Compounds for inhibiting alpha4beta7 integrin

Abstract

The present disclosure provides a compound of formula (I): # imgabs0 #, or a pharmaceutically acceptable salt thereof, as described herein. The disclosure also provides pharmaceutical compositions comprising compounds of Formula (I), processes for preparing compounds of Formula (I), therapeutic methods for treating inflammatory diseases.

Description

[0001] This application is a divisional application of the Chinese invention patent application (application date: August 12, 2020; application number: 202080057303.0 (International application number: PCT / US2020 / 045938); invention name: Compounds for inhibiting α4β7 integrin).

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 886,798, filed on August 14, 2019, the entire contents of which are hereby incorporated by reference in their entirety. Technical Field

[0004] The present disclosure generally relates to novel compounds with α4β7 integrin inhibitory effects, prodrugs of compounds with α4β7 integrin inhibitory effects, and methods of using and making the same. Background Art

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

[0006] Integrins are heterodimeric proteins composed of α and β subunits. There are 18 known α subunits and 8 known β subunits. α4β7 integrin is expressed on the surface of lymphocytes and recognizes the extracellular ligand mucosal addressing protein cell adhesion molecule-1 (MAdCAM-1). α4β7 integrin controls lymphocyte trafficking to intestinal tissue and retention therein through its interaction with MAdCAM-1, which is expressed on the venules of the intestinal mucosa and the high endothelial venules (HEV) of the intestinal associated lymphoid tissue (GALT). Inhibition of the interaction of integrins with their corresponding ligands has been proposed as an effective method for treating a variety of autoimmune and inflammatory diseases, and blocking the α4β7-MAdCAM-1 interaction has shown therapeutic benefits in inflammatory bowel diseases (Crohn's disease and ulcerative colitis).

[0007] There is a need for improved α4β7 integrin antagonist molecules for the treatment of autoimmune and inflammatory diseases, including inflammatory bowel disease. Summary of the invention

[0008] The present disclosure provides compounds that are inhibitors of α4β7 integrin. The present disclosure also provides compositions, including pharmaceutical compositions, kits including compounds, and methods of using (or administering) and preparing compounds. The compounds provided herein can be used to treat diseases, disorders or conditions mediated by α4β7 integrin. The present disclosure also provides compounds for treatment. The present disclosure further provides compounds used in methods for treating diseases, disorders or conditions mediated by α4β7 integrin. In addition, the present disclosure provides the use of compounds in the manufacture of drugs for treating diseases, disorders or conditions mediated by α4β7 integrin.

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

[0010]

[0011] or a pharmaceutically acceptable salt thereof, wherein:

[0012] is a single bond or a double bond; wherein A is an aromatic ring;

[0013] Each Z 1 , Z 2 , Z 3 and Z 4 Independently selected from N, N(CR c ), C(O) and CR c ; where each R c are independently selected from H, halo, cyano, hydroxyl, -NR a1 R a2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 Haloalkoxy;

[0014] R 1 is a 5-10 membered heteroaryl or a 6-10 membered heterocyclic group;

[0015] Where R 1 Each of the 5-10 membered heteroaryl and 6-10 membered heterocyclyl contains one to four N and optionally one to three C(O) as ring members; and

[0016] Where R 1 Each 5-10 membered heteroaryl and 6-10 membered heterocyclyl is optionally substituted by one to four R a Replace; and wherein each R a are independently selected from halo, cyano, hydroxyl, -NR a1 R a2 , C 1-4 Alkyl, C1-4 Alkoxy, C 1-4 Haloalkyl, C 1- 4-haloalkoxy, -C 1-4 Alkylene-

[0017] OC 1-4 Alkyl and C 3-10 Cycloalkyl;

[0018] Each R 2 , R 3 , R 5 and R 6 are independently selected from H, halo, cyano, hydroxyl, -NR a1 R a2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 Haloalkoxy;

[0019] R 4 is selected from 3-10 membered heterocyclyl, 5-10 membered heteroaryl and -NR b1 R b2 ;

[0020] Where R 4 The 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted by one to six R b

[0021] Replace; and wherein each R b are independently selected from halo, cyano, hydroxyl, -NR a1 R a2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-8 Haloalkyl and C 1-8 haloalkoxy; and

[0022] Each R b1 and R b2 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, -C 1-6 Alkylene-phenyl and -C 1-6 Haloalkylene-phenyl;

[0023] R 7 Selected from H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 1-4Alkylene-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-3-14 membered heterocyclic group, -C 1-4 Alkylene-C 6-10 Aryl, -C 1-4 Alkylene-5-10 membered heteroaryl and -L 1 -R 9 ;

[0024] Where L 1 Selected from -C 1-4 Alkylene-O-, -C 1-4 Alkylene-C(O)-, -C 1-4 Alkylene-O-

[0025] C(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-O-

[0026] C(O)-OC 1-4 Alkylene-, -C 1-4 Alkylene-NR a1 C(O)-O- and -C 1-4 Alkylene-OC(O)-

[0027] NR a1 -;

[0028] R 9 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl;

[0029] Where R 7 and R 9 Each C 3-10 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally independently selected from halo, hydroxy, C 1-4 Alkyl, C1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -NR a1 R a2 and -C 1-4 Alkylene-NR a1 R a2 of one

[0030] Up to four groups substituted;

[0031] R 8 Selected from H, C 1-6 Alkyl and C 1-6 haloalkyl; and

[0032] Each R a1 and R a2 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl. DETAILED DESCRIPTION

[0033] Definition and general parameters

[0034] The following description sets forth exemplary methods, parameters, etc. However, it should be recognized that such description is not intended to limit the scope of the present disclosure, but is provided as a description of exemplary embodiments.

[0035] As used in this specification, 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.

[0036] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -CONH2 is attached through a carbon atom. A dash at the front or end of a chemical group is for convenience; a chemical group can be depicted without one or more dashes without losing its ordinary meaning. A wavy line drawn through a line in a structure indicates the point of attachment of a group.

[0037] Unless chemically or structurally required, directionality is not indicated or implied by the order in which chemical groups are written or named.

[0038] For example, the wavy lines on the chemical groups shown below, The point of attachment is indicated, ie, it shows the broken bond through which the group is connected to another described group.

[0039] The prefix "C u-v " indicates that the following group has u to v carbon atoms. For example, "C 1-8 "Alkyl" indicates that the alkyl group has 1 to 8 carbon atoms.

[0040] The "about" value or parameter mentioned herein includes (and describes) embodiments involving the value or parameter itself. In certain embodiments, the term "about" includes an indication of ±10%. In other embodiments, the term "about" includes an indication of ±5%. In certain other embodiments, the term "about" includes an indication of ±1%. Moreover, for the term "about X", a description of "X" is included. Moreover, unless the context clearly provides otherwise, the singular forms "a", "an" and "the" include plural references. Therefore, for example, reference to "compound" includes a variety of such compounds, and reference to "determination" includes reference to one or more determinations known to those skilled in the art and their equivalents.

[0041] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group has 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 Alkyl) or 1 to 4 carbon atoms (i.e. C 1-4 Alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a particular number of carbons is named by a chemical name or identified by a molecular formula, all positional isomers having that number of carbons are contemplated; 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).

[0042] "Alkylene" (including those that are part of other groups) refers to branched and unbranched divalent "alkyl" groups. As used herein, alkylene has 1 to 20 carbon atoms (i.e., C 1-20 Alkylene), 1 to 8 carbon atoms (i.e., C 1-8 Alkylene), 1 to 6 carbon atoms (i.e., C 1-6 Alkylene) or 1 to 4 carbon atoms (i.e. C 1-4 Alkylene). Examples include: methylene, ethylene, propylene, 1-methylethylene, butene, 1-methylpropylene, 1,1-dimethylethylene, or 1,2-dimethylethylene. Unless otherwise stated, the definitions propylene and butene include all possible isomeric forms of the group in question having the same carbon number. Thus, for example, propylene also includes 1-methylethylene, and butene includes 1-methylpropylene, 1,1-dimethylethylene, and 1,2-dimethylethylene.

[0043] "Alkenyl" refers to a group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl) or 2 to 4 carbon atoms (i.e. C 2-4 Examples of the alkenyl group include vinyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0044] "Alkynyl" refers to a group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C 2-20 Alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 Alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl) or 2 to 4 carbon atoms (i.e. C 2-4 The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0045] "Alkoxy" and "alkoxyl" are used interchangeably and refer to the group "alkyl-O-". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy. "Haloalkoxy" refers to an alkoxy group as defined above in which one or more hydrogen atoms are replaced by a halogen.

[0046] "Acyl" refers to a group -C(=O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which can be optionally substituted as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl and benzoyl.

[0047] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) that comprise a fused system. As used herein, an aryl group has 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 Aryl) or 6 to 10 carbon ring atoms (i.e. C 6-10 Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthracenyl. However, aryl does not encompass or overlap in any way with heteroaryl as defined below. If one or more aryl groups are fused to a heteroaryl ring, the resulting ring system is a heteroaryl.

[0048] "Azide" refers to the group -N3.

[0049] "Cyano" or "carbonitrile" refers to the group -CN.

[0050] "Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having a single ring 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, a cycloalkyl group has 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e. C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e. C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e. C 3-8 Cycloalkyl) or 3 to 6 ring carbon atoms (i.e. C 3-6 Cycloalkyl). Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl also includes 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 fully aromatic ring systems.

[0051] "Bridged" refers to ring fusions in which non-adjacent atoms on the ring are linked by a divalent substituent such as an alkylene or heteroalkylene group or a single heteroatom. Quinuclidinyl and adamantyl are examples of bridged ring systems.

[0052] The term "fused" refers to a ring that is bound to an adjacent ring.

[0053] "Halogen" or "halo" includes fluorine, chlorine, bromine and iodine.

[0054] "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more hydrogen atoms are replaced by a halogen. For example, where the residue is substituted by more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted by two ("di") or three ("tri") halo groups, which may be, but are not necessarily, identical halogens. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0055] "Haloalkylene" refers to an unbranched or branched alkylene group as defined above wherein one or more hydrogen atoms are replaced by a halogen.

[0056] 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 in the ring (i.e., at least one cyclic heteroatom selected from O, N, S, S(O), S(O)2, and N-oxide groups). Unless otherwise indicated, a heterocyclyl group has 3 to about 20 cyclic atoms, such as 3 to 12 cyclic atoms, such as 3 to 10 cyclic atoms, such as 5 to 10 cyclic atoms or such as 5 to 6 cyclic atoms. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3, 4, 5, 6, or 7-membered ring) having about 1 to 6 cyclic carbon atoms in the ring and about 1 to 3 cyclic heteroatoms independently selected from the group consisting of O, N, S, S(O), S(O)2, and nitrogen oxides. When valence requirements allow, the rings of multiple fused rings (e.g., bicyclic heterocyclic radicals) systems can be connected to each other by fusion, spiro and bridging. Heterocycles include, but are not limited to, groups derived from azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, tetrahydro-2H-thiopyran 1,1-dioxide, quinuclidine, N- bromopyrrolidine, N- chloropiperidine, etc. Heterocycles include spiro, such as aza or oxo spiroheptane. Heterocyclic radicals also include partially unsaturated ring systems containing one or more double bonds, including fused ring systems with an aromatic ring and a non-aromatic ring, but not completely aromatic ring systems. Examples include dihydroquinolines (e.g., 3,4-dihydroquinoline), dihydroisoquinolines (e.g., 1,2-dihydroisoquinoline, dihydroimidazole, tetrahydroimidazole, etc.), indolines, isoindolines, isoindolinones (e.g., isoindolin-1-one), isatins, dihydrophthalazines, quinolones, spiro[cyclopropane-1,1'-isoindolin]-3'-ones, etc. Additional examples of heterocycles include, for example, 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, 3,6-diazabicyclo[3.1.1]heptyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonyl, and hexahydropyrazino[2,1-c][1,4]oxazinyl.

[0057] "Hydroxyl" and "hydroxy" are used interchangeably and refer to -OH. "Oxo" refers to the group (=O) or (O). In cases where tautomeric forms of compounds exist, hydroxy and oxo groups are interchangeable.

[0058] "Heteroaryl" refers to an aromatic group, including a group having an aromatic tautomer or resonance structure, a monocyclic, polycyclic or polycondensed ring, having at least one heteroatom in the ring, i.e., one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the nitrogen or sulfur may be oxidized. Therefore, the term includes rings with one or more cyclic O, N, S, S(O), S(O)2 and N-oxide groups. The term includes rings with one or more cyclic C(O) groups. As used herein, heteroaryl includes 5 to 20 ring atoms (i.e., 5 to 20 heteroaryl groups), 5 to 12 ring atoms (i.e., 5 to 12 heteroaryl groups) or 5 to 10 ring atoms (i.e., 5 to 10 heteroaryl groups) and 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur, and oxidized forms of heteroatoms. Examples of heteroaryl groups include pyridin-2(1H)-one, pyridazin-3(2H)-one, pyrimidin-4(3H)-one, quinolin-2(1H)-one, pyrimidinyl, purinyl, pyridinyl, pyridazinyl, benzothiazolyl and pyrazolyl. Heteroaryl does not encompass or overlap with aryl as defined above.

[0059] "Sulfonyl" refers to the group -S(O)2R, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.

[0060] Unless otherwise indicated, whenever a graphical representation of a group terminates in a single-bonded nitrogen atom, the group represents an -NH group. Similarly, unless otherwise expressed, hydrogen atoms are implied and assumed to be present where necessary to complete valency or provide stability according to the knowledge of those skilled in the art.

[0061] 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. Furthermore, unless otherwise expressly stated, combinations of groups are referred to herein as a moiety, such as arylalkyl, the last-mentioned group comprising the atoms by which the moiety is attached to the rest of the molecule.

[0062] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. Furthermore, the term "optionally substituted" means that any one or more hydrogen atoms on the designated atom or group may or may not be replaced with a moiety other than hydrogen.

[0063] The term "substituted" means that any one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents other than hydrogen, provided that the normal valence of the specified atom is not exceeded. The one or more substituents include but are not limited to alkyl, alkenyl, alkynyl, alkoxy, acyl, amine, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halogen, haloalkyl, assorted alkyl, heteroaryl, heterocyclic radical, hydroxyl, hydrazine, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, mercaptan, thioketone or a combination thereof. The polymer or similar indefinite structure (for example, the aryl of the substituted alkyl, the alkyl itself substituted by the substituted aryl group, the substituted aryl group substituted by the substituted assorted alkyl further substituted etc.) obtained by defining the substituent with unlimited additional further substituents is not intended to be included in this article. Unless otherwise indicated, the maximum number of continuous substitutions in compounds described herein is three. For example, the continuous 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 unallowed substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups with two adjacent oxygen ring atoms). Such unallowed substitution patterns are well known to the technician. When used to modify chemical groups, the term "substituted" can describe other chemical groups defined herein. For example, the term "substituted aryl" includes but is not limited to "alkyl aryl". Unless otherwise stated, where a group is described as optionally substituted, any substituent of these groups is itself unsubstituted.

[0064] In some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, and the one or more substituents include hydroxy, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, "substituted cycloalkyl" refers to a cycloalkyl group having one or more substituents, and the one or more substituents include alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxy; "substituted heterocyclyl" refers to a heterocyclyl group having one or more substituents, and the one or more substituents include alkyl, haloalkyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxy; "substituted aryl" refers to a heterocyclyl group having one or more substituents, and the one or more substituents include alkyl, haloalkyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxy; "Substituted heteroaryl" refers to a heteroaryl group with one or more substituents, the one or more substituents including halo, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy and cyano; "substituted heteroaryl" refers to a heteroaryl group with one or more substituents, the one or more substituents including halo, alkyl, haloalkyl, heterocyclyl, heteroaryl, alkoxy and cyano, and "substituted sulfonyl" refers to the group -S(O)2R, wherein R is substituted by one or more substituents, the one or more substituents including alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. In other embodiments, the one or more substituents may be further substituted by halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted by halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is unsubstituted.

[0065] Some compounds in the compound exist in tautomer form. Tautomers are in balance with each other. For example, compounds containing amides can exist in balance with imidic acid tautomers. No matter which tautomer is shown, and no matter the nature of the balance between the tautomers, it will be understood by those of ordinary skill in the art that compounds include amides and imidic acid tautomers. Therefore, compounds containing amides are understood to include their imidic acid tautomers. Likewise, compounds containing imidic acid are understood to include their amide tautomers.

[0066] Any formula or structure given herein is also intended to represent unlabeled forms of the compound as well as isotopically labeled forms. An isotopically labeled compound has a structure depicted by a 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 may be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C.15 N. 18 F. 31 P. 32 P. 35 S. 36 Cl and 125 I. Various isotopically labeled compounds of the present disclosure, for example, wherein a radioactive isotope such as 3 H. 13 C and 14 Such isotopically labeled compounds are useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including tissue distribution assays of drugs or substrates, or in radiation therapy of patients.

[0067] The present disclosure also includes compounds of the present disclosure, wherein 1 to n hydrogens attached to carbon atoms are replaced by deuterium, wherein n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of any compound of the present disclosure when administered to mammals, particularly humans. See, 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 methods well known in the art, for example by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0068] Deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, which relate to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes (such as deuterium) may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased half-life in vivo, reduced dosage requirements and / or improved therapeutic index. 18 F-labeled compounds can be used for PET or SPECT studies. Isotope-labeled compounds of the present disclosure and their prodrugs can generally be prepared by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents to carry out the procedures disclosed in the schemes or the examples and formulations described below. It should be understood that deuterium in this context is considered a substituent in the compounds of the present disclosure.

[0069] The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen", then that position is understood to be a hydrogen having its natural abundance isotopic composition. Therefore, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0070] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of their amino and / or carboxyl groups or groups similar thereto.

[0071] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of a given compound and is not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic bases and organic bases. By way of example only, salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dienylamines, trialnylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, monocyclic alkylamines, dicyclic alkylamines or tricyclic alkylamines, monoarylamines, diarylamines or triarylamines or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0072] Pharmaceutically acceptable acid addition salts can be prepared from inorganic acids 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.

[0073] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. Supplementary active ingredients may also be incorporated into the composition.

[0074] "Treatment" or "treating" is a method for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results include one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the extent of the disease or condition); b) slowing or preventing the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the deterioration or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis of the disease or condition); and / or c) alleviating the disease, i.e., causing regression of clinical symptoms (e.g., improving the disease state, providing partial or total remission of the disease or condition, enhancing the effect of another drug, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival).

[0075] "Prevention" or "preventing" means any treatment of a disease or condition that results in the clinical symptoms of the disease or condition not developing. 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.

[0076] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation, or experiment. The methods described herein can be used for human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0077] The term "therapeutically effective amount" or "effective amount" of a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, refers to an amount sufficient to achieve treatment to provide a therapeutic benefit such as improvement of symptoms or slowing of disease progression when administered to a subject. For example, a therapeutically effective amount may be an amount sufficient to alleviate the symptoms of a disease or condition that is responsive to inhibition of α4β7 integrin activity. The 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, which can be readily determined by those skilled in the art.

[0078] The term "inhibition" indicates a decrease in the baseline activity of a biological activity or process. "Inhibition of α4β7 integrin activity" or variants thereof refers to a decrease in the activity of α4β7 integrin in response to the presence of a compound of the present application, either directly or indirectly, relative to the activity of α4β7 integrin in the absence of a compound of the present application. "Inhibition of α4β7" refers to a decrease in the activity of α4β7 integrin in response to the presence of a compound described herein, either directly or indirectly, relative to the activity of α4β7 integrin in the absence of a compound described herein. In some embodiments, the inhibition of α4β7 integrin activity can be compared in the same subject before treatment or in other subjects who have not received treatment.

[0079] Compound

[0080] Provided herein are compounds useful as inhibitors of α4β7 integrin. In one aspect, provided are compounds having a structure of formula (I), or a pharmaceutically acceptable salt thereof:

[0081]

[0082] or a pharmaceutically acceptable salt thereof, wherein:

[0083] is a single bond or a double bond; wherein A is an aromatic ring;

[0084] Each Z 1 , Z 2 , Z 3 and Z 4 Independently selected from N, N(CR c ), C(O) and CR c ; where each R c are independently selected from H, halo, cyano, hydroxyl, -NR a1 R a2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 Haloalkoxy;

[0085] R 1 is a 5-10 membered heteroaryl or a 6-10 membered heterocyclic group;

[0086] Where R 1 Each of the 5-10 membered heteroaryl and 6-10 membered heterocyclyl contains one to four N and optionally one to three C(O) as ring members; and

[0087] Where R 1 Each 5-10 membered heteroaryl and 6-10 membered heterocyclyl is optionally substituted by one to four R a Replace; and wherein each R a are independently selected from halo, cyano, hydroxyl, -NR a1 R a2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -C 1-4 Alkylene-

[0088] OC 1-4 Alkyl and C 3-10 Cycloalkyl;

[0089] Each R 2 , R 3 , R 5 and R 6 are independently selected from H, halo, cyano, hydroxyl, -NR a1 R a2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 Haloalkoxy;

[0090] R 4 is selected from 3-10 membered heterocyclyl, 5-10 membered heteroaryl and -NR b1 R b2 ;

[0091] Where R 4 The 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted by one to six R b

[0092] Replace; and wherein each R b are independently selected from halo, cyano, hydroxyl, -NR a1 R a2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-8 Haloalkyl and C 1-8 haloalkoxy; and

[0093] Each R b1 and R b2 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, -C 1-6 Alkylene-phenyl and -C 1-6 Haloalkylene-phenyl;

[0094] R 7 Selected from H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 1-4 Alkylene-NR a1 R a2 , -C 1-4 Alkylene-C(O)NR a1 R a2 , -C 1-4 Alkylene-C 3-10 Cycloalkyl, -C 1-4Alkylene-3-14 membered heterocyclic group, -C 1-4 Alkylene-C 6-10 Aryl, -C 1-4 Alkylene-5-10 membered heteroaryl and -L 1 -R 9 ;

[0095] Where L 1 Selected from -C 1-4 Alkylene-O-, -C 1-4 Alkylene-C(O)-, -C 1-4 Alkylene-O-

[0096] C(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-O-

[0097] C(O)-OC 1-4 Alkylene-, -C 1-4 Alkylene-NR a1 C(O)-O- and -C 1-4 Alkylene-OC(O)-

[0098] NR a1 -;

[0099] R 9 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl;

[0100] Where R 7 and R 9 Each C 3- 10-cycloalkyl, 3-14-membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally independently selected from halo, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -NR a1 R a2 and -C 1-4 Alkylene-NR a1 R a2 of one

[0101] Up to four groups substituted;

[0102] R 8 Selected from H, C 1-6 Alkyl and C 1-6 haloalkyl; and

[0103] Each R a1 and R a2 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl.

[0104] In another aspect, provided is a compound of formula (II), or a pharmaceutically acceptable salt thereof:

[0105]

[0106] Where R 1 , R 2 , R 4 , R 6 and R 7 As defined above in formula (I) or elsewhere in this disclosure.

[0107] In another aspect, provided is a compound of formula (IIa), or a pharmaceutically acceptable salt thereof:

[0108]

[0109] Where R 2 , R 4 , R 6 , R 7 and R a As defined above in formula (I), (II) or elsewhere in this disclosure. 1 R is N or CH. d Selected from H, C 1-4 Alkyl and C 1-4 haloalkyl; and r is selected from the group consisting of 0, 1, 2 and 3.

[0110] In another aspect, provided is a compound of formula (IIb), or a pharmaceutically acceptable salt thereof:

[0111]

[0112] Where R a , R 2 , R 6 , R 7 and R b As defined above in formula (I), (II) or elsewhere in this disclosure. 1Selected from CR x1 and N. X 2 Selected from CR x1 R x2 NR x2 and O.R. x1 Selected from H and R b ; and R x2 Selected from H, C 1-4 Alkyl and C 1-4 Haloalkyl, R d Selected from H, C 1-4 Alkyl and C 1-4 haloalkyl. r is selected from the group consisting of 0, 1, 2, and 3; and m is selected from the group consisting of 0, 1, 2, 3, and 4.

[0113] In another aspect, provided is a compound of formula (IIc), or a pharmaceutically acceptable salt thereof:

[0114]

[0115] Where R 2 , R 6 and R 7 As defined above in formula (I), (II) or elsewhere in this disclosure. b C 1-4 Alkyl or C 1-6 Haloalkyl. d Selected from H, C 1-4 Alkyl and C 1-4 Halogenated alkyl.

[0116] In another aspect, provided is a compound of formula (IId), or a pharmaceutically acceptable salt thereof:

[0117]

[0118] Where R 7 As defined above in formula (I), (II) or elsewhere in this disclosure. Each R 2 and R 6 independently selected from halogen, C 1-4 Alkyl and C 1-4 Haloalkyl. b C 1-4 Alkyl or C 1-6 Haloalkyl. d H, C 1-4 Alkyl or C 1-4 Halogenated alkyl.

[0119] In another aspect, provided is a compound of formula (III), or a pharmaceutically acceptable salt thereof:

[0120]

[0121] Where R 1 , R 2 , R 4 , R 6 , R 7 and R c As defined above in formula (I) or elsewhere in this disclosure.

[0122] In another aspect, provided is a compound of formula (IIIa), or a pharmaceutically acceptable salt thereof:

[0123]

[0124] Where R 1 , R 2 , R 6 , R 7 , R b and R c As defined above in formula (I) or elsewhere in this disclosure. 1 Selected from CR x1 and N. X 2 Selected from CR x1 R x2 NR x2 and O.R. x1 Selected from H and R b . R x2 Selected from H, C 1-4 Alkyl and C 1-4 m is selected from the group consisting of 0, 1 and 2.

[0125] In another aspect, provided is a compound of formula (IIIb), or a pharmaceutically acceptable salt thereof:

[0126]

[0127] Where R 1 , R 2 , R 6 , R 7 and R c As defined above in formula (I) or elsewhere in this disclosure. 7 . R b C 1-4 Alkyl or C 1-6 Halogenated alkyl.

[0128] In another aspect, provided is a compound of formula (IV), or a pharmaceutically acceptable salt thereof:

[0129]

[0130] Where R 1 , R 2, R 4 , R 6 , R 7 and R c As defined above in formula (I) or elsewhere in this disclosure.

[0131] In some embodiments of Formula (I), (II), (III), (IIIa) or (IIIb), R 1 is selected from the group consisting of pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolyl, isoquinolyl, isoxazolyl, triazolyl, pyrazolyl, benzothiazolyl, pyridyl, quinolyl, isoquinolyl, quinazolinyl, dinonyl, pyrazinyl, pyrimidinyl, dinonyl pyrimidinyl, pyridazinyl and quinazolinyl. Each R 1 Optionally, one to four R a replace.

[0132] In some embodiments of Formula (I), (II), (III), (IIIa) or (IIIb), R 1 Selected from:

[0133]

[0134] Each R 1 Optionally, one to three R a In some embodiments, R 1 Selected from: Each R 1 Optionally, one to three R a In some embodiments, each R a independently selected from halo, CN, -OH, NR a1 R a2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 In some embodiments, each R a Independently selected from F, Cl, OH, CN, -NH2, -N(CH3)2, -CH3, -CH2F, -CHF2, -CF3, -OCH3 and -OCF3.

[0135] In some embodiments of Formula (I), (II), (III), (IIIa) or (IIIb), R 1 for

[0136]

[0137] And R d C 1-4In some embodiments, R d In some embodiments, R d In some embodiments, R 1 for

[0138] In some embodiments of Formula (I), (II), (III), (IIIa) or (IIIb), R 1 is optionally replaced by one to three R a Replaced In some embodiments, R 1 Selected from In some embodiments, R 1 for

[0139] In some embodiments of Formula (I), (II), (III), (IIIa) or (IIIb), R 1 is a 10-membered heterocyclic group containing two N and two C(O) as ring members and R 1 Optionally one to three R a In some embodiments, each R a is independently selected from F, Cl, OH, CN, -NH2, -N(CH3)2, -CH3, -CH2F, -CHF2, -CF3, -OCH3, and -OCF3. In some embodiments, R 1 Selected from Each of them is optionally replaced by one to three R a In some embodiments, R d is -CH3. In some embodiments, R 1 for In some embodiments, R 1 for

[0140] In some embodiments of Formula (I), (II), (III), (IIIa) or (IIIb), R 1 for

[0141] In some embodiments of Formula (I), (II), (III), (IIIa) or (IIIb), R 1 for In some embodiments, R d is -CH3. In some embodiments, R 1 for

[0142] In some embodiments of formula (I), Z 1 N. Z 2 , Z 3 and Z 4 CR c In some embodiments, Z 1 is 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 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 CR c ; and R c Selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 In some embodiments, Z 1 CR c And R c is selected from -CH3, -OCH3 and -CF3. In some embodiments, Z 1 It is C-OCH3.

[0143] In some embodiments of Formula (I), each R 3 and R 5 is independently selected from H and halo. 3 and R 5 For H.

[0144] In some embodiments of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (III), (IIIa), or (IIIb), each R 2 and R 6 are independently selected from H, halo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 In some embodiments, each R 2 and R 6 is independently selected from F and -CH3. 2 is F and R 6It is -CH3.

[0145] In some embodiments of Formula (I), (II), (IIa) or (III), R 4 is optionally replaced by one to three R b In some embodiments, R 4 The 3-8 membered heterocyclyl contains one to two heteroatoms or groups independently selected from S, N, O and S(O)2. b are independently selected from halo, hydroxy, cyano, -NR a1 R a2 , C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 In some embodiments, each R b Independently selected from F, Cl, CN, -OH, -CH3, -CH(CH3)2, -CF3 and -CH2CF3.

[0146] In some embodiments of Formula (I), (II), (IIa) or (III), R 4 is optionally replaced by one to three R b In some embodiments, R 4 Selected from and each of them is optionally replaced by one to three R b In some embodiments, each R b independently selected from halogen, C 1-4 Alkyl and C 1-4 In some embodiments, R 4 is optionally R b Replaced And R b is selected from -CH3, -CHF2, -CF3 and -CH2CF3. 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 Selected from In some embodiments, R 4 for In some embodiments, R 4 for In some embodiments, R 4 for In some embodiments, R 4 for

[0147] In some embodiments of Formula (I), (II), (IIa) or (III), R 4 for In some embodiments,

[0148] In some embodiments of Formula (I), (II), (IIa) or (III), R 4 For-NR b1 R b2 In some embodiments, each R b1 and R b2 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 In some embodiments, R b1 H and R b2 C 1-6 In some embodiments, R 4 for

[0149]

[0150] In some embodiments, R 4 for

[0151] In some embodiments of Formula (I), (II), (IIa) or (III), R 4 is optionally replaced by one to three R b substituted 5-10 membered heteroaryl; and each R b independently selected from halogen, C 1-4 Alkyl and C 1-4 In some embodiments, R 4 is optionally replaced by one to three R b In some embodiments, R 4 is optionally replaced by one to three R b In some embodiments, R 4 is optionally replaced by one to three R b In some embodiments, each R b is independently selected from -CH3, -CHF2, -CF3 and -CH2CF3. 4 for In some embodiments, R 4 for In some embodiments, R bSelected from -CH3, -CHF2, -CF3 and -CH2CF3.

[0152] In some embodiments of Formula (IIb) or (IIIa), X 1 For 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 CR x1 R x2 , R x1 Selected from H and C 1-4 Alkyl and R x2 is H. In some embodiments, X 2 It is -CH2-.

[0153] In some embodiments of Formula (III), (IIIa) or (IIIb), R c Selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 In some embodiments, R c is selected from the group consisting of F, Cl, CH3, -OCH3, -OCF3 and -CF3. c It is -OCH3.

[0154] In some embodiments of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (III), (IIIa), or (IIIb), R 7 Selected from H, C 1-6 Alkyl and C 3-6 In some embodiments, R 7 Selected from H, C 1-6 Alkyl and C 3-6 Cycloalkyl. 7 is selected from the group consisting of H, methyl, ethyl, propyl, butyl, cyclopropyl, -CH2-OC(O)C(CH)3 and phenyl. 7 is selected from H, methyl, ethyl, propyl and cyclopropyl. 7is selected from the group consisting of H, methyl, ethyl, propyl, butyl, -CH2C(O)N(CH3)2, -(CH2)2N(CH2CH3)2, -CH2-OC(O)CH3, -(CH2)2-OC(O)CH3, -CH2-OC(O)C(CH)3, -(CH2)2-OC(O)C(CH)3, -CH2-OC(O)-O-CH3, -CH(CH3)-OC(O)-O-CH3, -CH2-OC(O)-O-CH2CH3, -CH2-OC(O)-O-CH(CH3)2, -CH2-OC(O)-OC(CH3)3, and -(CH2)2C(O)CH3. In some embodiments, R 7 is H. In some embodiments, R 7 In some embodiments, R 7 In some embodiments, R 7 In some embodiments, R 7 It is phenyl.

[0155] In some embodiments of formula (I), R 8 For H.

[0156] In some embodiments, the compound of the present disclosure is selected from Examples 1-53.

[0157] In some embodiments, the compound of the present disclosure is selected from Examples 54-93.

[0158] Also provided are compounds described herein or pharmaceutically acceptable salts, isomers or mixtures thereof, wherein 1 to n hydrogen atoms attached to a carbon atom may be substituted by deuterium atoms or D, wherein 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 can increase resistance to metabolism and are therefore useful for increasing the half-life of compounds described herein or pharmaceutically acceptable salts, isomers or mixtures thereof when administered to mammals. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., 5(12): 524-527(1984). Such compounds are synthesized by methods well known in the art, for example, by using a starting material in which one or more hydrogen atoms have been replaced by deuterium.

[0159] In some embodiments, the compounds of the present disclosure contain one to six deuterium ( 2 H or D). In some embodiments, R 2 , R 3 , R 4, R 5 and R 6 In some embodiments, R 6 Contains one to six D. In some embodiments, R 6 It is CD3.

[0160] Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other substances that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. In addition, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. In contrast, if the product is a free base, an addition salt, specifically a pharmaceutically acceptable addition salt, 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 the base compound. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts.

[0161] "Solvates" are formed by the interaction of a solvent and a compound. Also provided are solvates of the salts of the compounds described herein. Also provided are hydrates of the compounds described herein.

[0162] A "prodrug" is a biologically active derivative of a drug that, when administered to the human body, is converted according to some chemical or enzymatic pathway into the biologically active parent drug.

[0163] In certain embodiments, there is provided an optical isomer, racemate or other mixture of a compound described herein or its pharmaceutically acceptable salt or mixture thereof. In these cases, a single enantiomer or diastereomer, i.e., an optically active form, can be obtained by asymmetric synthesis or by the resolution of a racemate. For example, the resolution of a racemate can be achieved by conventional methods, such as crystallization in the presence of a resolving agent, or using, for example, a chromatogram of a chiral high pressure liquid chromatography (HPLC) column. In addition, there is also provided Z- and E- forms (or cis and trans forms) of compounds described herein. Specifically, Z- and E- forms are included, even if only one name is specified for two carbon-carbon double bonds.

[0164] When chirality is not specified but is present, it is understood that the embodiment is directed to the particular diastereomer or enantiomerically enriched form; or a racemic or non-racemic mixture of such a compound.

[0165] "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 "non-racemic" mixture.

[0166] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.

[0167] "Atropisomers" are stereoisomers that arise due to hindered rotation about a single bond, where the barrier to rotation about the bond is sufficiently high to allow separation of the individual stereoisomers. Atropisomers of the compounds described herein are provided.

[0168] Compositions provided herein including compounds described herein or their pharmaceutically acceptable salts, isomers or mixtures thereof may include racemic mixtures or mixtures containing an enantiomeric excess of one enantiomer or a single diastereomer or a mixture of diastereomers. All such isomeric forms of these compounds are expressly included herein, as if each and every isomeric form were specifically and individually listed.

[0169] In certain embodiments, chelates, non-covalent complexes, and mixtures thereof of the compounds described herein or pharmaceutically acceptable salts, isomers, or mixtures thereof are also provided. "Chelates" are formed by the coordination of a compound to a metal ion at two (or more) points. "Non-covalent complexes" are formed by the interaction of a compound and another molecule, wherein no covalent bond is formed between the compound and the molecule. For example, complexation can be carried out by van der Waals interactions, hydrogen bonding, and electrostatic interactions (also referred to as ionic bonding).

[0170] Therapeutic uses of compounds

[0171] The methods described herein can be applied to cell populations in vivo or in vitro. "In vivo" means in a living individual, such as in an animal or a human. In this context, the methods described herein can be used for the treatment of 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 can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and biopsies thereof. In this context, the present invention can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the present invention can be used in vitro to determine the optimal administration schedule and / or administration dose of an α4β7 integrin inhibitor for a given indication, cell type, individual, and other parameters. The information collected from such use can be used for experimental purposes or in the clinic for the formulation of an in vivo treatment regimen. 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. The selected compound can be further characterized as a safety or tolerable dose for checking a human or non-human subject. Such properties can be checked using methods generally known to those skilled in the art.

[0172] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, or deuterated analogs thereof, can be used to treat subjects suffering from or suspected of having disease states, disorders, and conditions (also collectively referred to as "indications") that are responsive or believed to be responsive to inhibition of α4β7 integrin activity. In some embodiments, the compounds described herein can be used to inhibit the activity of α4β7 integrin. In some embodiments, the compounds described herein can be used to inhibit excessive or destructive immune responses, or the growth or proliferation of cells such as cancer cells, or to inhibit immunosuppression.

[0173] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, or deuterated analogs thereof, can be used to treat subjects suffering from or suspected of having disease states, disorders, and conditions (also collectively referred to as "indications") that are responsive or believed to be responsive to inhibition of α4β7 integrin activity. In some embodiments, the compounds described herein can be used to inhibit the activity of α4β7 integrin. In some embodiments, the compounds described herein can be used to inhibit excessive or destructive immune responses, or the growth or proliferation of cells such as cancer cells, or to inhibit immunosuppression.

[0174] method

[0175] In some embodiments, the present disclosure provides compounds described herein for use as inhibitors of α4β7 integrin. In some embodiments, the present disclosure provides a method of treating an inflammatory disease or disorder comprising administering a compound described herein.

[0176] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier.

[0177] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described herein and at least one additional therapeutic agent and at least one pharmaceutically acceptable excipient.

[0178] The present disclosure provides compounds described herein for use in therapy.

[0179] In another embodiment, the disclosure provides a compound as described herein for use in the manufacture of a medicament for treating a disease or condition provided herein.

[0180] In some embodiments, a compound as described herein is provided for use in treating a disease or condition suitable for treatment by inhibiting α4β7 integrin in a patient. Diseases or conditions that can be treated with the compounds as described herein include solid tumors, diabetes, inflammatory diseases, graft-versus-host disease, primary sclerosing cholangitis, HIV, autoimmune diseases, inflammatory bowel disease (IBD), alcoholic hepatitis, hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), systemic lupus erythematosus (SLE) and lupus nephritis.

[0181] In some embodiments, provided are compounds described herein for use in treating an inflammatory disease or condition mediated at least in part by α4β7 integrin in a patient.

[0182] "Administering" or "administration" refers to the delivery of one or more therapeutic agents to a patient. In some embodiments, administration is a monotherapy, in which the compound described herein is the only active ingredient administered to a patient in need of therapy. In another embodiment, administration is co-administration, such that two or more therapeutic agents are delivered together during treatment. In some embodiments, two or more therapeutic agents may be co-formulated into a single dosage form or "combination dosage unit," or formulated separately and then combined into a combination dosage unit, such as a single or double-layer tablet or capsule typically used for intravenous or oral administration.

[0183] In some embodiments, the compounds described herein are administered to human patients in need 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.

[0184] In some embodiments, the compounds described herein and at least one additional therapeutic agent are administered to a human patient in need thereof in an effective amount of each agent, independently from about 0.1 mg to about 1000 mg of the compound per dose or formulation per compound per dose. In some embodiments, the effective amount of the combination therapy of the compounds described herein and the additional compounds is independently from about 0.1 mg to about 200 mg per compound per dose. In some embodiments, the effective amount of the combination therapy of the compounds described herein and the additional compounds is independently from about 1 mg to about 100 mg per compound per dose. In other embodiments, the effective amount of the combination therapy of the compounds described herein and the additional compounds is, for each component, each 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.

[0185] In some embodiments, the dose of the compound described herein and / or the combination of the dose of the compound described herein and / or the dose of the additional therapeutic agent is administered once a day, twice a day, or three times a day. In another embodiment, the dose of the compound described herein and / or the dose of the additional therapeutic agent is administered as a loading dose of about 0.1 mg to about 1000 mg / compound on the first day and every day or on alternating days or weekly for up to one month, followed by a conventional regimen of the compound described herein and / or one or more additional therapeutic agents or therapies. For each component of the multi-component drug regimen, the maintenance dose can be about 0.1 mg to about 1000 mg, once a day, twice a day, three times a day, or once a week. A qualified caregiver or treating physician knows what dosage regimen is best for a particular patient or a particular existing condition, and will make an appropriate treatment regimen decision for the patient. Therefore, in another embodiment, a qualified caregiver is able to customize the dosage regimen of the compound described herein and / or the additional therapeutic agent as disclosed herein to suit the specific needs of the patient. It should be understood, therefore, that the actual dose of the compounds described herein and the dose of the additional therapeutic agent administered will generally be determined by a physician based on the relevant circumstances, including the condition to be treated, the route of administration chosen, the actual compound (e.g., salt or free base) administered and its relative activity, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0186] Co-administration may also include administration of component drugs, such as one or more compounds described herein and one or more additional (e.g., second, third, fourth, or fifth) therapeutic agents. Depending on the pharmacokinetic and / or pharmacodynamic properties of each agent or combination, such combinations of one or more compounds described herein and one or more additional therapeutic agents may be administered simultaneously or sequentially (one after another) within a reasonable time period (e.g., about 1 minute to 24 hours) for each administration. Co-administration may also involve treatment with a fixed combination, in which the agents of the treatment regimen may be combined in a fixed dose or a combined dosage medium (e.g., solid, liquid, or aerosol). In some embodiments, a kit may be used to administer a drug or a drug component.

[0187] Therefore, some embodiments of the present disclosure are methods of treating a disease or condition mediated at least in part by α4β7 integrin, the method comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds described herein and a formulation of one or more additional therapeutic agents, for example, via a kit. It should be understood that a qualified caregiver will administer or direct the administration of a therapeutically effective amount of any of the compounds or combinations of compounds disclosed herein.

[0188] "Intravenous administration" is the administration of substances directly into a vein or "intravenously". Compared with other administration routes, the intravenous (IV) route is a faster way to deliver fluids and drugs to the whole body. An infusion pump allows precise control of the flow rate and total amount of drug delivered. However, in cases where changes in flow rate will not have serious consequences, or if a pump is not available, the drip is usually simply made to flow by placing the bag above the patient's level and using a clamp to adjust the rate. Alternatively, if the patient requires a high flow rate and the IV access device has a large enough diameter to accommodate it, a rapid infusion device can be used. This is an inflatable cuff placed around the fluid bag to force fluid into the patient or a similar electrical device that can also heat the infused fluid. When the patient only needs the drug at certain times, intermittent infusion is used, which does not require additional fluid. It can use the same technology as intravenous drip (pump or gravity drip), but after the full dose of the drug has been given, the tube is disconnected from the IV access device. Some drugs are also given by IV push or bolus, which means that a syringe is connected to the IV access device and the drug is injected directly (slowly if the drug may irritate the vein or cause too fast an effect). Once the drug has been injected into the fluid stream of the IV tube, there must be some device to ensure that it reaches the patient from the tube. Usually, this is achieved by allowing the fluid stream to flow normally and thereby carry the drug into the bloodstream; however, sometimes a second fluid injection is used after the injection, as a "flush", to push the drug into the bloodstream more quickly. Therefore, in some embodiments, the compounds or combinations of compounds described herein can be administered by IV administration alone or in combination with certain components of the treatment regimen administered by oral or parenteral routes.

[0189] "Oral administration" is a route of administration in which a substance is taken up through the mouth, and includes buccal, sublabial, and sublingual administration, as well as parenteral administration, and through the respiratory tract, unless performed through, for example, a tube, so that the drug does not come into direct contact with any oral mucosa. Typical forms of oral administration of therapeutic agents include the use of tablets or capsules. Thus, in some embodiments, the compounds or combinations of compounds described herein can be administered by the oral route alone or in combination with certain components of a therapeutic regimen administered by IV or parenteral routes.

[0190] Pharmaceutical preparations

[0191] The compounds described herein can be administered in a pharmaceutical formulation.The present disclosure contemplates pharmaceutical formulations / compositions comprising, in addition to a carrier, a compound described herein or a combination of compounds described herein, optionally in combination with an additional therapeutic agent.

[0192] The pharmaceutical preparations / compositions contemplated by the present disclosure may also be intended to be administered by injection, and include aqueous solutions, oil suspensions, emulsions (with sesame oil, corn oil, cottonseed oil or peanut oil) and elixirs, mannitol, dextrose or sterile aqueous solutions and similar pharmaceutical vehicles. Aqueous solutions in saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols, etc. (and suitable mixtures thereof), cyclodextrin derivatives and vegetable oils may also be used. Suitable fluidity may be maintained, for example, by using a coating (such as lecithin), by maintaining the desired particle size in the case of a dispersion, and by using a surfactant. The action of microorganisms may be prevented by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.).

[0193] Sterile injectable solutions are prepared by mixing the required amounts of the component compounds in a suitable solvent together with various other ingredients as enumerated above or as required, followed by filtration sterilization. Generally speaking, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and the required other ingredients from those enumerated above. For sterile powders for preparing sterile injectable solutions, preferred preparation methods are vacuum drying and freeze drying techniques, which produce powders of the active ingredient plus any additional desired ingredients from previously sterile filtered solutions.

[0194] In preparing a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, optionally in combination with an additional agent / therapy for this purpose, the active ingredient is typically diluted with an excipient or carrier and / or encapsulated or mixed with such a carrier, which may be in the form of a capsule, sachet, paper or other container. When an excipient is used as a diluent, it may be a solid, semisolid or liquid material (as above) that acts as a solvent, carrier or medium for the active ingredient. Thus, the composition may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), ointment containing, for example, up to 20% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

[0195] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methylcellulose. The formulation may additionally contain: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; sweeteners; and flavoring agents.

[0196] The compositions of the present disclosure can be formulated so as to provide rapid, sustained or delayed release of the active ingredient after administration to a patient by procedures known in the art. In some embodiments, sustained release formulations are used. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations.

[0197] Certain compositions are preferably formulated in unit dosage form. The term "unit dosage form" or "combined dosage unit" refers to a physically discrete unit suitable as a single dose for human subjects and other mammals, each unit containing a predetermined amount of one or more of the active substances (e.g., a compound described herein, optionally combined with an additional therapeutic agent calculated to produce the desired effect, such as in association with a suitable pharmaceutical excipient in a tablet, capsule, ampoule or vial for injection). However, it should be understood that the amount of each active agent actually administered will be determined by the physician based on relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound administered and its relative activity, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0198] To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogenous mixture of a compound of the present disclosure. When these preformulation compositions are referred to as homogenous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0199] The tablets or pills of the present disclosure comprising the compounds described herein optionally in combination with a second agent may be coated or otherwise compounded to provide a dosage form with the advantage of prolonged action or to protect from the acidic conditions of the stomach. For example, the tablet or pill may comprise an internal dosage element and an external dosage element, the latter being in the form of a coating on the former. In some embodiments, the internal dosage element may comprise a compound as described herein, and the external dosage element may comprise a second or additional therapeutic agent, and vice versa. Alternatively, the combined dosage unit may be a side-by-side configuration as in a capsule or tablet, wherein a portion or half of the tablet or capsule is filled with a formulation of a compound as described herein, and another portion or half of the tablet or capsule comprises an additional therapeutic agent.

[0200] A variety of materials can 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. Those of ordinary skill in the art are aware of the techniques and materials used to make dosage forms of the formulations disclosed herein.

[0201] "Sustained release formulations" or "extended release formulations" are formulations designed to slowly release therapeutic agents into the body over an extended period of time, while "immediate release formulations" are formulations designed to rapidly release therapeutic agents into the body over a shortened period of time. In some cases, immediate release formulations may be coated so that the therapeutic agent is released only once it reaches the desired target (e.g., stomach) in the body. Those of ordinary skill in the art are able to develop sustained release formulations of compounds disclosed herein without excessive experimentation. Therefore, in some embodiments, the compounds described herein or combinations of compounds may be delivered alone by sustained release formulations, or delivered in combination with certain components of a therapeutic regimen administered orally, IV, or parenterally.

[0202] Lyophilized formulations can also be used to administer the compounds described herein, alone or in combination with additional therapeutic agents. One skilled in the art knows how to make and use lyophilized formulations of drug substances suitable for lyophilization.

[0203] Spray-dried formulations can also be used to administer the compounds described herein alone or in combination with additional therapeutic agents. Those skilled in the art know how to 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.

[0204] The compounds disclosed herein can be used to treat diseases or conditions mediated at least in part by α4β7 integrin. Non-limiting examples of diseases or conditions mediated at least in part by α4β7 integrin include, but are not limited to, acne, acid-induced lung injury, Addison's disease, adrenal hyperplasia, adrenocortical insufficiency, adult-onset Still's disease, adult respiratory distress syndrome (ARDS), age-related macular degeneration, aging, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopulmonary, allergic conjunctivitis, allergic contact dermatitis, allergy, allergic encephalomyelitis, allergic neuritis, allograft rejection, alopecia, alopecia areata, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, angina, angioedema, angiofibroma, anhidrotic ectodermal dysplasia, anti-glomerular basement membrane disease, disease, antigen-antibody complex-mediated disease, ankylosing spondylitis, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, ascites, aspergillosis, asthma, atherosclerosis, atherosclerotic plaques, atopic dermatitis, atrophic thyroiditis, autoimmune diseases, autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria), autoimmune polyendocrine disease, autoimmune thrombocytopenia (idiopathic purpuric thrombocytopenia, immune purpuric thrombocytopenia), autoimmune hepatitis, autoimmune thyroid disorders, autoinflammatory diseases, back pain, anthrax infection, Bechet's disease, inflammation caused by bee stings, Behcet's syndrome, Bell's Paralysis, beryllium poisoning, Blau syndrome, bone pain, bronchiolitis, bullous pemphigoid (BP) asthma, burns, bursitis, cardiomegaly, carpal tunnel syndrome, Castleman disease, catabolism disorders, cataracts, celiac disease, cerebral aneurysm, inflammation caused by chemical irritants, chorioretinitis, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, chronic heart failure, chronic lung disease of prematurity, chronic obstructive pulmonary disease (COPD), chronic pancreatitis, chronic prostatitis, chronic recurrent multifocal osteomyelitis, scarring alopecia, colitis, complex regional pain syndrome, complications of organ transplantation, conjunctivitis, connective tissue disease, contact dermatitis, cornea Graft neovascularization, corneal ulcer, Crohn's disease, cold pyrin-associated periodic syndrome, cutaneous lupus erythematosus (CLE), cryptococcosis, cystic fibrosis, interleukin-1 receptor antagonist (DIRA) deficiency, dermatitis, dermatitis endotoxemia, dermatomyositis, diabetic macular edema, diverticulitis, eczema, encephalitis, endometriosis, endotoxemia, eosinophilic pneumonia, epicondylitis, epidermolysis bullosa, erythema multiforme, erythroblastosis, esophagitis, familial amyloid 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, glomerulonephritis, gluten-sensitive enteropathy, gout, gouty arthritis, graft-versus-host disease (GVHD), granulomatous hepatitis, Graves' disease, growth plate injury, Guillain-Barré syndrome, intestinal disorders, hair loss, Hashimoto's thyroiditis, head injury, headache, hearing loss, heart disease, hemangioma, hemolytic anemia, hemophilic joints, Henoch-Schonlein purpura, hepatitis, hepatic steatosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hereditary periodic fever syndromes, hereditary disorders of connective tissue, herpes zoster and simplex, hidradenitis suppurativa (HS), hip replacement, Hodgkin's disease, Huntington's disease, hyaline membrane disease, excessive inflammatory response, hyperammonemia, hypercalcemia hyperlipidemia, hypercholesterolemia, hypereosinophilic syndrome (HES), hyperimmunoglobulinemia D with recurrent fever (HIDS), allergic pneumonitis, hypertrophic bone formation, dysplasia and other anemias, dysplastic 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), incontinence pigmenti (IP, Bloch-Siemens syndrome), infectious mononucleosis, infectious diseases including viral diseases such as AIDS (HIV infection), hepatitis A, hepatitis B, hepatitis C, hepatitis D Hepatitis and hepatitis E, herpes; inflammation, CNS inflammation, inflammatory bowel disease (IBD), lower respiratory tract inflammation including bronchitis or chronic obstructive pulmonary disease, upper respiratory tract inflammation including nasal and sinusitis such as rhinitis or sinusitis, respiratory tract inflammatory diseases, inflammatory ischemic events such as stroke or cardiac arrest, inflammatory lung disease, inflammatory myopathy such as myocarditis, inflammatory liver disease, inflammatory neuropathy, inflammatory pain, inflammation caused by insect bites, interstitial cystitis, interstitial lung disease, iritis, inflammation caused by irritants, ischemia / reperfusion, joint replacement, juvenile arthritis, juvenile rheumatoid arthritis, keratitis, renal damage caused by parasitic infections, renal transplant rejection, leptospirosis, leukocyte adhesion defects, lichen sclerosus (LS), Lambert-Eat on myasthenic syndrome, Loeffler syndrome, lupus, lupus nephritis, Lyme disease, Marfan syndrome (MFS), mast cell activation syndrome, mastocytosis, meningitis, meningioma, mesothelioma, mixed connective tissue disease, Muckle-Wells syndrome (urticaria deafness amyloidosis), mucositis, multiple organ injury syndrome, multiple sclerosis, muscular atrophy, muscular dystrophy, myasthenia gravis (MG), myelodysplastic syndrome, myocarditis, myositis, sinusitis, necrotizing enterocolitis, neonatal multisystem inflammatory disease (NOMID), neovascular glaucoma, nephrotic syndrome, neuritis, neuropathic diseases, non-allergen-induced asthma, obesity, eye allergies, optic neuritis,Transplant rejection, Osier-Weber syndrome, osteoarthritis, osteogenesis imperfecta, osteonecrosis, osteoporosis, osteoarthritis, otitis, congenital pachyonychia, Paget's disease, Paget's disease of bone, pancreatitis, Parkinson's disease, pediatric rheumatism, pelvic inflammatory disease, pemphigus, pemphigus vulgaris (PV), bullous pemphigoid (BP), pericarditis, periodic fever, periodontitis, peritoneal endometriosis, pernicious anemia (Addison's disease), whooping cough, PFAPA (periodic febrile aphthous pharyngitis and cervical adenopathy), pharyngitis and adenitis (PFAPA syndrome), inflammation caused by plant irritants, Pneumocystis infection, pneumonia, localized pneumonia, inflammation caused by poison ivy / urushiol oil, nodular Polyarthritis, Polychondritis, Polycystic kidney disease, Polymyalgia rheumatica, Giant cell arteritis, Polymyositis, Pouchitis, Reperfusion injury and transplant rejection, Primary biliary cirrhosis, Primary pulmonary hypertension, Primary sclerosing cholangitis (PSC), Proctitis, Psoriasis, Psoriasis vulgaris, Psoriatic arthritis, Psoriasis epidermidis, Psychological stress disorders, Lung diseases, Pulmonary fibrosis, Pyoderma gangrenosum, Pyogenic granuloma retrolenticular fibroplasia, Septic sterile arthritis, Raynaud's syndrome, Reiter's disease, Reactive arthritis, Kidney diseases, Kidney transplant rejection, Reperfusion injury, Respiratory distress syndrome, Retinal diseases, Retrolenticular fibroplasia, Raynaud's syndrome, Rheumatism Heart disease, rheumatic diseases, rheumatic fever, rheumatoid arthritis, rhinitis, rhinitis psoriasis, rosacea, sarcoidosis, Schnitzler syndrome, scleritis, sclerosis, scleroderma, scoliosis, seborrhea, sepsis, septic shock, severe pain, Sézary syndrome, sickle cell anemia, silica-induced diseases (silicosis), Sjögren's syndrome, skin diseases, skin irritation, rash, skin allergies (contact dermatitis or allergic contact dermatitis), sleep apnea, spinal cord injury, spinal stenosis, spondyloarthropathies, sports injuries, sprains and strains, Stevens-Johnson syndrome (SJS), stroke, subarachnoid hemorrhage, sunburn, synovitis, systemic inflammation Symptomatic response syndrome (SIRS), systemic lupus erythematosus, systemic mastocytosis (SMCD), systemic vasculitis, systemic juvenile idiopathic arthritis, temporal arteritis, tendinitis, tenosynovitis, thrombocytopenia, thyroiditis, thyroiditis, tissue transplantation, toxoplasmosis, trachoma, transplant rejection, traumatic brain injury, tubulointerstitial nephritis, tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), type 1 diabetes, type 2 diabetes, complications of type 1 or type 2 diabetes, ulcerative colitis, urticaria, uterine fibroids, uveitis, uveitis, vascular restenosis, vasculitis, vasculitis (NHLBI), vitiligo, Wegener's granulomatosis, and Whipple's disease.

[0205] In other embodiments, methods for alleviating the symptoms of a disease or disorder mediated at least in part by α4β7 integrin are provided. In some embodiments, these methods include identifying a mammal suffering from a disease or disorder mediated at least in part by α4β7 integrin, and providing the mammal with an amount of a compound as described herein, effective to improve (i.e., reduce) the severity of the symptoms.

[0206] In some embodiments, the disease or disorder mediated at least in part by α4β7 integrin is an inflammatory disease or LPS-induced endotoxin shock. In some embodiments, the disease is an autoimmune disease. In a specific embodiment, 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, monoarticular arthritis, osteoarthritis, gouty arthritis, juvenile arthritis, juvenile rheumatoid arthritis, juvenile rheumatoid arthritis or psoriatic arthritis. In other embodiments, the disease is inflammation. In 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.

[0207] 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 lesions 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 with the currently disclosed compounds, compositions and methods include shunt colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autistic enterocolitis, indeterminate colitis, Behcet's disease, gastroduodenal CD, jejunoileitis, ileitis, ileocolitis, Crohn's (granulomatous) colitis, irritable bowel syndrome, mucositis, radiation enteritis, short bowel syndrome, celiac disease, gastric ulcer, diverticulitis, pouchitis, proctitis and chronic diarrhea.

[0208] Treatment or prevention of IBD also includes improving or reducing one or more symptoms of IBD.As used herein, term "symptom of 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.Many such symptoms need to be quantitatively analyzed (for example, weight loss, fever, anemia, etc.).Some symptoms are easy to determine from blood tests (such as anemia) or tests for the presence of (such as rectal bleeding) in blood.Term "wherein said symptoms reduce" refers to the qualitative or quantitative reduction of detectable symptoms, including but not limited to the detectable impact on the recovery rate (such as weight gain rate) from the disease.Diagnosis is usually determined by the endoscopic observation of mucosa and the pathological examination of endoscopic biopsy samples.

[0209] The course of IBD varies and is usually associated with intervals of disease remission and disease exacerbation. The various methods for characterizing the disease activity and severity of IBD and the response to the treatment of the subject suffering from IBD have been described. Treatment according to the inventive method is generally applicable to the subject suffering from the IBD of any level or disease activity degree.

[0210] In some embodiments, diseases or conditions treated by administering a compound of the composition described herein include acute gout and ankylosing spondylitis, allergic disorders, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis and multiple sclerosis, atherosclerosis, bacterial infections, bone cancer pain and pain caused by endometriosis, BRAF-resistant melanoma, brain stem glioma or pituitary adenoma, burns, bursitis, anal cancer, endocrine system cancer, kidney cancer or ureteral cancer (e.g. renal cell carcinoma and renal pelvis cancer), penile cancer, small intestine cancer, thyroid cancer, urethral cancer, blood cancers such as acute myeloid leukemia, tongue cancer, cervical cancer, endometrial cancer, fallopian tube cancer, renal pelvis cancer, vaginal cancer or vulvar cancer, chronic myeloid leukemia, chronic or acute leukemia, chronic pain, classic Bartter syndrome, common cold conjunctivitis, coronary heart disease, skin or intraocular melanoma, dermatitis, dysmenorrhea, eczema, endometriosis, familial adenomatous polyposis, fibromyalgia, fungal Infection, gout, gynecological tumors, uterine sarcoma, fallopian tube cancer, headache, hemophilic arthropathy, Parkinson's disease, AIDS, herpes zoster, Hodgkin's disease, Huntington's disease, hyperprostaglandin E syndrome, influenza, iritis, juvenile arthritis, juvenile rheumatoid arthritis, juvenile rheumatoid arthritis, back and neck pain, lymphocytic lymphoma, myofascial disorders, myositis, neuralgia, neurodegenerative disorders such as Alzheimer's disease, neuritis, neuropathic pain, vulvar cancer, Parkinson's disease, pediatric malignancies, pulmonary fibrosis, colorectal cancer, rhinitis, sarcoidosis, soft tissue sarcoma, scleritis, skin cancer, solid tumors in children, spinal axis tumors, sprains and strains, gastric cancer, stroke, subacute and chronic musculoskeletal pain syndromes such as bursitis, surgical or dental procedures, symptoms associated with influenza or other viral infections, synovitis, toothache, ulcers, uterine cancer, uterine sarcoma, uveitis, vasculitis, viral infections, viral infections (e.g., influenza), and wound healing.

[0211] Criteria that can be used to assess disease activity in subjects with ulcerative colitis can be found, for example, in Truelove et al., (1955) Br Med J 2: 1041-1048. Using these criteria, disease activity can be characterized in subjects with IBD as mild disease activity or severe disease activity. Subjects who do not meet all criteria for severe disease activity and exceed the criteria for mild disease activity are classified as having moderate disease activity.

[0212] The currently disclosed therapeutic methods are also applicable to any point in the disease process. In some embodiments, these methods are applied to the subject with IBD during the time period of relief (i.e., inactive disease). In such embodiments, the inventive method provides benefits by extending the relief time period (e.g., extending the time period of inactive disease) or by preventing, reducing or delaying the onset of active disease. In other embodiments, the method can be applied to the subject with IBD during active disease. Such methods provide benefits by reducing the duration of active disease, reducing or improving one or more symptoms of IBD or treating IBD.

[0213] Measures for determining the therapeutic efficacy of IBD in clinical practice have been described, and include, for example, the following: symptom control; fistula closure; the extent of need for corticosteroid therapy; and improvement in quality of life. The inflammatory bowel disease questionnaire (IBDQ) can be used to assess health-related quality of life (HRQL), which is widely used in clinical practice to assess the quality of life of IBD subjects. (See Guyatt et al. (1989) Gastroenterology 96: 804-810.) In some embodiments, the disease or disorder is immune-mediated liver damage, disease or disorder.

[0214] 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 occurring in subjects with chronic and active alcohol abuse. (See Akriviadis E. et al., Ann Gastroenterol. 2016 Apr-Jun; 29 (2): 236-237). Alcoholic hepatitis may lead to cirrhosis and liver cell 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 independent treatments or in combination with current treatments for alcoholic hepatitis.

[0215] In some embodiments, the disease or disorder mediated at least in part by α4β7 integrin is fatty liver disease. In some embodiments, the disease is hepatic steatosis, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The compounds herein can be used as independent treatments or in combination with current treatments for fatty liver disease.

[0216] In one aspect, the present disclosure provides a method of treating or preventing human immunodeficiency virus (HIV) infection in a subject in need thereof, the method 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.

[0217] In some embodiments, the disease or condition mediated at least in part by α4β7 integrin is systemic lupus erythematosus (SLE), lupus nephritis, lupus-related or other autoimmune disorders, or a symptom of SLE. Symptoms of systemic lupus erythematosus include joint pain, joint swelling, arthritis, fatigue, hair loss, mouth ulcers, swollen lymph nodes, sensitivity to sunlight, rash, headache, numbness, tingling, seizures, vision problems, personality changes, abdominal pain, nausea, vomiting, abnormal heart rhythm, coughing up blood and difficulty breathing, patchy skin color, and Raynaud's phenomenon.

[0218] Combination therapy

[0219] Also provided are methods of treatment in which a compound described herein is administered to a patient in combination with one or more additional active agents or therapies.

[0220] Thus, in some embodiments, a method of treating a disease or condition at least partially mediated by α4β7 integrin and / or a disease or condition that coexists with, is aggravated or triggered by, a disease or condition at least partially mediated by α4β7 integrin (e.g., allergic disorders and / or autoimmune and / or inflammatory diseases and / or acute inflammatory reactions) comprises administering to a patient in need thereof an effective amount of a compound described herein, optionally in combination with an additional agent (e.g., a second, third, fourth, or fifth active agent), which can be used to treat a disease or condition at least partially mediated by α4β7, an allergic disorder associated with or coexisting with a disease or condition at least partially mediated by α4β7 integrin and / or an autoimmune and / or inflammatory disease and / or acute inflammatory reaction. Treatment with a second, third, fourth, or fifth active agent may be performed before, simultaneously with, or after treatment with a compound described herein. In some embodiments, a compound described herein is combined with another active agent in a single dosage form. Suitable therapeutic agents that can be used in combination with the compounds described herein include, but are not limited to, the therapeutic agents provided herein, or a combination comprising at least one therapeutic agent provided herein.

[0221] The present invention includes methods of treatment in which the compounds described herein are administered in combination with agents for treating inflammatory diseases or conditions. Examples of agents for treating 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; antifungal agents; ASK1 inhibitors; ATPase inhibitors; beta adrenergic receptor antagonists; BTK inhibitors; calcineurin inhibitors; carbohydrate metabolism regulators; cathepsin S inhibitors; CCR9 chemokine antagonists; CD233 modulators; CD29 modulators; CD3 antagonists; CD40 ligand inhibitors; CD40 ligand receptor antagonists; chemokine CXC ligand inhibitors; CHST15 gene inhibitors; collagen modulators; CSF-1 antagonists; CX3CR1 chemokine modulators; ecobiotics; eotaxin ligand inhibitors; EP4 prostaglandin receptor agonists; F1F0 ATP synthase modulators; farnesoid X receptor agonists; fecal microbiota transplantation (FMT); fractalkine ligand inhibitors; free fatty acid receptor 2 antagonists; GATA 3 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; Lactoferrin stimulators; LanC-like protein 2 modulators; Leukocyte elastase inhibitors; Leukocyte proteinase-3 inhibitors; MAdCAM inhibitors; Melanin-concentrating hormone (MCH-1) antagonists; Melanocortin agonists; Metalloproteinase-9 inhibitors; Microbiome-targeted therapies; Natriuretic peptide receptor C agonists; Neuregulin-4 ligands; NLPR3 inhibitors; NKG2 D-activated NK receptor antagonists; NR1H4 receptor (FXR) agonists or modulators; Nuclear factor κB inhibitors; Opioid receptor antagonists; OX40 ligand inhibitors; Oxidoreductase inhibitors; P2X7 purinergic receptor modulators; PDE4 inhibitors; Pellino homolog 1 inhibitors;PPARα / β agonist; PPARγ agonist; protein fimH inhibitor; P-selectin glycoprotein ligand-1 inhibitor; Ret tyrosine kinase receptor inhibitor; RIP-1 kinase inhibitor; RIP-2 kinase inhibitor; RNA polymerase inhibitor; sphingosine 1 phosphatase 1 stimulator; sphingosine-1 phosphate receptor-1 agonist; sphingosine-1 phosphate receptor-5 agonist; sphingosine-1 phosphate receptor-1 antagonist; sphingosine-1 phosphate receptor-1 modulator; stem cell antigen-1 inhibitor; superoxide dismutase enzyme 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; capsaicin VR1 agonists; and zonulin inhibitors, and combinations thereof. ;

[0222] Adenosine A3 receptor antagonists include PBF-677.

[0223] Adrenomedullin ligands include adrenomedullin.

[0224] Antibiotics include ciprofloxacin, metronidazole, vancomycin, and rifaximin.

[0225] ASK1 inhibitors include GS-4997.

[0226] Alpha-fetoprotein modulators include ACT-101.

[0227] Anti-CD28 inhibitors including JNJ-3133

[0228] Beta-adrenergic receptor antagonists include NM-001.

[0229] BTK inhibitors include GS-4059.

[0230] Calcineurin inhibitors: These include tacrolimus and cyclosporine.

[0231] Carbohydrate metabolism modulators include ASD-003.

[0232] Cathepsin S inhibitors include VBY-129.

[0233] CCR9 chemokine antagonists include CCX-507.

[0234] CD233 modulators include GSK-2831781.

[0235] CD29 modulators include PF-06687234.

[0236] CD3 antagonists include NI-0401.

[0237] CD4 antagonists include IT-1208.

[0238] CD40 ligand inhibitors include SAR-441344 and letolizumab.

[0239] CD40 gene inhibitors include NJA-730.

[0240] CD40 ligand receptor antagonists include FFP-104 and BI-655064.

[0241] Chemokine CXC ligand inhibitors include LY-3041658.

[0242] CHST15 gene inhibitors include STNM-01.

[0243] Collagen modulators include ECCS-50 (DCCT-10).

[0244] COT protein kinase inhibitors include GS-4875.

[0245] CSF-1 antagonists include JNJ-40346527 (PRV-6527) and SNDX-6352.

[0246] CX3CR1 chemokine modulators include E-6130.

[0247] Ecobiological agents include SER-287.

[0248] Eotaxin ligand inhibitors include bertilimumab.

[0249] EP4 prostaglandin receptor agonists include KAG-308.

[0250] F1F0 ATP synthase modulators include LYC-30937EC.

[0251] Fractalkine ligand inhibitors include E-6011.

[0252] Free fatty acid receptor 2 antagonists including GLPG-0974

[0253] GATA 3 transcription factor inhibitors include SB-012.

[0254] Glucagon-like peptide 2 agonists include teduglutide.

[0255] Glucocorticoid agonists include budesonide, beclomethasone dipropionate, and dexamethasone sodium phosphate.

[0256] Glucocorticoid receptor modulators / TNF ligand inhibitors include ABBV-3373.

[0257] Guanylate cyclase receptor agonists include dukanatide.

[0258] HIF prolyl hydroxylase inhibitors include DS-1093 and AKB-4924.

[0259] HIF prolyl hydroxylase-2 inhibitors / hypoxia inducible factor-1 stimulators include GB-004.

[0260] Histone deacetylase inhibitors include givinostat.

[0261] Histone deacetylase-6 inhibitors include CKD-506.

[0262] HLA class II antigen modulators include HLA class II protein modulators.

[0263] ICAM1 gene inhibitors include alicaforsen.

[0264] IL-12 antagonists include ustekinumab (IL12 / IL23).

[0265] IL-13 antagonists include tralokinumab.

[0266] IL-18 antagonists include GSK-1070806

[0267] IL-22 agonists include RG-7880.

[0268] IL-23 antagonists include tirazumab, risankizumab (BI-655066), migizizumab (LY-3074828), brevitzumab (AMG-139), and PTG-200.

[0269] IL-23A inhibitors include guselkumab.

[0270] IL-6 antagonists include olokizumab.

[0271] IL-7 receptor antagonists include OSE-127.

[0272] IL-8 receptor antagonists include clotrimazole.

[0273] Integrin alpha-4 / beta-1 antagonists include natalizumab.

[0274] Integrin α-4 / β-7 antagonists include etrolizumab (α4β7 / aEb7), vedolizumab, carotegast methyl, TRK-170 (α4β7 / α4β1), PN-10943, and PTG-100.

[0275] Integrin antagonists include E-6007.

[0276] Interleukin ligand inhibitors include bimekizumab (IL-17A / IL-17F).

[0277] Interleukin receptor 17A antagonists include brodalumab.

[0278] Interleukin-1β ligands include K(D)PT.

[0279] Interleukin 1-like receptor 2 inhibitors include BI-655130.

[0280] IL-6 receptor modulators include olamkicept.

[0281] JAK tyrosine kinase inhibitors include tofacitinib (1 / 3), peftinib (1 / 3), TD-3504, TD-1473. Jak1 tyrosine kinase inhibitors include compounds disclosed in WO2008 / 109943. Examples of other JAK inhibitors include, but are not limited to, AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110, lestaurtinib, momelotinib (CYT0387), NS-018, pactinib ( pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly known as tasocitinib citrate), XL019, upadacitinib (ABT-494), filgotinib, GLPG-0555, SHR-0302, and PF-06700841 (JAK1 / Tyk2).

[0282] Jak3 tyrosine kinase inhibitors include PF-06651600.

[0283] Lactoferrin stimulators include recombinant human lactoferrin (VEN-100).

[0284] LanC-like protein 2 modulators include BT-11.

[0285] Leukocyte elastase inhibitors / leukocyte proteinase-3 inhibitors include tiprelestat.

[0286] MAdCAM inhibitors include SHP-647 (PF-547659).

[0287] Melanin concentrating hormone (MCH-1) antagonists include CSTI-100.

[0288] Melanocortin agonists include ASP-3291 and PL-8177.

[0289] Metalloproteinase-9 inhibitors include GS-5745.

[0290] Natriuretic peptide receptor C agonists include plecanatide.

[0291] Neuregulin-4 ligands include NRG-4.

[0292] NKG2 D-activated NK receptor antagonists include JNJ-4500.

[0293] NLPR3 inhibitors include dapansutrile, BMS-986299, SB-414, MCC-950, IFM-514, JT-194, PELA-167, and NBC-6.

[0294] NR1H4 receptor (FXR) agonists or modulators include tropifexor and GS-9674.

[0295] Nuclear factor κB inhibitors include Thetanix.

[0296] Opioid receptor antagonists include naltrexone and IRT-103.

[0297] OX40 ligand inhibitors include KHK-4083.

[0298] Oxidoreductase inhibitors include olsalazine.

[0299] Pellino homolog 1 inhibitors include BBT-401.

[0300] P2X7 purinergic receptor modulators include SGM-1019.

[0301] PDE 4 inhibitors include apremilast.

[0302] PPAR alpha / beta agonists include elafibranor (GFT-1007).

[0303] PPARγ agonists include GED-0507-34-Levo.

[0304] Protein fimH inhibitors include EB-8018.

[0305] P-selectin glycoprotein ligand-1 inhibitors include SEL-K2, AbGn-168h, and neihulizumab.

[0306] Ret tyrosine kinase receptor inhibitors include GSK-3179106.

[0307] RIP-1 kinase inhibitors include GSK-2982772.

[0308] RIP-2 kinase inhibitors include GSK-2983559.

[0309] Sphingosine 1 phosphatase 1 stimulators include etrasimod.

[0310] Sphingosine-1-phosphate receptor-1 agonists include mocravimod (KRP-203) and BMS-986166.

[0311] Sphingosine-1-phosphate receptor-1 agonists / sphingosine-1-phosphate receptor-5 agonists include ozanimod.

[0312] Sphingosine-1-phosphate receptor-1 antagonists include amifatimod (MT-1303).

[0313] Sphingosine-1-phosphate receptor-1 modulators include OPL-002.

[0314] Stem Cell Antigen-1 inhibitors include Ampion (DMI-9523).

[0315] Superoxide dismutase modulators include midismase.

[0316] Syk inhibitors include GS-9876.

[0317] TLR-3 antagonists include PRV-300.

[0318] TLR-4 antagonists include JKB-122.

[0319] 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.

[0320] TLR-9 agonists include cobitolimod, IMO-2055, IMO-2125, lefitolimod, litenimod, MGN-1601, and PUL-042.

[0321] TNFα ligand inhibitors include adalimumab, certolizumab pegol, infliximab, golimumab, DLX-105, Debio-0512, HMPL-004, CYT-020-TNFQb, Hemay-007, and V-565.

[0322] TNF antagonists include AVX-470, tulinercept, and etanercept.

[0323] TPL-2 inhibitors include GS-4875.

[0324] Tumor necrosis factor 14 ligand modulators include AEVI-002.

[0325] Tumor necrosis factor 15 ligand inhibitors include PF-06480605.

[0326] Tyk2 tyrosine kinase inhibitors include PF-06826647 and BMS-986165.

[0327] Type I IL-1 receptor antagonists include anakinra.

[0328] Zonulin inhibitors include larazotide acetate.

[0329] Included herein are methods of treatment in which the compounds described herein are administered in combination with an anti-inflammatory agent. Anti-inflammatory agents include, but are not limited to, NSAIDs, nonspecific and COX-2 specific cyclooxygenase inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptor antagonists, immunosuppressants, and methotrexate.

[0330] Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, a combination of diclofenac sodium and misoprostol, sulindac, oxapromazine, 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., with an IC of 1.0 higher than that of COX-1). 50 At least 50 times lower IC 50 Compounds that inhibit COX-2) such as celecoxib, valdecoxib, lumiracoxib, etoricoxib and / or rofecoxib.

[0331] In another embodiment, the anti-inflammatory agent is a salicylate. Salicylates include but are not limited to acetylsalicylic acid or aspirin, sodium salicylate and choline and magnesium salicylate.

[0332] 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.

[0333] In some embodiments, the anti-inflammatory therapeutic is a gold compound, such as gold sodium thiomalate or auranofin.

[0334] 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.

[0335] In some embodiments, the anti-inflammatory compound is an anti-C5 monoclonal antibody (such as eculizumab or pexelizumab), a TNF antagonist such as etanercept or infliximab, which is an anti-TNFα monoclonal antibody.

[0336] 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.

[0337] Included herein are methods of treatment in which the compounds described herein are administered in combination with a class of agents for treating IBD. Examples of classes of agents for treating IBD that can be used in combination with the compounds described herein include ASK1 inhibitors, beta adrenergic receptor antagonists, BTK inhibitors, beta-glucuronidase inhibitors, bradykinin receptor modulators, calcineurin inhibitors, calcium channel inhibitors, cathepsin S inhibitors, CCR3 chemokine antagonists, CD40 ligand receptor antagonists, chemokine CXC ligand inhibitors, CHST15 gene inhibitors, collagen regulators, CSF-1 antagonists, cyclooxygenase inhibitors, cytochrome P4503A4 inhibitors, eotaxin ligand inhibitors, EP4 prostaglandin receptor agonists, fractalkine ligand inhibitors, free fatty acid receptor 2 antagonists, GATA 3 transcription factor inhibitors, glucagon-like peptide 2 agonists, glucocorticoid agonists, guanylate cyclase receptor agonists, histone deacetylase inhibitors, HLA Class II antigen modulators, IL-12 antagonists, IL-13 antagonists, IL-23 antagonists, IL-6 antagonists, IL-6 receptor modulators, interleukin-7 receptor modulators, IL-7 antagonists, IL-8 antagonists, integrin α-4 / β-1 antagonists, integrin α-4 / β-7 antagonists, integrin α-E antagonists, integrin antagonists, integrin β-7 antagonists, interleukin ligand inhibitors, interleukin receptor 17A antagonists, interleukin-1β ligands, interleukin-1β ligand modulators, IRAK4 inhibitors, JAK tyrosine kinase inhibitors, Jak1 tyrosine kinase inhibitors, Jak3 tyrosine kinase inhibitors, LanC-like protein 2 modulators, lipoxygenase modulators, MAdCAM inhibitors, matrix metalloproteinase inhibitors, melanocortin agonists, metalloproteinase-9 inhibitors, natriuretic peptide receptor C agonists, neuregulin-4 ligands, NKG2 D activated NK receptor antagonist, opioid receptor antagonist, opioid receptor delta antagonist, oxidoreductase inhibitor, P2X7 purinergic receptor agonist, PDE4 inhibitors, phagocytosis stimulating peptide modulators, potassium channel inhibitors, PPARα agonists, PPARδ agonists, PPARγ agonists, protein fimH inhibitors, P-selectin glycoprotein ligand-1 inhibitors, RNA polymerase inhibitors, sphingosine 1 phosphatase 1 stimulators, sphingosine 1 phosphatase modulators, sphingosine-1-phosphate receptor-1 agonists, sphingosine-1-phosphate receptor-1-antagonists, sphingosine-1-phosphate receptor-1-modulators, sphingosine-1-phosphate receptor-5-modulators, STAT3 gene inhibitors, stem cell antigen 1 inhibitors, superoxide dismutase modulators, superoxide dismutase stimulators, SYK inhibitors, TGFβ1 ligand inhibitors, thymosin agonists, TLR antagonists, TLR agonists, TNFα ligand inhibitors, TNF antagonists, tumor necrosis factor 14 ligand modulators, type II TNF receptor modulators, Tpl 2 inhibitors and zonulin inhibitors.

[0338] Included herein are methods of treatment in which the compounds described herein are administered in combination with an agent for treating IBD. Examples of agents for treating IBD that can be used in combination with the compounds described herein or pharmaceutically acceptable salts, mixtures of stereoisomers, tautomers, or deuterated analogs thereof include those provided herein for treating inflammatory diseases or conditions, as well as ABX-464, adalimumab; alicaforsen, ALLO-ASC-CD, AMG-966, anakinra, apremilast; Alequel; AMG-139; amimud, ASD-003, ASP-3291, AX-1505, B BT-401, balsalazide; beclomethasone dipropionate; BI-655130, BMS-986184; budesonide; CEQ-508; certolizumab; Clostridium butyricum; ChAdOx2-HAV, dexamethasone sodium phosphate, DNVX-078, etanercept; ETX-201, golimumab; GS-4997, GS-9876, GS-4875, GS-4059, infliximab; mesalamine, HLD-400, LYC-30937EC; IONIS-JBI1-2.5Rx, JNJ-64304500, JNJ-4447, naltrexone; natalizumab; nehulizumab, olsalazine; PH-46-A, propionyl-L-carnitine; PTG-100; remestemcel-L; tacrolimus; teduglutide; tofacitinib; ASP-1002; ustekinumab; vedolizumab; AVX-470; INN-108; SGM-1019; PF-06480605; PF-06651600; PF-06687234; RBX-8225, SER-287; Thetanix; TOP-1288; VBY-129; 99mTc-annexin V-128; bacitrazumab; DLX-105; dukanatide; E-6011; F FP-104; filgotinib; forrecitumab; GED-0507-34-Levo; givista; GLPG-0974; iberogast; JNJ-40346527; K(D)PT; KAG-308; KHK-4083; KRP-203; larazotide acetate; LY-3074828, midismase; olozumab; OvaSave; P-28-GST; PF-547659; prednisolone; QBECO; RBX-2660, JKB-122; SB-012; STNM-01; Debio-0512; TRK-170; zhukasaixin; ABT-494; Ampion; BI-655066; carotegast methyl; cobimetidine; elafibranor; edrelizumab; GS-5745; HMPL-004; LP-02, ozanimod; peftinib; RHB-104; rifaximin; tirazumab; trorocitumab; brodalumab; laquinimod; plecanatide; vidofludimus; and AZD-058.

[0339] Included herein are methods of treatment in which the compounds described herein are administered in combination with an agent for treating graft-versus-host disease. Examples of agents for treating graft-versus-host disease that can be used in combination with the compounds described herein include those provided herein for treating inflammatory diseases or conditions, as well as [18F]F-AraG, AM-01, AAT-IV, Allocetra, AMG-592, arsenic trioxide, ATIR-101, basiliximab, belatacept, belimumab, bortezomib, brentuximab, and vedotin. vedotin), brimonidine, brimonidine tartrate, CE-1145, cyclosporine, clazakizumab, CSL-964, CYP-001, defibrotide, dilanubicel, 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-Gua rd, TOP-1288, TZ-101, voclosporin; CCR5 chemokine antagonist: PRO-140; CD40 ligand receptor antagonist: iscalimab; complement C1s subcomponent inhibitors: sutimlimab, Cinryze, BIVV-009; B lymphocyte antigen CD20 inhibitor: obinutuzumab; CASP9 gene stimulator: Revocel; CD3 antagonist or CD7 inhibitor: T-Guard;Complement factor C5a inhibitor: olendalizumab; dipeptidyl peptidase IV inhibitor: begelomab; JAK1 / 2 tyrosine kinase inhibitor: ruxolitinib; Jak1 tyrosine kinase inhibitor: itatinib; interleukin-2 ligand: aldesleukin; interleukin-22 ligand: F-652; IL-2 receptor α subunit inhibitor: inolimomab; IL-6 receptor agonist: PLX- 1; IL-6 receptor antagonist: clazakizumab; OX40 ligand inhibitor: KY-1005; examples of such OX40 inhibitors are compounds disclosed in US8,450,460, the entire contents of which are incorporated herein by reference; signal transducer CD24 regulator: CD24-IgFc; somatostatin receptor agonist: anti-thymocyte immunoglobulin (Thymoglobulin); and sphingosine-1 phosphate receptor-1 agonist: ponesimod. ;

[0340] Included herein are methods of treatment in which the compounds described herein are administered in combination with agents 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 those 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.

[0341] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of: combination drugs for HIV, other drugs used to treat 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 reversal agents, compounds targeting HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene regulators, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, TAT protein inhibitors, HIV-1 Nef regulators, Hck tyrosine kinase regulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor regulators, COMM domain-containing protein 1 regulators, HIV ribonuclease H inhibitors, defensin regulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or pharmaceutically acceptable salts of any of the foregoing substances or any combination thereof.

[0342] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of HIV protease inhibiting 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 used to treat HIV, or pharmaceutically acceptable salts of any of the foregoing substances, or any combination thereof.

[0343] In some embodiments, the one or more additional therapeutic agents are immunomodulators, such as immunostimulants or immunosuppressants. In certain other embodiments, immunomodulators are agents that can change immune checkpoint functions including CTLA-4, LAG-3, B7-H3, B7-H4, Tim3, BTLA, KIR, A2aR, CD200 and / or PD-1 pathways. In other embodiments, immunomodulators are immune checkpoint regulators. Exemplary immune checkpoint regulators include anti-CTLA-4 antibodies (e.g., Ipilimumab), anti-LAG-3 antibodies, anti-B7-H3 antibodies, anti-B7-H4 antibodies, anti-Tim3 antibodies, anti-BTLA antibodies, anti-KIR antibodies, anti-A2aR antibodies, anti-CD200 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CD28 antibodies, anti-CD80 or anti-CD86 antibodies, anti-B7RP1 antibodies, anti-B7-H3 antibodies, anti-HVEM antibodies, anti-CD137 or anti-CD137L antibodies, anti-OX40 or anti-OX40L antibodies, anti-CD40 or anti-CD40L antibodies, anti-GAL9 antibodies, anti-IL-10 antibodies and A2aR drugs. For some of these immune pathway gene products, it is envisioned to use antagonists or agonists of such gene products, such as small molecule regulators of such gene products. In some embodiments, immunomodulators include those agents that can change the function of cytokine-mediated signal transduction pathway mediators.

[0344] In some embodiments, a compound disclosed herein (e.g., a compound described herein) can be combined with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents at any dose of the compound described herein (e.g., 10 mg to 1000 mg of the compound).

[0345] The compounds described herein may be combined with the agents provided herein at any dosage of the compound (eg, 50 mg to 500 mg of the compound), as if each combination of dosages were specifically and individually listed.

[0346] In some embodiments, a kit comprising a pharmaceutical composition and at least one pharmaceutically acceptable carrier is provided, the pharmaceutical composition comprising a compound as described herein or a compound as described herein and at least one additional therapeutic agent or a pharmaceutically acceptable salt thereof. In some embodiments, a kit is provided, which comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, a stereoisomer, a mixture of stereoisomers, a tautomer or a deuterated analogue and one or more (e.g., one, two, three, four, one or two, one to three or one to four) combinations of additional therapeutic agents. Any pharmaceutical composition provided in the present disclosure can be used in a kit, as each composition is specifically and individually listed for use in a kit. In some embodiments, the kit includes instructions for treating inflammatory diseases or illnesses. In some embodiments, the instructions in the kit relate to the use of a pharmaceutical composition for treating IBD.

[0347] List of abbreviations and acronyms

[0348] Abbreviation meaning

[0349] % Percent

[0350] ℃ Celsius

[0351] Ac Acetyl

[0352] AcOH Acetic acid

[0353] ACN / CH3CN / MeCN Acetonitrile

[0354] ADME absorption, distribution, metabolism and excretion

[0355] AIBN 2,2'-Azobis(2-methylpropionitrile)

[0356] Aq. Aqueous

[0357] ASK apoptosis signal-regulating kinase

[0358] Bicarb

[0359] Bn Benzyl

[0360] BOC / Boc tert-butyloxycarbonyl

[0361] Bpin Borane Pinacol

[0362] br Width

[0363] CAS Chemical Abstracts Service

[0364] CNS Central Nervous System

[0365] COPD Chronic Obstructive Pulmonary Disease

[0366] CREST Calcification, Raynaud's syndrome, esophagus

[0367] CVP Cyclophosphamide, vincristine, prednisone

[0368] d Twin Peaks

[0369] D / d Deuterium

[0370] DAST Diethylaminosulfur trifluoride

[0371] 1,4-Diazabicyclo[2.2.2]octane

[0372] DCC N,N'-Dicyclohexylcarbodiimide

[0373] DCE Dichloroethane

[0374] DCM Dichloromethane / Dichloromethane

[0375] dd double doublet

[0376] DIEA N,N-Diisopropylethylamine

[0377] DMA N,N-Dimethylacetamide

[0378] DMAP 4-dimethylaminopyridine

[0379] DME Dimethoxyethane

[0380] DMF Dimethylformamide

[0381] DMPK Drug Metabolism and Pharmacokinetics

[0382] DMSO Dimethyl sulfoxide

[0383] DPPA Diphenylphosphorylazide

[0384] EC 50 Half maximum effective concentration

[0385] equiv / eq equivalent

[0386] EA Ethyl acetate

[0387] Et2O Ether

[0388] EtOAc / AcOEt Ethyl acetate

[0389] EtOH

[0390] F Fahrenheit

[0391] FBS Fetal Bovine Serum

[0392] g

[0393] Gp glycoprotein

[0394] h / hr hour

[0395] HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- hex hexane

[0396] HPLC High Pressure Liquid Chromatography

[0397] Hz Hertz

[0398] IL interleukin

[0399] IUPAC International Union of Pure and Applied Chemistry J Coupling constant (MHz)

[0400] JAK Janus kinase

[0401] Kg / kg kilogram

[0402] L Liter

[0403] LCMS / LC-MS Liquid chromatography-mass spectrometry

[0404] LHMDS Lithium Hexamethyldisilazide

[0405] LiMg-TMP 2,2,6,6-Tetramethylpiperidinylmagnesium chloride

[0406] M Moore

[0407] m multiplet

[0408] M+ mass peak

[0409] M+H mass peak hydrogenation

[0410] m-CPBA m-Chloroperbenzoic acid

[0411] Me Methyl

[0412] Me2N Dimethylamine

[0413] Mel Methyl Iodide

[0414] MeOH Methanol

[0415] MeOTs Methyl tosylate

[0416] mg milligram

[0417] MHz Megahertz

[0418] min / m minutes

[0419] ml / mL milliliter

[0420] mM millimole

[0421] mmol millimole

[0422] mol mole

[0423] MS

[0424] MS Multiple Sclerosis

[0425] MsCl Methanesulfonyl chloride

[0426] MTBE Methyl tert-butyl ether

[0427] M / Z mass / charge

[0428] N Normal

[0429] NADH Nicotinamide adenine dinucleotide reduced

[0430] NaOH Sodium hydroxide

[0431] NBS N-Bromosuccinimide

[0432] ng

[0433] NIS N-iodosuccinimide

[0434] nM nanomolar

[0435] NMR Nuclear Magnetic Resonance

[0436] ON Overnight

[0437] PEG Polyethylene glycol

[0438] PET Positron emission tomography

[0439] Ph Phenyl

[0440] PhMe Toluene

[0441] PhNO2 Nitrobenzene

[0442] PhNTf2 N-phenyltrifluoromethanesulfonamide

[0443] pH expresses the acidity or alkalinity of a solution

[0444] prep

[0445] RA Rheumatoid arthritis

[0446] Rf retention factor

[0447] RPM Revolutions per minute

[0448] RT / r Room temperature

[0449] s seconds

[0450] s Single peak

[0451] sat. saturated

[0452] SFC Supercritical Fluid Chromatography

[0453] SLE Systemic lupus erythematosus

[0454] SPECT Single Photon Emission Computed Tomography

[0455] SYK spleen tyrosine kinase

[0456] t Triplet

[0457] TBACl Tetrabutylammonium chloride

[0458] TBS / TBDMS tert-Butyldimethylsilyl

[0459] tBuOH tert-butyl alcohol

[0460] TCA Trichloroacetic acid

[0461] TEA / NEt3 Triethylamine

[0462] temp. Temperature

[0463] TES Triethylsilane

[0464] TFA Trifluoroacetic acid

[0465] TFAA Trifluoroacetic anhydride

[0466] THF Tetrahydrofuran

[0467] TLC Thin layer chromatography

[0468] TMP Tetramethylpiperidine

[0469] TMS Trimethylsilyl

[0470] Tol Toluene

[0471] TPL2 Tumor progression locus 2 kinase

[0472] Trityl

[0473] Vac

[0474] w / v weight / volume

[0475] w / w weight / weight

[0476] δ Chemical shift (ppm)

[0477] μg microgram

[0478] μL / μl microliter

[0479] μM micromolar

[0480] μm micrometer

[0481] μmol micromole

[0482] synthesis

[0483] The compounds of the present disclosure can be prepared using methods disclosed herein and conventional modifications thereof, which will be apparent in view of the disclosure herein and methods well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods can also be used. Typical compounds of formula (I), for example, compounds having structures described by one or more of formula (I) or other formulas disclosed herein or compounds, or the synthesis of pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers or deuterated analogs thereof can be achieved as described in the following examples.

[0484] General approach

[0485] Typical embodiments of compounds according to the present disclosure can be synthesized using the general reaction schemes and / or examples described below. In view of the description herein, it will be apparent that the general scheme can be changed by replacing the starting material with other materials having similar structures to produce corresponding different products. The description of the synthesis then provides many examples of how the starting material changes to provide corresponding products. The starting material is usually obtained from a commercial source or synthesized using a disclosed method for synthesizing compounds as an embodiment of the present disclosure, and the inspection of the structure of the compound to be synthesized will provide the identification of each of the substituent groups. In view of the examples herein, through a simple inspection process, the identification of the final product will usually cause the identification of the obvious starting material to be presented.

[0486] General Scheme 1

[0487]

[0488] General Scheme 1 describes a general route for preparing compounds of formula (I). Amino acid esters (AA2) are prepared from intermediate AA1 having a hydroxyl or halogen group as Q and a halogen group as X under various conditions (e.g., Schollkopf, Maruoka, etc.). After appropriate protection of the free amine with a protecting group (PG) (e.g., Trityl, Boc), AA2 is converted to a boronic acid or boronate ester (AA3) under standard conditions (e.g., Miyaura). R is introduced under various cross-coupling conditions. 1 , to give AA4. After removal of the amine protecting group (PG) under appropriate conditions, the amine is coupled with an acid to give AA5.

[0489] General Scheme 2

[0490]

[0491] In some embodiments, AA4 is prepared as outlined in General Scheme 2, which describes another general route to prepare compounds of Formula (I). From intermediate AA6 having a halogen group as Q and an amino group, R on AA7 can be prepared by several chemical steps such as urea formation and ring closure. 1 Amino acid esters (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 is coupled with an acid to give the heterocyclic compound AA5.

[0492] Intermediate A

[0493]

[0494] Synthesis of tert-butyl 4-bromo-2,6-difluorobenzoate (A1): To a stirred solution of 4-bromo-2,6-difluorobenzoic acid (5g, 21.1mmol) in DCM (50mL) and tert-butanol (50mL), di-tert-butyl dicarbonate (9.2g, 42.2mol) was added, followed by 4-dimethylaminopyridine (0.8g, 6.3mmol). The reaction mixture was stirred for 12h at RT. The reaction mixture was concentrated under reduced pressure, dissolved in EA (100mL) and washed with 10% citric acid aqueous solution (100mL). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude material. The substance was suspended in hexane, the solid was filtered out, and the filtrate was evaporated under reduced pressure to give compound A1.

[0495] Synthesis of (R)-2,6-difluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoic acid tert-butyl ester (A2): XPhos Pd G3 (42 mg, 0.06 mmol) was added 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). The reaction mixture was bubbled with nitrogen and then heated to 90 ° C for 12 h. The mixture was cooled to RT 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.

[0496] 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 RT for 20 min. The reaction mixture was concentrated under reduced pressure to give a crude material. The material was purified by silica gel column chromatography and eluted with EA in hexane to give intermediate A. MS (m / z) 284.1 [M+H] + .

[0497] Intermediate B

[0498]

[0499] Synthesis of (R)-2,6-difluoro-4-(3-(trifluoromethyl)morpholinyl)benzoic acid (B): To a 150 mL pressure vessel containing a stirring bar, 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) were added. The reaction vessel was then sealed and heated at 90 °C overnight. The reaction mixture was cooled to RT and filtered through a celite pad, 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 eluent. THF (6 mL) and an aqueous LiOH solution (6.2 mL, 1.0 M) were added to the material. The reaction mixture was stirred at 60°C for 20 hours. The reaction mixture was cooled to RT and acidified with 1.0M HCl, then extracted with EA. The organic layers were combined and dried over Na2SO4. The solvent was removed under reduced pressure to obtain Intermediate B.

[0500] Intermediate C

[0501]

[0502] Synthesis of (R)-2-fluoro-6-methyl-4-(3-(trifluoromethyl)morpholinyl)benzoic acid (C): The title compound was prepared according to the procedure presented for the synthesis of intermediate B starting with methyl 4-bromo-2-fluoro-6-methylbenzoate.

[0503] Intermediate D

[0504]

[0505] 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 procedure presented for the synthesis of intermediate A starting with tert-butyl 4-bromo-2-fluoro-6-methylbenzoate.

[0506] Intermediate E

[0507]

[0508] Synthesis of (R)-tert-butyl 2,3,6-trifluoro-4-((1,1,1-trifluorobutyl-2-yl)amino)benzoate (E1): XPhos Pd G3 (42 mg, 0.06 mmol) was added to a stirred suspension of tert-butyl 4-bromo-2,3,6-trifluorobenzoate (250 mg, 0.55 mmol), (R)-1,1,1-trifluorobutyl-2-amine (85 mg, 0.67 mmol) and cesium carbonate (904 mg, 2.8 mmol) in toluene (5 mL). The reaction mixture was bubbled with nitrogen and then heated to 90 ° C for 2 h. The mixture was cooled to RT 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 E1.

[0509] Synthesis of (R)-2,3,6-trifluoro-4-((1,1,1-trifluorobutyl-2-yl)amino)benzoic acid (E): TFA (1 mL) was added to a stirred solution of E1 (188 mg, 0.55 mmol) in DCM (1 mL). The reaction mixture was stirred at RT for 20 min. The reaction mixture was concentrated under reduced pressure to give a crude material. The material was purified by silica gel column chromatography and eluted with EA in hexane to give intermediate E.

[0510] Intermediate F

[0511]

[0512] Synthesis of (R)-methyl 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 at RT for 45 min. Water was added and the organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to provide F1 without further purification.

[0513] Synthesis of (R)-methyl 4-(cyclopropyl(1,1,1-trifluorobutan-2-yl)amino)-2,6-difluorobenzoate (F2): To a solution of 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 reactants were heated to 95 °C overnight. The reaction mixture was filtered through celite, concentrated in vacuo, and purified by silica gel chromatography eluting with Hex / EA 0-60% to give F2

[0514] Synthesis of (R)-4-(cyclopropyl(1,1,1-trifluorobutan-2-yl)amino)-2,6-difluorobenzoic acid (F): To a THF solution of F2 (360 mg, 1.07 mmol) was added 1.0 M LiOH (5 mL). The reaction was stirred at 40 °C overnight. 2.0 M HCl (20 mL) was added and extracted 3 times with EA. The combined organics were washed with brine and concentrated in vacuo to give Intermediate F without further purification.

[0515] Intermediate G

[0516]

[0517] 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 min, followed by the addition of NIS (2.04 g, 9.0 mmol). The mixture was then heated at 60 ° C for another 12 h, the solvent was then removed under reduced pressure, and the residue was dissolved in EA, washed with water, and washed with saturated NaHCO3 aqueous solution. The organic layer was concentrated under reduced pressure, and the crude product was suspended in DME (3.80 mL). K2CO3 (0.98 g, 7.0 mmol) and MeI (1.0 g, 7.0 mmol) were added to the mixture, and the mixture was heated at 95 ° C for 2 h. After 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 afford Intermediate G.

[0518] Intermediate H

[0519]

[0520] 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 was added NaH (25 mg, 0.62 mmol) and the reaction mixture was stirred for 30 min, 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 RT, concentrated under reduced pressure, and purified by silica gel chromatography eluting with Hex / EA 0%-100% to give the title compound.

[0521] Synthesis of 3-iodo-1,4-dimethyl-5-(trifluoromethyl)pyridin-2(1H)-one (H): TFAA (1.6 g, 8 mmol) was added to a stirred solution of H1 (0.72 g, 4 mmol) in pure TFA (16 mL). The reaction mixture was heated to 100 ° C for 5 min in a sealed vial, followed by addition of NIS (1.08 g, 5 mmol) and further heated at 60 ° C for 3 hours. The reaction mixture was cooled and TFA was removed under reduced pressure. The residue was dissolved in EA and washed with saturated sodium bicarbonate and then with brine. The organic layer was filtered and then concentrated to give intermediate G without further purification.

[0522] Intermediate I

[0523]

[0524] 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) was added a solution of n-BuLi in hexanes (4.62 g, 7.96 mmol) at -78 °C. The mixture was stirred at -78 °C for 20 min, followed by a solution of 1-bromo-4-(bromomethyl)-2-methylbenzene (1.5 g, 5.68 mmol) in THF (37 mL) dropwise. The reactant was stirred at -78 °C for 40 min and quenched with water (10 mL). The cold bath was removed, and the reactant was allowed to warm to RT and extracted with EA, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give a crude material. The crude product was purified using flash chromatography eluting with EA in hexanes (10% to 100%) to afford compound I1.

[0525] 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) were added bis(pinacolato)diboron (262 mg, 1.03 mmol) and KOAc (238 mg, 2.42 mmol), and the mixture was purged with nitrogen for 6 min. CataCXium A Pd G3 (29.5 mg, 0.04 mmol) was added, and the mixture was heated at 90 °C for 1 h. Upon completion, the reaction was quenched with water, extracted with EA, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give compound I2, which was used without further purification.

[0526] 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): To a solution of compound I2 (130 mg, 0.157 mmol), 3-iodo-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one (65.0 mg, 0.204 mmol) in DME (1.50 mL) was added a 1 M aqueous solution of K3PO4 (117 mg, 0.550 mmol) and the mixture was purged with nitrogen for 6 min. XPhos Pd G3 (13.0 mg, 0.016 mmol) was then added and the mixture was purged with nitrogen for another 3 min and thermally heated at 77 °C for 45 min. Then the solvent is removed under reduced pressure, and the mixture is dissolved in EA, washed with H o, dried over Na sO and concentrated under reduced pressure to give a crude material. The crude material is purified by flash chromatography using a hexane solution of EA (20% to 100%) and then a solution of MeOH in EA (0% to 35%) to give I3.

[0527] Synthesis of (S)-2-amino-3-(4-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-3-methylphenyl)propanoic acid methyl ester (I): To a solution of compound I3 (185 mg, 0.387 mmol) in ACN (13 mL) was added an aqueous solution of 2M HCl (67.6 mg, 1.16 mmol), and the mixture was stirred at room temperature for 3 h. Upon completion, the solvent was removed under reduced pressure, and the crude material was purified using flash chromatography eluting with EA in hexane (0% to 100%) and then MeOH in DCM (0% to 35%) to give Intermediate I.

[0528] Intermediate J

[0529]

[0530] 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 procedure presented for the synthesis of intermediate I1 starting with 1-bromo-4-(bromomethyl)-2-fluorobenzene.

[0531] 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 starting with J1 according to the procedure presented for the synthesis of intermediate I2.

[0532] 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 starting with compound J2 according to the presented method for the synthesis of I3.

[0533] 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 procedure presented for the synthesis of intermediate I starting with compound J3.

[0534] Intermediate K

[0535]

[0536] Synthesis of methyl 3-(3-(5-bromopyridin-2-yl)ureido)isonicotinate (K1): To a solution of 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 and then cooled to 0°C. Triphosgene (14.69 g, 49.5 mmol, 0.35 equiv) dissolved in DCM (90.0 mL) was slowly added at 0°C. The mixture was stirred at 0°C for 2 h 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 it was stirred at 65°C for 2 h. After cooling to RT, the solid was filtered off and collected to give K1.

[0537] 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 eq) was added followed by MeOTs (39.4 g, 211.7 mmol, 1.5 eq). 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 produce a slurry and the resulting solid was collected on filter paper to give K2.

[0538] 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 at 110 °C in vacuum with a heat gun for 10 min. After cooling to RT, 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-iodopropanoate (19.7 g, 60.0 mmol, 2.00 equiv) dissolved in DMA (40 mL) was added and stirred at 50 °C for 1 h. After cooling to 30 ° C, the zinc reagent was added dropwise to a previously 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 RT, 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 / hexanes to give K3.

[0539] Synthesis of (S)-methyl 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 procedure presented for the synthesis of intermediate I starting with compound K3.

[0540] Intermediate L

[0541]

[0542] Synthesis of O-benzyl-N-(tert-butyloxycarbonyl)-L-serine cyclopropyl ester (L1): DMAP (8.27 g, 68 mmol), EDCI (25.96 g, 135 mmol) and cyclopropanol (39 g, 677 mmol) were added to a solution of O-benzyl-N-(tert-butyloxycarbonyl)-L-serine (20 g, 68 mmol) in DCM (135 mL). The mixture was stirred for 4 h, diluted with EA (500 mL) and washed with water (500 mL) and 0.5 N citric acid (2×500 mL). The organic layer was evaporated and the residue was eluted by silica gel chromatography with 50% EA in hexane to give L1.

[0543] Synthesis of (tert-butyloxycarbonyl)-L-serine cyclopropyl ester (L2): To a solution of L1 (5.5 g, 16 mmol) in EA (10 mL) was added palladium on carbon catalyst (3.5 g, 5% Pd). The contents were stirred on a Parr oscillator at RT for 3 hours under 50 PSI of hydrogen. 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.

[0544] Synthesis of (R)-cyclopropyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (L3): To a solution of L2 (2.8 g, 11.4 mmol) in DCM were added iodine (3.2 g, 13 mmol, 1.1 eq), imidazole (0.855 g, 13 mmol, 1.1 eq) and PPh3 (2.96 g, 12 mmol, 1.05 eq) 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 in hexanes (0%-20%) to give L3.

[0545] Synthesis of (S)-cyclopropyl 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 particles) was added to a flame-dried round-bottom flask vial containing a stir bar. DMF (4.2 mL) and TMSCl (0.49 mL, 3.8 mmol) were added, and the mixture was stirred for 30 minutes. The supernatant was decanted with 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 to keep the resulting exotherm below 50° C. and then stirred for 30 minutes. The iodine zinc reagent was then withdrawn via syringe and added to a second flask containing intermediate K2 (1.4 g, 4.2 mmol, 1 eq), palladium acetate (0.094 g, 0.42 mmol, 0.1 eq), Xphos (0.24 g, 0.5 mmol, 0.12 eq) and DMF (7.8 mL), and the reaction mixture was stirred for 3 days at 45° C. 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.

[0546] Synthesis of (S)-cyclopropyl 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.

[0547] Intermediate M

[0548]

[0549] Synthesis of methyl 3-(3-(6-iodopyridin-3-yl)ureido)isonicotinate (M1): 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.) were added to a 500 mL RB flask. The reaction mixture was heated to 50 °C for 10 min. Thereafter, diphenylphosphoryl azide (6.37 mL, 29.5 mmol, 1.3 eq.) was added dropwise to the reaction mixture. The reactants were allowed to stir for 60 min. The reaction mixture was cooled to RT and partitioned between ethyl acetate and water (200 ml each). The organics were separated and washed with brine (100 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography using methanol in DCM 0%-20% as eluent to give the title compound (M1).

[0550] Synthesis of 3-(6-iodopyridin-3-yl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (M2): The title compound was prepared starting with M1 according to the procedure presented for the synthesis of intermediate K2.

[0551] Synthesis of (S)-methyl 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 starting with M2 according to the procedure presented for the synthesis of intermediate K3.

[0552] Synthesis of (S)-methyl 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 procedure presented for the synthesis of intermediate K starting with M3.

[0553] Intermediate N

[0554]

[0555] Synthesis of (S)-3-(3-(4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)phenyl)ureido)isonicotinate (N1): The title compound was prepared starting with methyl (S)-3-(4-aminophenyl)-2-((tert-butoxycarbonyl)amino)propanoate according to the presented method for the synthesis of intermediate M1.

[0556] 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 starting with N1 according to the procedure presented for the synthesis of intermediate M2.

[0557] 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 procedure presented for the synthesis of intermediate L starting with N2.

[0558] Intermediate O

[0559]

[0560] Synthesis of methyl 3-(3-(4-iodo-2-methoxyphenyl)ureido)isonicotinate (O1): The title compound was prepared according to the procedure presented for the synthesis of intermediate M1 starting with 4-iodo-2-methoxyaniline.

[0561] Synthesis of 3-(4-iodo-2-methoxyphenyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (O2): The title compound was prepared starting with O1 according to the procedure presented for the synthesis of intermediate M2.

[0562] 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 starting with O2 according to the presented method for the synthesis of M3.

[0563] 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 procedure presented for the synthesis of intermediate M starting with O3.

[0564] Intermediate P

[0565]

[0566] Synthesis of (R)-2-chloro-6-fluoro-4-(3-(trifluoromethyl)morpholinyl)benzoic acid (P): 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) were added to a 150 mL pressure vessel containing a stirring bar. The reaction vessel was then sealed and heated at 90 °C overnight. The reaction mixture was cooled to RT and filtered through a diatomaceous earth pad, rinsed with EtOAc, and the filtrate was evaporated to dryness under reduced pressure. The material was purified by silica gel chromatography using EtOAc in hexane as eluent to give a yellow oil. To this material, THF (2.6 mL) and LiOH aqueous solution (0.78 mL, 1.0 M) were added. The reaction mixture was stirred at 40 ° C for 20 hours and at 50 ° C for another 4 hours. The reaction mixture was cooled to RT and acidified with 1.0 M HCl, then extracted with EtOAc. The organic layers were combined and dried over Na2SO4. The solvent was removed under reduced pressure to obtain P.

[0567] Intermediate Q

[0568]

[0569] Synthesis of (S)-4-(3-(2,2-difluoroethyl)morpholinyl)-2-fluoro-6-methylbenzoic acid (Q): 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) were added to a 150 mL pressure vessel containing a stirring bar. The reaction vessel was then sealed and heated at 90 °C overnight. The reaction mixture was cooled to RT and 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 eluent. To this material was added THF (6 mL) and LiOH aqueous solution (6.2 mL, 1.0 M). The reaction mixture was stirred at 60 ° C for 20 hours. The reaction mixture was cooled to RT and acidified with 1.0 M HCl, then extracted with EA. The organic layers were combined and dried over Na2SO4. The solvent was removed under reduced pressure to obtain Q.

[0570] Intermediate R

[0571] Synthesis of (S)-methyl 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 a solution of 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 Hünig's base (0.237 mL, 1.36 mmol) was added followed by (S)-methyl 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.

[0572]

[0573] Synthesis of (S)-methyl 2-((tert-butyloxycarbonyl)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 an aqueous solution of 10% citric acid. Additional water was added to precipitate the product, which was collected by filtration to produce R2.

[0574] Synthesis of (S)-methyl 2-((tert-butyloxycarbonyl)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 toluenesulfonate (16 μL, 0.11 mmol) and the reaction was stirred for 4 hours. Water was added to precipitate the product and the solid was collected to give R3.

[0575] Synthesis of (S)-methyl 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 a solution of R3 (37 mg, 0.08 mmol) in ethyl acetate (0.7 mL) was added a 4 M solution of hydrogen chloride in dioxane (0.2 mL, 0.8 mmol) and the reaction was stirred for 16 hours. It was concentrated to give R.

[0576] Intermediate S

[0577]

[0578] Synthesis of 5-amino-3,6-dihydro-2H-pyran-4-carboxylic acid ethyl ester (S1): To a solution of 3-oxotetrahydro-2H-pyran-4-carboxylic acid ethyl ester (2.0 g, 12 mmol) in methanol (71 mL) was added ammonium acetate (4.57 g, 59 mmol), 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.

[0579] Synthesis of (S)-methyl 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 presented method for the synthesis of intermediate R starting with S1.

[0580] Intermediate T

[0581]

[0582] Synthesis of (S)-methyl 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 starting with methyl 2-aminocyclopent-1-ene-1-carboxylate according to the presented method for the synthesis of intermediate R.

[0583] Intermediate U

[0584]

[0585] 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 starting with methyl 4-amino-2,5-dihydrofuran-3-carboxylate according to the presented method for the synthesis of intermediate R.

[0586] Intermediate V

[0587]

[0588] Synthesis of (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)propanoic acid ethyl ester (V): The title compound was prepared starting with 4-amino-5,6-dihydro-2H-pyran-3-carboxylic acid methyl ester according to the method presented for the synthesis of intermediate R.

[0589] Intermediate W

[0590]

[0591] Synthesis of methyl 4-amino-2,5-dihydrofuran-3-carboxylate (W1): The title compound was prepared according to the procedure presented for the synthesis of intermediate S1 starting with methyl 4-oxotetrahydrofuran-3-carboxylate.

[0592] Synthesis of methyl 4-(3-(4-iodophenyl)ureido)-2,5-dihydrofuran-3-carboxylate (W2): The title compound was prepared starting with W1 according to the procedure presented for the synthesis of intermediate S2.

[0593] 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 was prepared according to the procedure presented for the synthesis of intermediate O, starting with W2 instead of O1.

[0594] Example 1

[0595] 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 for 5 min. 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 for another 5 min. The mixture was then heated at 77° C. for 7 min under stirring. After 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 a crude material. The crude product was purified by flash chromatography eluting with EA in hexane (20% to 80%) to give compound 1A.

[0596]

[0597] Synthesis of (S)-methyl 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 4M solution of HCl in dioxane (76.2 mg, 2.10 mmol), and the mixture was stirred at room temperature for 2 h. After completion, the solvent was removed under reduced pressure, and the crude product 1B was used in the next step without further purification.

[0598] 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 h. Upon completion, the mixture was diluted with 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 in hexanes (12% to 100%) to give the ester. To a solution of the ester (91.0 mg, 0.144 mmol) in THF (4.80 mL) was added a 1 M aqueous solution of LiOH (10.0 mg, 0.432 mmol), and the mixture was stirred at room temperature for 40 min. After 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 eluted with an aqueous solution of acetonitrile (0.4% TFA) to give 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).

[0599] Example 2

[0600]

[0601] 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 for 5 min. To this mixture was added a 1 M aqueous solution of XPhos Pd G3 (52.0 mg, 0.062 mmol) and K3PO4 (460 mg, 2.0 mmol), and the reaction was purged with nitrogen for an additional 5 min. The mixture was then heated at 90 °C for 10 min with stirring, after which the solvent was removed under reduced pressure. 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 in hexanes (20% to 80%) to give Compound 2A.

[0602] 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 starting with 2A according to the procedure presented for the synthesis of 1B.

[0603] 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 starting with 2B and intermediate A according to the procedure presented for the synthesis of 1. 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).

[0604] Example 3

[0605]

[0606] Synthesis of (S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholinyl)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 presented for the synthesis of 1 using Intermediate 1B and Intermediate B. MS (m / z) 648.3 [M+H]+. 1H 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).

[0607] Example 4

[0608] Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1,4-dimethyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)phenyl)propanoate (4): 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 for 5 min. 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 for another 5 min. The mixture was then heated at 77 °C with stirring for 7 min. After 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 in hexanes (20% to 100%) to give compound 4A.

[0609]

[0610] 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 starting with compound 4A according to the procedure presented for the synthesis of 1B.

[0611] Synthesis of (S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholinyl)benzamido)-3-(4-(1,4-dimethyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)phenyl)propanoic acid (4): The title compound was prepared starting from compound 4B and intermediate B according to the presented method for the synthesis of 1. 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).

[0612] Example 5

[0613]

[0614] 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)morpholinyl)benzamido)propanoic acid (5): The title compound was prepared starting from Intermediate I and Intermediate C according to the presented method for the synthesis of 1. 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).

[0615] Example 6

[0616]

[0617] Synthesis of (S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholinyl)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 procedure presented for the synthesis of 1 starting with Intermediate J and Intermediate B. MS (m / z) 666.1 [M+H]+. 1HNMR(400MHz,DMSO-d6)δ8.87(dd,J=7.9,2.4Hz,1H),7.19-7.03(m,2H),6.77(d,J=8.1 Hz,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,3 H), 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).

[0618] Example 7

[0619]

[0620] 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) was added a solution of n-BuLi in hexanes (2.11 g, 2.11 mmol) at -78°C. The mixture was stirred at -78°C for 20 min, and then a solution of 2-(4-(bromomethyl)-2-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (500 mg, 1.51 mmol) in THF (7.50 mL) was added dropwise. The reaction was stirred at -78°C for 40 min and quenched with water. The cooling bath was removed and the reaction was allowed to warm to room temperature and extracted with EA, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give compound 7A which was used without further purification.

[0621] 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 K3PO4 (342 mg, 0.1.61 mmol) and the mixture was purged with nitrogen for 6 min. XPhos Pd G3 (11.7 mg, 0.014 mmol) was then added and the mixture was purged with nitrogen for another 4 min and heated at 90 °C for 30 min. Then remove the solvent under reduced pressure, and the mixture is dissolved in EA, washed with water, through Na2SO4 dry and concentrated under reduced pressure to obtain crude material. This crude product is purified by flash chromatography using a hexane solution of EA (20% to 100%) and then a EA solution of MeOH (0% to 25%) elution to obtain compound 7B.

[0622] Synthesis of methyl (S)-2-amino-3-(3-chloro-4-(4,5,6-trimethyl-3-oxo-3,4-dihydropyrazin-2-yl)phenyl)propanoate (7C): The title compound was prepared according to the procedure presented for the synthesis of intermediate J starting with compound 7B.

[0623] 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)morpholinyl)benzamido)propanoic acid (7): The title compound was prepared starting from 7C and intermediate C according to the presented method for the synthesis of 1. MS (m / z) 625.2 [M+H]+. 1H 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).

[0624] Example 8

[0625]

[0626] Synthesis of (S)-methyl 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 presented 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).

[0627] Example 9

[0628]

[0629] 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 was added 1.0 M LiOH (0.04 mL, 0.04 mmol) and the mixture was stirred at RT for 1 h. Then 4.0 M HCl in dioxane (0.1 mL, 0.4 mmol) was added and the mixture was stirred overnight. The reaction mixture was concentrated, filtered and purified by reverse phase HPLC (MeCN / H2O) to give 9.

[0630] Example 10

[0631]

[0632] Synthesis of (S)-methyl 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 presented for the synthesis of 1 using Intermediate K and Intermediate D. MS (m / z) 617.3 [M+H]+. 1H 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).

[0633] Embodiment 11

[0634]

[0635] 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 starting with 10 according to the procedure presented for the synthesis of Example 9. 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).

[0636] Example 12

[0637]

[0638] Synthesis of (S)-methyl 2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholinyl)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 presented for the synthesis of 1 using Intermediate K and Intermediate B. MS (m / z) 649.5 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ9.09(d,J=7.6Hz,1H),9.00(s,1H),8.57(dd,J=5.0,1.5Hz,1H),8.50(d,J=2.0Hz, 1H),8.01-7.80(m,2H),7.42(d,J=8.0Hz,1H),6.79(d,J=11.8Hz,2H),5.09-4.81(m,1H),4.70(td,J=9.0,5 .7Hz,1H),4.17(d,J=12.7Hz,1H),4.07-3.88(m,1H),3.75(d,J=12.9Hz,1H),3.67(d,J=1.6Hz,3H),3.61(d ,J=1.6Hz,3H),3.58-3.51(m,1H),3.44(d,J=12.7Hz,1H),3.29-3.19(m,2H),3.12(dd,J=14.2,9.9Hz,1H).

[0639] Example 13

[0640]

[0641] Synthesis of (S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholinyl)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 starting with 12 according to the procedure presented for the synthesis of Example 9. 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).

[0642] Embodiment 14

[0643]

[0644] Synthesis of (S)-methyl 2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholinyl)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 according to the method presented for the synthesis of 1 using Intermediate K and Intermediate C. MS (m / z) 644.8 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ9.00(s,1H),8.93(d,J=7.9Hz,1H),8.57(dd,J=5.0,1.6Hz,1H),8.50(s,1H ),7.93(dd,J=16.9,6.6Hz,2H),7.42(d,J=8.1Hz,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).

[0645] Embodiment 15

[0646]

[0647] Synthesis of (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholinyl)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 starting with 14 according to the procedure presented for the synthesis of Example 9. MS (m / z) 631.2 [M+H]+. 1HNMR(400MHz,DMSO-d6)δ9.00(s,1H),8.79(d,J=8.1Hz,1H),8.57(d,J=5.0Hz,1H),8.50(s,1 H),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).

[0648] Example 16

[0649]

[0650] Synthesis of (S)-methyl 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 presented method 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).

[0651] Embodiment 17

[0652]

[0653] 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 starting with 16 according to the procedure presented for the synthesis of Example 9. 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).

[0654] Embodiment 18

[0655]

[0656] Synthesis of (S)-methyl 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 presented method 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).

[0657] Embodiment 19

[0658]

[0659] 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 starting with 18 according to the procedure presented for the synthesis of Example 9. 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).

[0660] Embodiment 20

[0661] Synthesis of (S)-cyclopropyl 2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholinyl)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 presented method 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).

[0662]

[0663] Embodiment 21

[0664]

[0665] Synthesis of (S)-ethyl 2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholinyl)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate (21): To a solution of 15 (600 mg, 0.8 mmol) in DCM (13 mL) were added DIAD (1.15 mL, 8.0 mmol), EtOH (0.47 mL, 8.0 mmol) and PPh3 (1.27 g, 4.83 mmol) and the mixture was stirred for 10 min. The reaction mixture was concentrated in vacuo and then purified by silica gel column chromatography eluting with EA in hexanes 0%-100% 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).

[0666] Embodiment 22

[0667]

[0668] Synthesis of (S)-methyl 2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholinyl)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 presented 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).

[0669] Embodiment 23

[0670]

[0671] Synthesis of (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholinyl)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 starting with 22 according to the procedure presented for the synthesis of Example 9. MS (m / z) 631.2 [M+H]+. 1HNMR (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 =2.5Hz,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=1 2.8Hz,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).

[0672] Embodiment 24

[0673]

[0674] Synthesis of (S)-methyl 2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholinyl)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 presented for the synthesis of 1 using Intermediate N and Intermediate 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).

[0675] Embodiment 25

[0676]

[0677] Synthesis of (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholinyl)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 starting with 24 according to the procedure presented for the synthesis of Example 9. MS (m / z) 630.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ8.97(s,1H),8.74(d,J=8.0Hz,1H),8.55(d,J=5.0Hz,1H),7.90(d,J=5.0Hz,1H),7.40(d,J=8.3Hz,2 H),7.22(d,J=8.3Hz,2H),6.69(dd,J=13.0,2.2Hz,1H),6.65(d,J=2.3Hz,1H),4.90-4.78(m,1H),4.65(tt,J=8.0,4.3Hz,1H) ,4.15(d,J=12.5Hz,1H),3.95(dd,J=11.5,3.6Hz,1H),3.73(d,J=12.6Hz,1H),3.60(s,3H),3.55(td,J=11.8,11.3,3.0Hz,1 H), 3.36 (d, J = 11.5Hz, 1H), 3.27 (d, J = 12.4Hz, 1H), 3.21 (dd, J = 14.1, 4.2Hz, 1H), 3.01 (dd, J = 14.2, 10.7Hz, 1H), 2.05 (s, 3H).

[0678] Embodiment 26

[0679]

[0680] Synthesis of (S)-methyl 2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholinyl)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 presented 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).

[0681] Embodiment 27

[0682]

[0683] Synthesis of (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholinyl)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 starting with 26 according to the procedure presented for the synthesis of Example 9. 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).

[0684] Embodiment 54

[0685]

[0686] Synthesis of (S)-ethyl 2-(2-chloro-6-fluoro-4-((R)-3-(trifluoromethyl)morpholinyl)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 presented method 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).

[0687] Embodiment 55

[0688]

[0689] Synthesis of (S)-2-(2-chloro-6-fluoro-4-((R)-3-(trifluoromethyl)morpholinyl)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 starting with 54 according to the procedure presented for the synthesis of Example 9. 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).

[0690] Embodiment 56

[0691]

[0692] Synthesis of methyl (S)-2-(4-((S)-3-(2,2-difluoroethyl)morpholinyl)-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. 36-5.97(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,1 H), 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).

[0693] Embodiment 57

[0694]

[0695] Synthesis of (S)-2-(4-((S)-3-(2,2-difluoroethyl)morpholinyl)-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 starting with 56 according to the procedure presented for the synthesis of Example 9. 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=8.2 Hz,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(m 4H)364(d J=112Hz 1H)352(d,J=3.3Hz,1H),3.33(s,1H),3.31(s,3H),3.22-3.14(m,1H),3.0 9-2.93(m,2H),2.71(s,2H),2.43-2.34(m,1H),2.04(s,3H),1.79(s,1H).

[0696] Embodiment 58

[0697]

[0698] Synthesis of methyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholinyl)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 presented 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).

[0699] Embodiment 59

[0700]

[0701] Synthesis of (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholinyl)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 starting with 58 according to the procedure presented for the synthesis of Example 9. MS (m / z) 635.2 [M+H]+. 1H NMR(400MHz, DMSO-d6)δ8.72(d,J=8.0Hz,1H),7.41-7.30(m,2H),7.13-7.05(m,2H),6.68(dd,J=12.9,2.3Hz,1 H),6.64(d,J=2.4Hz,1H),4.84(dd,J=8.9,3.5Hz,1H),4.63(ddd,J=12.0,8.0,4.4Hz,1H),4.28(d,J=1.8Hz,2H ),4.14(d,J=12.6Hz,1H),3.95(dd,J=11.3,3.7Hz,1H),3.88(t,J=5.6Hz,2H),3.73(d,J=12.7Hz,1H),3.62-3. 49(m,1H),3.31(s,5H),3.18(dd,J=14.2,4.3Hz,1H),2.99(dd,J=14.2,10.6Hz,1H),2.71(s,1H),2.04(s,3H).

[0702] Embodiment 60

[0703]

[0704] Synthesis of (S)-methyl 2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholinyl)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 according to the method presented 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).

[0705] Embodiment 61

[0706]

[0707] Synthesis of (S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholinyl)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 starting with 60 according to the procedure presented for the synthesis of Example 9. MS (m / z) 639.2 [M+H]+. 1HNMR(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),6.7 8(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, 4.8 Hz, 1H), 3.02 ( dd, J = 14.2, 9.7 Hz, 1H), 2.33 ( qd, J = 4.3, 3.0, 2.4 Hz, 2H).

[0708] Embodiment 62

[0709]

[0710] Synthesis of methyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholinyl)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 presented for the synthesis of 8 using the ethyl ester of intermediate S and intermediate C. MS (m / z) 671.2 [M+Na]. 1H 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).

[0711] Embodiment 63

[0712]

[0713] Synthesis of (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholinyl)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 starting with 62 according to the procedure presented for the synthesis of Example 9. MS (m / z) 635.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ8.72(d,J=8.0Hz,1H),7.41-7.33(m,2H),7.15-7.03(m,2H),6.68(dd,J=12.9,2. 3Hz,1H),6.64(d,J=2.3Hz,1H),4.84(dd,J=9.0,3.6Hz,1H),4.69-4.56(m,3H),4.14(d,J=12.6Hz,1H),3. 95(dd,J=11.4,3.6Hz,1H),3.79(t,J=5.5Hz,2H),3.76-3.68(m,1H),3.61-3.49(m,1H),3.35(d,J=12.3Hz ,1H),3.27(d,J=12.5Hz,1H),3.21(s,4H),2.99(dd,J=14.2,10.6Hz,1H),2.40-2.25(m,2H),2.04(s,3H).

[0714] Embodiment 64

[0715]

[0716] Synthesis of (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholinyl)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 presented 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).

[0717] Embodiment 65

[0718]

[0719] Synthesis of ethyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholinyl)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 a solution of 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 RT for 60 min. 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 afford compound 65. MS(m / z)647.3[M+H]+. 1H NMR(400MHz,DMSO-d d6)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).

[0720] Embodiment 66

[0721] Synthesis of (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholinyl)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 procedure presented 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).

[0722]

[0723] Embodiment 67

[0724]

[0725] Synthesis of (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholinyl)benzamido)-3-(6-(1-methyl-2,4-dioxo-1578-tetrahydro-2H-pyrano[43-d]pyrimidin-3(4H)-yl)pyridin-3-yl)propanoic acid ethyl ester (67): The title compound was prepared according to the method presented 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).

[0726] Embodiment 68

[0727]

[0728] Synthesis of (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholinyl)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 starting with 67 according to the procedure presented for the synthesis of Example 9. 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).

[0729] Embodiment 69

[0730]

[0731] Synthesis of (S)-2-(4-((S)-3-(2,2-difluoroethyl)morpholinyl)-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 according to the method presented for the synthesis of 1 using the ethyl ester 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).

[0732] Embodiment 70

[0733]

[0734] Synthesis of (S)-2-(4-((S)-3-(2,2-difluoroethyl)morpholinyl)-2-fluoro-6-methylbenzamido)-3-(4-(1-methyl-2,4-dioxo-1,2,5,7-tetrahydrofuro[3,4-d]pyrimidin-3(4H)-yl)phenyl)propanoic acid (70): The title compound was prepared according to the method presented for the synthesis of 1 using the ethyl ester of intermediate W and intermediate Q. MS (m / z) 617.2 [M+H]+. 1H NMR(400MHz, DMSO-d6)δ8.68(d,J=8.0Hz,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, 4.5Hz,1H),5.06(t,J=3.6Hz,2H),4.86(t,J=3.6Hz,2H),4.64(ddd,J=11.9,8.1,4.2Hz,1H),4.01(d,J=9.3Hz,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).

[0735] α4β7 integrin cell capture assay

[0736] The efficacy of the inhibitors in preventing the interaction of α4β7 integrin with MadCAM-1 was measured by monitoring the capture of cells expressing α4β7 integrin on plates coated with the extracellular domain of recombinant MadCAM-1.

[0737] 384-well plates (Corning 3702) were coated with MadCAM-1 extracellular domain by dispensing 20 mL of MAdCAM-1 at 10 mg / mL per well and incubating overnight at 4° C. Plates were then washed with PBS and blocked with 3% BSA for 2 hours and then washed again.

[0738] RPMI8866 cells were centrifuged and plated at 0.5 × 10 6Cells were resuspended in assay medium (DMEM + 0.5% FBS + 0.5mM MnCl2) at a density of 10 cells / mL. The cells were then distributed (60 μL / well) into 384-well plates (Greiner 781280) that were previously spotted with 60 nL of test compound per well. The plates were incubated at 37°C for 1 hour. 50 μL of cells were transferred to a blocked MadCAM-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 plates were incubated at room temperature for 90 minutes. The plates were then washed 3 times with 70 μL PBS per well and imaged on a Cellomics ArrayScan instrument. The cells bound to the plates were counted and plotted against compound concentration to determine the EC50 of the test compound. The results are presented in Tables 1 and 2.

[0739] α4β1 cell capture assay

[0740] The efficacy of the inhibitors in preventing the interaction of α4β1 integrin with VCAM-1 was measured by monitoring the capture of α4β1-expressing cells to plates coated with the recombinant VCAM-1 extracellular domain.

[0741] 384-well plates (Corning 3702) were coated with VCAM-1 extracellular domain by dispensing 20 μL of VCAM-1 at 0.5 mg / ml per well and incubating overnight at 4° C. Plates were then washed with PBS and blocked with 3% BSA for 2 hours and then washed again.

[0742] Jurkat cells were centrifuged and cultured at 0.5 × 10 6 Cells were resuspended in assay medium (DMEM + 0.5% FBS + 0.5 mM MnCl2) at a density of 10 cells / ml. The cells were then dispensed (60 μL / well) into a 384-well plate (Greiner 781280) that had been previously spotted with 60 nL of the test compound per well. The plates were incubated at 37°C for 1 hour. 50 μL of cells were transferred to a 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 plates were incubated at room temperature for 90 minutes. The plates were then washed 3 times with 70 μL PBS per well and imaged on a Cellomics ArrayScan instrument. The cells bound to the plate were counted and plotted against compound concentration to determine the EC of the test compound. 50The results are presented in Tables 1 and 2.

[0743] Table 1

[0744]

[0745] Table 2

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766] All references, including publications, patents and patent documents are incorporated herein by reference, as if separately incorporated by reference. The present disclosure provides references to various embodiments and technologies. However, it should be understood that many changes and modifications can be made while remaining within the spirit and scope of the present disclosure. It is described by understanding that it is considered to be an illustration of the claimed subject matter, and it is not intended that the attached claims are limited to the illustrated specific embodiments. The titles used throughout the present disclosure are provided for convenience and should not be interpreted as limiting the claims in any way. The embodiments illustrated under any title can be combined with the embodiments illustrated under any other title.

[0767] In particular, the present invention relates to the following embodiments:

[0768] 1. A compound of formula (I):

[0769]

[0770] or a pharmaceutically acceptable salt thereof, wherein:

[0771] is a single bond or a double bond; wherein A is an aromatic ring;

[0772] Each Z 1 , Z 2 , Z 3 and Z 4 Independently selected from N, N(CR c ), C(O) and CR c ; where each R c are independently selected from H, halo, cyano, hydroxyl, -NR a1 R a2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 Haloalkoxy;

[0773] R 1 is a 5-10 membered heteroaryl or a 6-10 membered heterocyclic group;

[0774] Where R 1 Each of the 5-10 membered heteroaryl and 6-10 membered heterocyclyl contains one to four N and optionally one to three C(O) as ring members; and

[0775] Where R 1 Each 5-10 membered heteroaryl and 6-10 membered heterocyclyl is optionally substituted by one to four R a Replace; and wherein each R a are independently selected from halo, cyano, hydroxyl, -NR a1 Ra2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -C 1-4 Alkylene-OC 1-4 Alkyl and C 3-10 Cycloalkyl;

[0776] Each R 2 , R 3 , R 5 and R 6 are independently selected from H, halo, cyano, hydroxyl, -NR a1 R a2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 Haloalkoxy;

[0777] R 4 is selected from 3-10 membered heterocyclyl, 5-10 membered heteroaryl and -NR b1 R b2 ;

[0778] Where R 4 The 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted by one to six R b Replace; and wherein each R b are independently selected from halo, cyano, hydroxyl, -NR a1 R a2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-8 Haloalkyl and C 1-8 haloalkoxy; and

[0779] Each R b1 and R b2 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, -C 1-6 Alkylene-phenyl and -C 1-6 Haloalkylene-phenyl;

[0780] R 7 Selected from H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 1-4 Alkylene-NR a1R a2 , -C 1-4 Alkylene-C(O)NR a1 R a2 , -C 1-4 Alkylene-C 3-10 Cycloalkyl, -C 1-4 Alkylene-3-14 membered heterocyclic group, -C 1-4 Alkylene-C 6-10 Aryl, -C 1-4 Alkylene-5-10 membered heteroaryl and -L 1 -R 9 ;

[0781] Where L 1 Selected from -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-

[0782] C(O)-O-, -C 1-4 Alkylene-C(O)-OC 1-4 Alkylene-, -C 1-4 Alkylene-O-

[0783] C(O)-O-, -C 1-4 Alkylene-OC(O)-OC 1-4 Alkylene-, -C 1-4 Alkylene-

[0784] NR a1 C(O)-O- and -C 1-4 Alkylene-OC(O)-NR a1 -;

[0785] R 9 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl;

[0786] Where R 7 and R 9 Each C 3-10 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally independently selected from halo, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, C1-4 Haloalkyl, C 1-4 Haloalkoxy, -NR a1 R a2 and-

[0787] C 1-4 Alkylene-NR a1 R a2 substituted by one to four groups of

[0788] R 8 Selected from H, C 1-6 Alkyl and C 1-6 haloalkyl; and

[0789] Each R a1 and R a2 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl.

[0790] 2. The compound according to embodiment 1, wherein the compound has formula (II):

[0791]

[0792] or a pharmaceutically acceptable salt thereof.

[0793] 3. The compound according to embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein

[0794] The compound has formula (IIa):

[0795]

[0796] where Y 1 N or CH;

[0797] R d Selected from H, C 1-4 Alkyl and C 1-4 haloalkyl; and

[0798] r is selected from 0, 1, 2 and 3.

[0799] 4. A compound according to any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIb):

[0800]

[0801] Where X 1 Selected from CR x1 and N;

[0802] X 2Selected from CR x1 R x2 NR x2 and O;

[0803] Where R x1 Selected from H and R b ;and

[0804] R x2 Selected from H, C 1-4 Alkyl and C 1-4 Haloalkyl;

[0805] R d Selected from H, C 1-4 Alkyl and C 1-4 Haloalkyl;

[0806] r is selected from 0, 1, 2 and 3; and

[0807] m is selected from 0, 1, 2, 3 and 4.

[0808] 5. A compound according to any one of embodiments 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIc):

[0809]

[0810] Where R b C 1-4 Alkyl or C 1-6 haloalkyl; and

[0811] R d Selected from H, C 1-4 Alkyl and C 1-4 Halogenated alkyl.

[0812] 6. A compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (IId):

[0813]

[0814] Where R b C 1-4 Alkyl or C 1-6 Haloalkyl;

[0815] R d C 1-4 Alkyl or C 1-4 haloalkyl; and

[0816] Each R 2 and R 6 independently selected from halogen, C 1-4 Alkyl and C 1-4 Halogenated alkyl.

[0817] 7. The compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein

[0818] The compound has formula (III):

[0819]

[0820] 8. The compound according to Embodiment 1 or 7, or a pharmaceutically acceptable salt thereof, wherein

[0821] The compound has formula (IIIa):

[0822]

[0823] Where X 1 Selected from CR x1 and N;

[0824] X 2 Selected from CR x1 R x2 NR x2 and O;

[0825] Where R x1 Selected from H and R b ;and

[0826] R x2 Selected from H, C 1-4 Alkyl and C 1-4 haloalkyl; and

[0827] m is selected from 0, 1 and 2.

[0828] 9. A compound according to any one of Embodiments 1, 7 and 8, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (IIIb):

[0829]

[0830] Where R b C 1-4 Alkyl or C 1-6 Halogenated alkyl.

[0831] 10. A compound according to any one of embodiments 1, 2 and 7-9, or a pharmaceutically acceptable

[0832] The salt of which R 1 Selected from:

[0833]

[0834] Where R dSelected from H, C 1-4 Alkyl and C 1-4 haloalkyl; and wherein each R 1 Optionally, one to three R a replace.

[0835] 11. A compound according to any one of embodiments 1, 2 and 7-10, or a pharmaceutically acceptable salt thereof, wherein R 1 for And where R d C 1-4 alkyl.

[0836] 12. A compound according to any one of embodiments 1, 2 and 7-11, or a pharmaceutically acceptable salt thereof, wherein R 1 for

[0837] 13. A compound according to any one of embodiments 1, 2 and 7-9, wherein R 1 Selected from

[0838]

[0839] 14. A compound according to any one of embodiments 1, 2 and 7-9, wherein R 1 for

[0840] 15. The compound according to embodiment 1, wherein Z 1 is N, and Z 2 , Z 3 and Z 4 Each of is CH.

[0841] 16. The compound according to Embodiment 1 or 15, or a pharmaceutically acceptable salt thereof, wherein each R 3 and R 5 are independently selected from H and halo.

[0842] 17. A compound according to any one of Embodiments 1, 15 and 16, or a pharmaceutically acceptable salt thereof, wherein each R 3 and R 5 For H.

[0843] 18. A compound according to any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein each R 2 and R 6 are independently selected from H, halo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 Halogenated alkoxy.

[0844] 19. A compound according to any one of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, wherein each R 2 and R 6 Independently selected from F and -CH3.

[0845] 20. A compound according to any one of embodiments 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R 2 is F, and R 6 It is -CH3.

[0846] 21. A compound according to any one of embodiments 1-3, 7 and 10-20, or a pharmaceutically acceptable salt thereof, wherein R 4 is optionally replaced by one to three R b substituted 6-membered heterocyclic group; and wherein each R b independently selected from halogen, C 1-4 Alkyl and C 1-4 Halogenated alkyl.

[0847] 22. A compound according to any one of embodiments 1-21, or a pharmaceutically acceptable salt thereof, wherein R b Selected from -CH3, -CHF2 and -CF3.

[0848] 23. A compound according to any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, wherein R b It is -CF3.

[0849] 24. A compound according to any one of embodiments 1-3, 7 and 10-21, or a pharmaceutically acceptable salt thereof, wherein R 4 is optionally R b Replaced And where R b Selected from -CH3, -CHF2, -CF3, -CH2CHF2 and -CH2CF3.

[0850] 25. A compound according to any one of embodiments 1-3, 7, 10-21 and 24, or a pharmaceutically acceptable salt thereof, wherein R 4 for

[0851] 26. A compound according to any one of embodiments 1-3, 7, 10-21 and 24-25, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from

[0852] 27. A compound according to any one of embodiments 1-3, 7 and 10-20, or a pharmaceutically acceptable salt thereof, wherein R 4 For-NR b1 R b2 ; and where R b1 and R b2 Independently selected from H, C 1-4 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl.

[0853] 28. A compound according to any one of embodiments 1-3, 7, 10-20 and 27, or a pharmaceutically acceptable salt thereof, wherein R 4 for

[0854] 29. A compound according to any one of Embodiments 4 and 8, or a pharmaceutically acceptable salt thereof, wherein X 1 is N and X 2 is O.

[0855] 30. A compound according to any one of embodiments 7-12 and 14-29, or a pharmaceutically acceptable salt thereof, wherein R c Selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 Halogenated alkoxy.

[0856] 31. A compound according to any one of embodiments 7, 8-12 and 14-30, or a pharmaceutically acceptable salt thereof, wherein R c Selected from F, Cl, CH3, -OCH3, -OCF3 and -CF3.

[0857] 32. A compound according to any one of embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein R 7 Selected from H, C 1-6 Alkyl and C 3-6 Cycloalkyl.

[0858] 33. A compound according to any one of embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein R 7 Selected from H, methyl, ethyl, propyl, butyl, cyclopropyl, -CH2-OC(O)C(CH)3 and phenyl.

[0859] 34. The compound according to any one of embodiments 1-33, or a pharmaceutically acceptable salt thereof, R 7 Selected from H, methyl, ethyl and cyclopropyl.

[0860] 35. The compound according to any one of embodiments 1-34, or a pharmaceutically acceptable salt thereof, R 7 For H.

[0861] 36. A compound according to any one of embodiments 1-34, or a pharmaceutically acceptable salt thereof, wherein R 7 It is methyl.

[0862] 37. A compound according to any one of embodiments 1-34, or a pharmaceutically acceptable salt thereof, wherein R 7 It is ethyl.

[0863] 38. The compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R 8 For H.

[0864] 39. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Examples 1-93.

[0865] 40. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0866]

[0867]

[0868]

[0869]

[0870]

[0871] 41. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0872]

[0873]

[0874] 42. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0875]

[0876] 43. A pharmaceutical composition comprising a compound according to any one of embodiments 1-42 and at least one pharmaceutically acceptable carrier.

[0877] 44. A method for treating a disease or condition associated with α4β7 integrin, the method comprising administering to a subject an effective amount of a compound according to any one of embodiments 1-42, or a pharmaceutically acceptable salt thereof, or a composition according to embodiment 43.

[0878] 45. The method of embodiment 44, wherein the disease or condition is an inflammatory disease.

[0879] 46. ​​The method of any one of embodiments 44-45, 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).

[0880] 47. The method of any one of embodiments 44-45, further comprising administering an additional therapeutic compound.

[0881] 48. Use of a compound according to any one of embodiments 1-42, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition mediated by α4β7 integrin.

[0882] 49. Use of a compound according to any one of embodiments 1-42, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an inflammatory disease.

[0883] 50. Use of a compound according to any one of embodiments 1-42, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating inflammatory bowel disease (IBD).

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: --- is a single bond or a double bond; wherein A is an aromatic ring; Each Z 1 , Z 2 , Z 3 and Z 4 Independently selected from N, N(CR c ), C(O) and CR c ; where each R c are independently selected from H, halo, cyano, hydroxyl, -NR a1 R a2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 Haloalkoxy; R 1 is a 5-10 membered heteroaryl or a 6-10 membered heterocyclic group; Where R 1 Each of the 5-10 membered heteroaryl and 6-10 membered heterocyclyl contains one to four N and optionally one to three C(O) as ring members; and Where R 1 Each 5-10 membered heteroaryl and 6-10 membered heterocyclyl is optionally substituted by one to four R a Replace; and wherein each R a are independently selected from halo, cyano, hydroxyl, -NR a1 R a2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -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 selected from H, halo, cyano, hydroxyl, -NR a1 R a2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 Haloalkoxy; R 4 is selected from 3-10 membered heterocyclyl, 5-10 membered heteroaryl and -NR b1 R b2 ; Where R 4 The 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted by one to six R b Replace; and wherein each R b are independently selected from halo, cyano, hydroxyl, -NR a1 R a2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-8 Haloalkyl and C 1-8 haloalkoxy; and Each R b1 and R b2 Independently selected from 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 Selected from H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 1-4 Alkylene-NR a1 R a2 , -C 1-4 Alkylene-C(O)NR a1 R a2 , -C 1-4 Alkylene-C 3-10 Cycloalkyl, -C 1-4 Alkylene-3-14 membered heterocyclic group, -C 1-4 Alkylene-C 6-10 Aryl, -C 1-4 Alkylene-5-10 membered heteroaryl and -L 1 -R 9 ; Where L 1 Selected from -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 -; R 9 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; Where R 7 and R 9 Each C 3-10 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally independently selected from halo, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -NR a1 R a2 and -C 1-4 Alkylene-NR a1 R a2 substituted by one to four groups of R 8 Selected from H, C 1-6 Alkyl and C 1-6 haloalkyl; and Each R a1 and R a2 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl.

2. The compound according to claim 1, wherein the compound has formula (II): or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIa): where Y 1 N or CH; R d Selected from H, C 1-4 Alkyl and C 1-4 haloalkyl; and r is selected from 0, 1, 2 and 3.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIb): Where X 1 Selected from CR x1 and N; X 2 Selected from CR x1 R x2 NR x2 and O; Where R x1 Selected from H and R b ;and R x2 Selected from H, C 1-4 Alkyl and C 1-4 Haloalkyl; R d Selected from 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.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIc): Where R b C 1-4 Alkyl or C 1-6 haloalkyl; and R d Selected from H, C 1-4 Alkyl and C 1-4 Halogenated alkyl.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IId): Where R b C 1-4 Alkyl or C 1-6 Haloalkyl; R d C 1-4 Alkyl or C 1-4 haloalkyl; and Each R 2 and R 6 independently selected from halogen, C 1-4 Alkyl and C 1-4 Halogenated alkyl.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (III):

8. The compound according to claim 1 or 7, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIIa): Where X 1 Selected from CR x1 and N; X 2 Selected from CR x1 R x2 NR x2 and O; Where R x1 Selected from H and R b ;and R x2 Selected from H, C 1-4 Alkyl and C 1-4 haloalkyl; and m is selected from 0, 1 and 2.

9. The compound according to any one of claims 1, 7 and 8, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIIb): Where R b C 1-4 Alkyl or C 1-6 Halogenated alkyl.

10. The compound according to any one of claims 1, 2 and 7-9, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: Where R d Selected from H, C 1-4 Alkyl and C 1-4 haloalkyl; and wherein each R 1 Optionally, one to three R a replace.

Images