H),4.14(d, J=12.6Hz,1H),3.94(dd,J=11.4,3.6Hz,1H),3.73(d,J=12.7Hz,1H),3.54(td,J=11.7,3.5Hz,1H),3.35(d,J= 12.2Hz,1H),3.29(s,3H),3.18(dd,J=14.3,4.3Hz,1H),3.05-2.89(m,3H),2.61(t,J=7.4Hz,2H),2.04(s,3H). Example 65 [ka]

[0375] Synthesis of ethyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1-methyl-2,4-dioxo-1,2,4,5,6,7-hexahydro-3H-cyclopenta[d]pyrimidin-3-yl)phenyl)propanoate (65): To 64 (30 mg, 0.05 mmol), TPP (38 mg, 0.145 mmol), and EtOH (0.03 mL, 0.48 mmol) in DCM was added DIAD (0.05 mL, 0.24 mmol). The mixture was stirred at 6 The mixture was stirred at room temperature for 10 minutes. Upon completion, the mixture was acidified with TFA and the volatiles were removed under reduced pressure. The crude material was dissolved in DMSO and chromatographed on C-18 modified silica gel eluting with acetonitrile in water (0.4% TFA) to give compound 65. MS (m / z) 647.3 [M+H]+. 1H NMR(400MHz,DMSO-dd6)δ8.86(d,J=7.6Hz,1H),7.39-7.28(m,2H),7.12-7.01(m,2H),6.75-6.67(m,1H),6.66(d ,J=2.3Hz,1H),4.92-4.76(m,1H),4.65(ddd,J=9.9,7.6,5.2Hz,1H),4.19-4.06(m,3H),3.95(dd,J=11.4,3.7Hz, 1H),3.73(d,J=12.7Hz,1H),3.62-3.43(m,1H),3.36(d,J=12.4Hz,1H),3.29(s,4H),3.15(dd,J=14.1,5.3Hz,1H ),3.10-3.00(m,1H),2.97(q,J=7.6,6.6Hz,2H),2.61(t,J=7.5Hz,2H),2.13-1.92(m,5H),1.17(t,J=7.1Hz,3H). Example 66

[0376] Synthesis of (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1-methyl-2,4-dioxo-1,2,5,7-tetrahydrofuro[3,4-d]pyrimidin-3(4H)-yl)phenyl)propanoic acid (66): The title compound was prepared according to the method proposed for the synthesis of 1 using the ethyl ester of intermediate U and intermediate C. MS (m / z) 621.2 [M+H 1H NMR(400MHz,DMSO-d6)δ8.72(d,J=8.0Hz,1H),7.42-7.30(m,2H),7.16-7.03(m,2H),6.68(dd,J=12 .9,2.3Hz,1H),6.64(d,J=2.3Hz,1H),5.06(t,J=3.6Hz,2H),4.86(t,J=3.6Hz,3H),4.64(ddd,J=10 .7,8.0,4.2Hz,1H),4.14(d,J=12.6Hz,1H),3.94(dd,J=11.4,3.6Hz,1H),3.73(d,J=12.5Hz,1H),3 .63-3.47(m,1H),3.35(d,J=12.2Hz,1H),3.23(s,5H),2.99(dd,J=14.2,10.7Hz,1H),2.03(s,3H). [ka] Example 67 [ka]

[0377] Synthesis of ethyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-d]pyrimidin-3(4H)-yl)pyridin-3-yl)propanoate (67): The title compound was prepared according to the method proposed for the synthesis of 8 using the ethyl ester of intermediate V and intermediate C. MS (m / z) 664.0 [M+H]+. 1H NMR(400MHz,DMSO-d6)δ8.90(d,J=7.7Hz,1H),8.45(d,J=2.3Hz,1H),7.95(s,1H),7.89(dd,J=8.2,2.4Hz,1H),7 .30(dd,J=8.1,0.7Hz,1H),6.75-6.64(m,2H),4.84(dd,J=8.8,3.5Hz,1H),4.71(ddd,J=10.4,7.8,5.2Hz,1H),4 .29(s,2H),4.19-4.06(m,3H),3.99-3.84(m,3H),3.73(d,J=12.5Hz,1H),3.59-3.49(m,1H),3.31(s,4H),3.28- 3.16(m,2H),3.07(dd,J=14.3,10.3Hz,1H),2.89(s,2H),2.77-2.66(m,4H),2.06(s,3H),1.18(t,J=7.1Hz,3H). Example 68 [ka]

[0378] Synthesis of (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-d]pyrimidin-3(4H)-yl)pyridin-3-yl)propanoic acid (68): The title compound was prepared according to the method proposed for the synthesis of Example 9 starting from 67. MS (m / z) 636.3 [M+H]+. 1H NMR(400MHz,DMSO-d6)δ8.77(d,J=8.1Hz,1H),8.46(d,J=2.3Hz,1H),7.88(dd,J=8.2,2.4Hz,1H),7.33-7.26(m,1H) ,6.73-6.62(m,2H),4.84(dd,J=8.8,3.6Hz,1H),4.67(ddd,J=11.9,8.0,4.2Hz,1H),4.29(s,2H),4.14(d,J=12.6Hz ,1H),3.95(dd,J=11.4,3.6Hz,1H),3.88(d,J=11.0Hz,1H),3.73(d,J=11.8Hz,1H),3.59-3.48(m, 1H),3.35(d,J=12.3Hz,1H),3.31(s,5H),3.02(dd,J=14.3,10.9Hz,1H),2.73(s,2H),2.03(s,3H). Example 69 [ka]

[0379] Synthesis of (S)-2-(4-((S)-3-(2,2-difluoroethyl)morpholino)-2-fluoro-6-methylbenzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoic acid (69): The title compound was prepared following the procedure proposed for the synthesis of 1 using the ethyl esters of intermediate K and intermediate Q. MS (m / z) 627.1 [M+H]+.1H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.75(d,J=8.2Hz,1H),8.57(d,J=5.0Hz,1H),8.50(d,J=2.4H) z,1H),7.94(dd,J=8.3,2.4Hz,1H),7.92-7.89(m,1H),7.42(d,J=8.0Hz,1H),6.53(t,J=6.1Hz,2H ),6.36-5.96(m,1H),4.75-4.61(m,1H),4.03(m,1H),3.90(d,J=9.1Hz,1H),3.84(d,J=11.8Hz,1H ),3.61(s,3H),3.58-3.46(m,1H),3.35-3.13(m,2H),3.04(dd,J=14.4,10.9Hz,2H),2.03(s,3H). Example 70 [ka]

[0380] (S)-2-(4-((S)-3-(2,2-difluoroethyl)morpholino)-2-fluoro-6-methylbenzamido)-3-(4-(1-methyl-2,4-dioxo-1,2,5,7-tetrahydrofuro[3,4-d]pyrimidin-3(4H)-yl)phenyl (H)propanoic acid (70): The title compound was prepared according to the method proposed for the synthesis of 1 using the ethyl esters of intermediates W and Q. MS (m / z) 617.2 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 8.0 Hz, 1H), 7.42-7.30 (m, 2H), 7.16-7.04 (m, 2H), 6.61-6.44 (m, 2H), 6.16 (tt, J = 56.3, 4.5 Hz, 1H), 5.06 (t, J = 3.6 Hz, 2H), 4.86 (t, J = 3.6 Hz, 2H), 4.64 (ddd, J = 11.9, 8.1, 4.2 Hz, 1H), 4.01 (d, J = 9.3 Hz, 1H), 3.89 (d d,J=11.2,3.5Hz,1H),3.84(d,J=11.6Hz,1H),3.69-3.58(m,1H),3.52(td,J=11.6,3.1Hz,1H),3.31(d,J=12.6Hz,1H),3. 23(s,3H),3.19(dd,J=14.3,4.3Hz,1H),3.08-2.85(m,2H),2.43-2.25(m,1H),2.03(s,3H),1.75(dd,J=19.1,14.8Hz,1H). α4β7 integrin cell capture assay

[0381] The potency of inhibitors in preventing α4β7 integrin interaction with MadCAM-1 was measured by monitoring the capture of α4β7 integrin-expressing cells on recombinant MadCAM-1 extracellular domain-coated plates.

[0382] 384-well plates (Corning 3702) were coated with the MAdCAM-1 extracellular domain by dispensing 20 μL of MAdCAM-1 at 10 μg / mL per well and incubating overnight at 4° C. Plates were then washed with PBS, blocked with 3% BSA for 2 hours, and washed again.

[0383] Spin down RPMI8866 cells and collect 0.5 x 10 6The cells were resuspended in assay medium (DMEM + 0.5% FBS + 0.5 mM MnCl2) at a density of 1000 cells / mL. The cells were then dispensed (60 μL / well) into a 384-well plate (Greiner 781280) previously spotted with 60 nL of test compound per well. The plate was incubated at 37°C for 1 hour. 50 μL of cells were transferred to the blocked MACAM-1-coated plate and incubated at 37°C for 30 minutes. 10 μL of 12% glutaraldehyde containing Hoechst 33342 (0.06 mg / mL) was added to the cells (2% glutaraldehyde and 0.01 mg / mL final concentration). The plate was incubated at room temperature for 90 minutes. The plate was then washed three times with 70 μL of PBS per well and imaged on a Cellomics ArrayScan instrument. Plate-bound cells were counted and plotted against compound concentration to determine the EC 50 The results are shown in Tables 1 and 2. α4β1 cell capture assay

[0384] The efficacy of inhibitors to prevent α4β1 integrin interaction with VCAM-1 was measured by monitoring the capture of α4β1-expressing cells to recombinant VCAM-1 extracellular domain-coated plates.

[0385] 384-well plates (Corning 3702) were coated with VCAM-1 extracellular domain by dispensing 20 μL of VCAM-1 at 0.5 μg / mL per well and incubating overnight at 4° C. Plates were then washed with PBS, blocked with 3% BSA for 2 hours, and washed again.

[0386] Spin down Jurkat cells and collect 0.5 x 10 6 The cells were then resuspended in assay medium (DMEM + 0.5% FBS + 0.5 mM MnCl) at a density of 1000 cells / mL. The cells were then plated onto a 384-well plate (Gr) pre-spotted with 60 nL of test compound per well. Cells were then dispensed (60 μL / well) onto the blocked VCAM-1 coated plate (Beiner 781280). The plate was incubated at 37°C for 1 hour. 50 μL of cells were transferred to the blocked VCAM-1 coated plate and incubated at 37°C for 30 minutes. 10 μL of 12% glutaraldehyde containing Hoechst 33342 (0.06 mg / mL) was added to the cells (2% glutaraldehyde and 0.01 mg / mL Hoechst 33342 final concentration). The plate was incubated at room temperature for 90 minutes. The plate was then washed three times with 70 μL of PBS per well and imaged on a Cellomics ArrayScan instrument. The plate-bound cells were counted and plotted against compound concentration to determine the EC 50 The results are shown in Tables 1 and 2. [Table 2] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10]

Table 3-11

Table 3-12

Table 3-13

Table 3-14

Table 3-15

Table 3-16

Table 3-17

Table 3-18

Table 3-19

Table 3-20

Table 3-21

[0387] All references, including publications, patents, and patent documents, are incorporated herein by reference, as if individually incorporated by reference. The present disclosure refers to various embodiments and technologies. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the present disclosure. The description is to be considered as exemplary of the claimed subject matter, and is made with the understanding that it is not intended to limit the scope of the appended claims to the particular embodiments illustrated. Headings used throughout this disclosure are provided for convenience and should not be construed in any way to limit the scope of the claims. Embodiments shown under any heading may be combined with embodiments shown under any other heading.

[0388] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) A compound of formula (I), [ka] or a pharmaceutically acceptable salt thereof, wherein: [ka] is a single bond or a double bond, A is an aromatic ring, each Z 1 , Z 2 , Z 3 , and Z 4 are independently N, N(CR c ), C(O), and CR c Each R c are independently H, halo, cyano, hydroxyl, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, and C 1~4 haloalkoxyl; R 1 is a 5- to 10-membered heteroaryl or a 6- to 10-membered heterocyclyl, R 1each 5-10 membered heteroaryl and 6-10 membered heterocyclyl contains 1-4 N and optionally 1-3 C(O) as ring member(s); R 1 Each 5- to 10-membered heteroaryl and 6- to 10-membered heterocyclyl is selected from 1 to 4 R a and each R a are independently halo, cyano, hydroxyl, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, C 1~4 Haloalkoxyl, -C 1~4 Alkylene-OC 1~4 Alkyl, and C 3~10 cycloalkyl; Each R 2 , R 3 , R 5 , and R 6 are independently H, halo, cyano, hydroxyl, -NR a1 R a2 , C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, and C 1~4 haloalkoxyl; R 4 is 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, and —NR b1 R b2 is selected from R 4 The 3- to 10-membered heterocyclyl and the 5- to 10-membered heteroaryl may each be selected from the group consisting of 1 to 6 R b and each R b are independently halo, cyano, hydroxyl, -NR a1 R a2 , C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~8 Haloalkyl, and C 1~8 haloalkoxyl; Each R b1 and R b2 are independently H, C1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, -C 1~6 Alkylene-phenyl, and -C 1-6 haloalkylene-phenyl; R 7 is H, C 1-10 Alkyl, C 1~10 Haloalkyl, C 3~10 Cycloalkyl, 3-14 membered heterocyclyl, 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 , -C 1~4 Alkylene-C 3~10 Cycloalkyl, -C 1~4 alkylene-3 to 14-membered heterocyclyl, -C 1~4 Alkylene-C 6~10 Aryl, -C 1~4 alkylene-5 to 10-membered heteroaryl, and -L 1 -R 9 is selected from L 1 -C 1~4 Alkylene -O-, -C 1~4 Alkylene-C(O)-, -C 1~4 Alkylene-OC(O)-, -C 1~4 Alkylene-OC(O)-C 1~4 Alkylene-, -C 1~4 Alkylene-C(O)-O-, -C 1~4 Alkylene-C(O)-O -C 1~4 Alkylene-, -C 1~4 Alkylene-OC(O)-O-, -C 1~4 Alkylene-OC(O)-OC 1~4 Alkylene-, -C 1~4 Alkylene-NR a1 C(O)-O- and -C 1~4 Alkylene-OC(O)-NR a1 - selected from R9 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 3-14 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl; R 7 and R 9 Each C 3~10 Cycloalkyl, 3-14 membered heterocyclyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are independently selected from halo, hydroxyl, C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, C 1~4 Haloalkoxyl, -NR a1 R a2 , and -C 1~4 Alkylene-NR a1 R a2 optionally substituted with 1 to 4 groups selected from R 8 is H, C 1~6 Alkyl, and C 1~6 haloalkyl; Each R a1 and R a2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 3~10 cycloalkyl; or a pharmaceutically acceptable salt thereof. (Section 2) The compound is a compound of formula (II), [ka] or a pharmaceutically acceptable salt thereof. (Section 3) the compound is a compound of formula (IIa), [ka] In the formula, Y 1 is N or CH, R d But H, C1~4 Alkyl, and C 1~4 haloalkyl; 3. The compound according to item 1 or 2, wherein r is selected from 0, 1, 2, and 3, or a pharmaceutically acceptable salt thereof. (Section 4) the compound is a compound of formula (IIb), [ka] In the formula, X 1 But, CR x1 and N, X 2 But, CR x1 R x2 , N.R. x2 and O; R x1 But H and R b is selected from R x2 But H, C 1~4 Alkyl, and C 1~4 haloalkyl; R d But H, C 1~4 Alkyl, and C 1~4 haloalkyl; r is selected from 0, 1, 2, and 3; 4. The compound according to any one of items 1 to 3, wherein m is selected from 0, 1, 2, 3, and 4, or a pharmaceutically acceptable salt thereof. (Section 5) the compound is a compound of formula (IIc), [ka] In the formula, R b But C 1~4 Alkyl, or C 1~6 is haloalkyl, R d But H, C 1~4 Alkyl, and C 1~4 5. The compound according to any one of items 1 to 4 above, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from haloalkyl. (Section 6) the compound is of formula (IId), [ka] In the formula, R b But C 1~4 Alkyl, or C 1~6 is haloalkyl, R d But C 1~4 Alkyl, or C 1~4 is haloalkyl, Each R 2 and R 6 But independently, Halo, C 1~4 Alkyl, and C 1~4 6. The compound according to any one of items 1 to 5, wherein the compound is selected from haloalkyl, or a pharmaceutically acceptable salt thereof. (Section 7) Item 1. The compound according to item 1, which is a compound of formula (III) or a pharmaceutically acceptable salt thereof. [ka] (Section 8) the compound is of formula (IIIa), [ka] In the formula, X 1 But, CR x1 and N, X 2 But, CR x1 R x2 , N.R. x2 and O; R x1 But H and R b is selected from R x2 But H, C 1~4 Alkyl, and C 1~4 haloalkyl; The compound according to any one of the above items 1 to 7, wherein m is selected from 0, 1, and 2. is a pharmaceutically acceptable salt thereof. (Section 9) the compound is a compound of formula (IIIb), [ka] In the formula, R b But C 1~4 Alkyl, or C 1~6 The compound according to any one of items 1, 7 and 8, which is haloalkyl, or a pharmaceutically acceptable salt thereof. (Section 10) R 1 but, [ka] wherein R d But H, C 1~4 Alkyl, and C 1~4 haloalkyl, and each R 1 However, independently, 1 to 3 R a The compound according to any one of items 1, 2, and 7 to 9, or a pharmaceutically acceptable salt thereof, optionally substituted with (Section 11) R 1 but, [ka] where R d But C 1~4 The compound or a pharmaceutically acceptable salt thereof according to any one of items 1, 2, and 7 to 10, wherein R is alkyl. (Section 12) R 1 but [ka] 12. The compound according to any one of items 1, 2, and 7 to 11, or a pharmaceutically acceptable salt thereof, wherein: (Section 13) R 1 but, [ka] The compound according to any one of items 1, 2, and 7 to 9, selected from: (Section 14) R 1 but, [ka] The compound according to any one of items 1, 2, and 7 to 9, wherein (Section 15) Z 1 is N and Z 2 , Z 3 , and Z 4 The compound according to item 1, wherein each of is CH. (Section 16) Each R 3 and R 5 Item 16. The compound according to item 1 or 15, wherein is independently selected from H and halo, or a pharmaceutically acceptable salt thereof. (Section 17) Each R 3 and R 5 17. The compound according to any one of items 1, 15 and 16, wherein is H, or a pharmaceutically acceptable salt thereof. (Section 18) Each R 2 and R 6 But independently, H, halo, C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, and C 1~4 18. The compound according to any one of items 1 to 17, wherein the compound is selected from haloalkoxyl, or a pharmaceutically acceptable salt thereof. (Section 19) Each R 2 and R 6 are independently selected from F and -CH3, or a pharmaceutically acceptable salt thereof. (Section 20) R 2 is F and R 6 20. The compound according to any one of items 1 to 19, wherein is —CH 3 , or a pharmaceutically acceptable salt thereof. (Section 21) R 4 However, 1 to 3 R b and each R is a 6-membered heterocyclyl optionally substituted withb But independently, Halo, C 1~4 Alkyl, and C 1~4 The compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 3, 7, and 10 to 20, wherein the compound is selected from haloalkyl. (Section 22) R b 22. The compound according to any one of items 1 to 21, wherein is selected from -CH3, -CHF2, and -CF3, or a pharmaceutically acceptable salt thereof. (Section 23) R b 23. The compound according to any one of items 1 to 22, wherein is -CF3, or a pharmaceutically acceptable salt thereof. (Section 24) R 4 But R b optionally replaced with [ka] and R b 22. The compound or pharmaceutically acceptable salt thereof according to any one of items 1 to 3, 7, and 10 to 21, wherein is selected from -CH3, -CHF2, -CF3, -CH2CHF2, and -CH2CF3. (Section 25) R 4 but, [ka] 25. The compound according to any one of items 1 to 3, 7, 10 to 21, and 24, or a pharmaceutically acceptable salt thereof, wherein: (Section 26) R 4 but, [ka] 26. The compound according to any one of items 1 to 3, 7, 10 to 21, and 24 to 25, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: (Section 27) R 4 But, -NR b1 R b2 and R b1 and Rb2 However, independently, H, C 1~4 Alkyl, C 1~6 Haloalkyl, and C 3~6 Item 28: The compound or pharmaceutically acceptable salt thereof according to any one of items 1 to 3, 7, and 10 to 20, wherein the aryl group is selected from cycloalkyl. R 4 but, [ka] 28. The compound according to any one of items 1 to 3, 7, 10 to 20, and 27, or a pharmaceutically acceptable salt thereof, wherein (Section 29) X 1 is N and X 2

[0023] Item 9. The compound according to any one of items 4 and 8, wherein is O, or a pharmaceutically acceptable salt thereof. (Section 30) R c But, Halo, C 1~4 Alkyl, C 1~4 Alkoxyl, C 1~4 Haloalkyl, and C 1~4 30. The compound or a pharmaceutically acceptable salt thereof according to any one of items 7 to 12 and 14 to 29, wherein the compound is selected from haloalkoxyl. (Section 31) R c The compound or a pharmaceutically acceptable salt thereof according to any one of items 7, 8 to 12, and 14 to 30, wherein is selected from F, Cl, CH3, -OCH3, -OCF3, and -CF3. (Section 32) R 7 But H, C 1~6 Alkyl, and C 3~6 32. The compound according to any one of items 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R is selected from cycloalkyl. (Section 33) R 7 32. The compound according to any one of items 1 to 31, wherein is selected from H, methyl, ethyl, propyl, butyl, cyclopropyl, —CH2—OC(O)C(CH)3, and phenyl, or a pharmaceutically acceptable salt thereof. (Section 34) R 7 34. The compound according to any one of items 1 to 33, wherein is selected from H, methyl, ethyl, and cyclopropyl, or a pharmaceutically acceptable salt thereof. (Section 35) R 7 35. The compound according to any one of items 1 to 34, wherein is H, or a pharmaceutically acceptable salt thereof. (Section 36) R 7 35. The compound according to any one of items 1 to 34, wherein is methyl, or a pharmaceutically acceptable salt thereof. (Section 37) R 7 35. The compound according to any one of items 1 to 34, wherein is ethyl, or a pharmaceutically acceptable salt thereof. (Section 38) R 8 The compound according to the above item 1, wherein is H, or a pharmaceutically acceptable salt thereof. (Section 39) A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Examples 1 to 93. or a pharmaceutically acceptable salt thereof. (Section 40) A compound or a pharmaceutically acceptable salt thereof, wherein said compound is [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, selected from: (Section 41) A compound or a pharmaceutically acceptable salt thereof, wherein said compound is [ka] [ka] or a pharmaceutically acceptable salt thereof, selected from: (Section 42) A compound or a pharmaceutically acceptable salt thereof, wherein said compound is [ka] or a pharmaceutically acceptable salt thereof, selected from: [ka] (Section 43) A pharmaceutical composition comprising the compound according to any one of items 1 to 42 above and at least one pharmaceutically acceptable carrier. (Section 44) A method for treating a disease or condition associated with α4β7 integrin, comprising administering to a subject an effective amount of the compound according to any one of items 1 to 42, or a pharmaceutically acceptable salt thereof, or the composition according to item 43. (Section 45) 45. The method according to item 44 above, wherein the disease or condition is an inflammatory disease. (Section 46) 46. ​​The method according to any one of items 44 to 45, wherein the disease or condition is selected from inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, graft-versus-host disease (GVHD), and primary sclerosing cholangitis (PSC). (Section 47) 46. ​​The method according to any one of items 44 to 45, further comprising administering an additional therapeutic compound. (Section 48) Use of the compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 42 in the manufacture of a medicament for treating a disease or condition mediated by α4β7 integrin. (Item 49) 43. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 42 in the manufacture of a medicament for treating an inflammatory disease. (Section 50) 43. Use of the compound according to any one of items 1 to 42 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating inflammatory bowel disease (IBD).

Claims

[Claim 1] The invention described in the specification.

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