Compounds for the inhibition of α4β7 integrin

Abstract

To provide novel α4β7 integrin antagonists suitable for the treatment of autoimmune and inflammatory diseases, including inflammatory bowel disease.SOLUTION: The present invention provides a compound represented by the formula (III) or a pharmaceutically acceptable salt thereof. [R1 represents 5-10 membered heteroaryl or 6-10 membered heterocyclyl; R2 and R6 independently represent H, a halogen atom, cyano, hydroxyl, C1-4 alkyl, C1-4 alkoxyl, C1-4 haloalkyl, C1-4 haloalkoxyl or the like; R4 represents 3-10 membered heterocyclyl, 5-10 membered heteroaryl or the like; R7 represents H, C1-10 alkyl or the like; Rc represents a halogen atom, C1-4 alkyl, C1-4 alkoxyl, C1-4 haloalkyl, C1-4 haloalkoxyl or the like].SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 886,798, filed on August 14, 2019, the entire content of which is incorporated herein by reference.

[0002] The present disclosure generally relates to novel compounds having α4β7 integrin inhibitory activity, prodrugs of compounds having α4β7 integrin inhibitory activity, and methods of using and manufacturing the same.

Background Art

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

[0004] Integrins are heterodimeric proteins composed of α and β subunits. There are 18 known α subunits and 8 known β subunits. α4β7 integrin is expressed on the surface of lymphocytes and recognizes the extracellular ligand mucosal addressing cell adhesion molecule - 1 (MAdCAM - 1). It does so. α4β7 integrin is expressed on the veins in the intestinal mucosa and high endothelial venules (HEVs) in gut-associated lymphoid tissues (GALT), and manages lymphocyte transport and retention in the intestinal tissue through interaction with MAdCAM-1. Inhibiting the interaction of integrin with its respective ligand has been proposed as an effective way to treat various 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).

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

Summary of the Invention

Means for Solving the Problems

[0006] The present disclosure provides a compound that is an inhibitor of α4β7 integrin. The present disclosure also provides a composition comprising a pharmaceutical composition, a kit comprising a compound, and methods of using (or administering) a compound and methods of producing a compound. The compounds provided herein are useful in treating diseases, disorders, or conditions mediated by α4β7 integrin. The present disclosure also provides compounds for use in therapy. The present disclosure further provides compounds for use in a method of treating a disease, disorder, or condition mediated by α4β7 integrin. Moreover, the present disclosure provides the use of a compound in the manufacture of a medicament for the treatment of a disease, disorder, or condition mediated by α4β7 integrin.

[0007] In one aspect, a compound having the structure of formula (I),

Chemical formula

Chemical formula

Mode for Carrying Out the Invention

[0008] Definitions and General Parameters The following description clarifies exemplary methods, parameters, etc. However, such a description is not intended to limit the scope of the present disclosure, but rather should be recognized as being provided as an explanation of exemplary embodiments instead.

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

[0010] A dash ("-") not between two letters or symbols is used to indicate the point of attachment for a substituent. For example, -CONH2 is attached via a carbon atom. Dashes at the front or end of a chemical group are for convenience, and the chemical groups can be depicted with or without one or more dashes without losing their normal meaning. A wavy line drawn across a line in a structure indicates the point of attachment of a group. Unless required chemically or structurally, the order in which chemical groups are written or named does not indicate or imply directionality.

[0011] For example, a wavy line on a chemical group as shown below,

Chemical Formula

[0012] “C u~vThe prefix "C" 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.

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

[0014] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C 1~20 alkyl), 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, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl group having a specific number of carbons is named by a chemical name or identified by a molecular formula, all possible positional isomers having that number of carbons can be included. Thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), iso-butyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0015] "Alkylene" (including those which are part of another group) 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, butylene, 1-methylpropylene, 1,1-dimethylethylene, or 1,2-dimethylethylene. Unless otherwise specified, the definitions of propylene and butylene include all possible isomeric forms of the group in question having the same number of carbons. Thus, for example, propylene includes 1-methylethylene, and butylene includes 1-methylpropylene, 1,1-dimethylethylene, and 1,2-dimethylethylene.

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

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

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

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

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

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

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

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

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

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

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

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

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

[0029] As used herein, the terms "heterocyclyl" or "heterocyclic" refer to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic 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 specified, a heterocyclyl group has from 3 to about 20 ring atoms, such as from 3 to 12 ring atoms, such as from 3 to 10 ring atoms, such as from 5 to 10 ring atoms, or such as from 5 to 6 ring atoms. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) having from about 1 to 6 cyclic carbon atoms and from about 1 to 3 cyclic heteroatoms independently selected from the group consisting of O, N, S, S(O), S(O)2, and N-oxide. The rings of a polycondensed ring (e.g., bicyclic heterocyclyl) system can be connected to each other via condensation, spiro, and bridging bonds where valence requirements permit. Examples of heterocycles include, but are not limited to, groups derived from azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, tetrahydro-2H-thiopyran, 1,1-dioxide, quinuclidine, N-bromopyrrolidine, N-chloropyrrolidine, etc. Heterocycles include spiro rings such as, for example, azo- or oxo-spiroheptane. A heterocyclyl group also includes a partially unsaturated ring system containing one or more double bonds and a fused ring system having one aromatic ring and one non-aromatic ring but not a fully aromatic ring system. Examples include dihydroquinoline, such as 3,4-dihydroquinoline, dihydroisoquinoline, such as 1,2-dihydroisoquinoline, dihydroimidazole, tetrahydroimidazole, etc., indoline, isoindoline, isoindrone (e.g., isoindolin-1-one), isatin, dihydrophthalazine, quinolinone, spiro[cyclopropane-1,1'-isoindoline]-3'-one, etc.Examples of additional complex rings include, for example, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl, and hexahydropyrazino[2,1-c][1,4]oxazinyl.

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

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

[0032] "Sulfonyl" refers to a -S(O)2R group, where R is alkyl, haloalkyl, It is heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0033] Whenever the graphical representation of a group ends with a singly-bonded nitrogen atom, that group represents an -NH group, unless otherwise indicated. Similarly, unless otherwise specified, hydrogen atom(s) are implied and considered to be present as necessary to complete the valence or provide stability, taking into account the knowledge of those skilled in the art.

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

[0035] The terms "optionally" or "optionally may" mean that the event or situation described thereafter may or may not occur, and that the description includes both the case where the event or situation occurs and the case where the event or situation does not occur. Also, the term "optionally substituted" refers to any one or more hydrogen atoms on a specified atom or group that may or may not be replaced by a moiety other than hydrogen.

[0036] 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, amino, amide, amidino, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar indefinite structures obtained by defining substituents with further substituents added ad infinitum (e.g., a substituted aryl having a substituted alkyl, where the substituted alkyl itself is substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc., a substituted aryl) are not intended to be included herein. Unless otherwise stated, the maximum number of consecutive substitutions in the compounds described herein is 3. For example, consecutive substitution of a substituted aryl group by two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the foregoing definitions are not intended to include unacceptable substitution patterns (e.g., a methyl substituted with five fluorine or heteroaryl groups having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" can describe other chemical groups as defined herein. For example, the term "substituted aryl" includes, but is not limited to, "alkylaryl". Unless otherwise specified, when a group is described as optionally substituted, any substituent of the group is itself unsubstituted.

[0037] In some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In additional embodiments, "substituted cycloalkyl" refers to a cycloalkyl group having one or more substituents including alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl, and "substituted heterocyclyl" refers to a heterocyclyl group having one or more substituents including alkyl, haloalkyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl, "substituted aryl" refers to an aryl group having one or more substituents including halo, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano, "substituted heteroaryl" refers to a heteroaryl group having one or more substituents including halo, alkyl, haloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano, and "substituted sulfonyl" refers to the group -S(O)2R where R is substituted with one or more substituents including alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, one or more of the substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

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

[0039] Any formula or structure given herein is also intended to represent both the unlabeled form and the isotopically labeled form of the compound. An isotopically labeled compound has a structure shown by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present disclosure include 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I, etc., including but not limited to isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine. Various isotopically labeled compounds of the present disclosure are, for example, 3 H, 13 C, and 14 C, etc., incorporated with radioactive isotopes. Such isotopically labeled compounds are used in detection or imaging techniques such as metabolic studies, reaction kinetics studies, positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including tissue distribution assays of drugs or substrates, or It may be useful in the radioactive treatment of patients.

[0040] The present disclosure also includes compounds of the present disclosure in which 1 to n hydrogens bonded to a carbon atom are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful for extending 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 means well known in the art, for example, by employing starting materials in which one or more hydrogens are replaced by deuterium.

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

[0042] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotope 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", that position is understood to have the hydrogen with the isotopic composition of the natural abundance of hydrogen. For this reason, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0043] In many cases, the compounds of the present disclosure can form acidic salts and / or basic salts due to the presence of amino groups and / or carboxyl groups or similar groups.

[0044] The term "pharmaceutically acceptable salts" of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and are not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic bases and organic bases. Salts derived from inorganic bases include, by way of example only, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, and magnesium salts. Salts derived from organic bases include salts of primary, secondary, and tertiary amines such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dialkenylamines, trialkenylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, mono-, di- or tricycloalkylamines, mono-, di- or triarylamines, or mixed amines, but are not limited thereto. 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.

[0045] 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, and the like. 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, and the like.

[0046] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any solvent, dispersion medium, coating, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. The use of any conventional media or agent in a therapeutic composition is contemplated as long as it is not incompatible with the active ingredient. Supplementary active ingredients can also be incorporated into the composition.

[0047] "Treatment" or "treating" is an approach for obtaining beneficial or desirable results, including clinical results. Beneficial or desirable clinical results can include one or more of the following: namely, a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition and / or attenuating the degree of the disease or condition), b) delaying or preventing the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (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 complete remission of the disease or condition, enhancing the effect of another drug, delaying the progression of the disease, improving the quality of life, and / or prolonging survival).

[0048] "Prevention" or "preventing" means any treatment of a disease or condition that does not result in the clinical symptoms of the disease or condition developing. In some embodiments, the compound may be administered to a subject (including a human) at risk or having a family history of a disease or condition.

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

[0050] The term "therapeutically effective amount" or "effective amount" of a compound or a pharmaceutically acceptable salt, isomer, or mixture thereof described herein means an amount sufficient to provide a therapeutic benefit when administered to a subject, such as improving symptoms or retarding the progression of a disease. For example, a therapeutically effective amount may be an amount sufficient to reduce the symptoms of a disease or condition in response 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, and can be readily determined by one of ordinary skill in the art.

[0051] The term "inhibition" indicates a decrease in the baseline activity of a biological activity or process. "Inhibition of the activity of α4β7 integrin" or variations thereof refers to a decrease in the activity of α4β7 integrin as a direct or indirect response to the presence of a compound of the present application relative to the activity of α4β7 integrin in the absence of the compound of the present application. "Inhibition of α4β7" refers to a decrease in the activity of α4β7 integrin as a direct or indirect response to the presence of a compound described herein relative to the activity of α4β7 integrin in the absence of the compound described herein. In some embodiments, the inhibition of α4β7 integrin activity may be compared in the same subject before treatment or in another untreated subject. Compound

[0052] This specification provides compounds that function as inhibitors of α4β7 integrin. In one aspect, a compound having the structure of formula (I),

Chem.

Chem.

[0053] In another aspect, a compound of formula (II), or a pharmaceutically acceptable salt thereof, is provided,

Chemical formula

[0054] In another aspect, a compound of formula (IIa), or a pharmaceutically acceptable salt thereof, is provided,

Chemical formula

[0055] In another aspect, there is provided a compound of formula (IIb), or a pharmaceutically acceptable salt thereof, [Chemical formula] wherein R a , R 2 , R 6 , R 7 , and R b are as defined above in formula (I) and formula (II), or as defined elsewhere in the present disclosure. X 1 is selected from CR x1 and N. X 2 is selected from CR x1 R x2 , NR x2 , and O. R x1 is selected from H and R b , and R x2 is selected from H, C 1~4 alkyl, and C 1~4 haloalkyl. R d is 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.

[0056] In another aspect, there is provided a compound of formula (IIc), or a pharmaceutically acceptable salt thereof, [Chemical formula] wherein R 2 , R 6 , and R 7 are as defined above in formula (I) and formula (II), or as defined elsewhere in the present disclosure. R b is C 1~4 alkyl, or C 1~6 haloalkyl. R d is selected from H, C 1~4 alkyl, and C 1~4 haloalkyl.

[0057] In another aspect, there is provided a compound of formula (IId), or a pharmaceutically acceptable salt thereof, [Chemical formula] wherein R 7 is as defined above in formula (I) or formula (II), or as defined elsewhere in this disclosure. Each R 2 and R 6 is independently selected from halo, C 1~4 alkyl, and C 1~4 haloalkyl. R b is C 1~4 alkyl, or C 1~6 haloalkyl. R d is H, C 1~4 alkyl, or C 1~4 haloalkyl.

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

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

[0060] In another aspect, a compound of formula (IIIb), or a pharmaceutically acceptable salt thereof, is provided,

Chemical formula

[0061] In another aspect, a compound of formula (IV), or a pharmaceutically acceptable salt thereof, is provided,

Chemical formula

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

[0063] In some embodiments of formula (I), (II), (III), (IIIa), or (IIIb), R 1 is

Chemical formula

Chemical formula

[0064] In some embodiments of formula (I), (II), (III), (IIIa), or (IIIb), R 1 is​​ [Chemical formula] and R d is C 1~4 alkyl. In some embodiments, R d is methyl or ethyl. In some embodiments, R d is methyl. In some embodiments, R 1 is [Chemical formula] is.

[0065] In some embodiments of formula (I), (II), (III), (IIIa), or (IIIb), R 1 is a a optionally substituted with 1 to 3 R [Chemical formula] is. In some embodiments, R 1 is [Chemical formula] selected from. In some embodiments, R 1 is [Chemical formula] is.

[0066] In some embodiments of formula (I), (II), (III), (IIIa), or (IIIb), R 1 is a 10-membered heterocyclyl containing two N's and two C(O)'s as ring members, and R 1 is optionally substituted with 1 to 3 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 1and [Chem.] selected from, each of which is optionally substituted with 1 to 3 R a In some embodiments, R d is -CH3. In some embodiments, R 1 is [Chem.] In some embodiments, R 1 is [Chem.] In some embodiments of formula (I), (II), (III), (IIIa), or (IIIb), R

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

[0068] is 1 is [Chem.] In some embodiments, R d is -CH3. In some embodiments, R 1 is [Chem.] In some embodiments of formula (I), Z

[0069] is N. Z 1 Z 2 , Z 3 , and Z 4 is CR c In some embodiments, Z 1is N, and Z 2 , Z 3 , and Z 4 is CH. In some embodiments, Z 3 is N, and Z 1 , Z 2 , and Z 4 is CR c . In some embodiments, Z 1 and Z 2 are N. In some embodiments, Z 1 and Z 3 are N. In some embodiments, Z 1 is CR c , and R c is C 1~4 alkyl, C 1~4 alkoxyl, C 1~4 haloalkyl, and C 1~4 haloalkoxyl. In some embodiments, Z 1 is CR c , and R c is selected from -CH3, -OCH3, and -CF3. In some embodiments, Z 1 is C-OCH3.

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

[0071] In some embodiments of formula (I), (II), (IIa), (IIb), (IIc), (IId), (III) , (IIIa), or (IIIb), each R 2 and R 6 is independently selected from H, halo, C 1~4 alkyl, C 1~4 alkoxyl, C 1~4 haloalkyl, and C 1~4 haloalkoxyl. In some embodiments, each R 2 and R6 is independently selected from F and -CH3. In some embodiments, R 2 is F, and R 6 is -CH3.

[0072] In some embodiments of formula (I), (II), (IIa), or (III), R 4 is a 3- to 8-membered heterocyclyl optionally substituted with one to three R b . In some embodiments, the 3- to 8-membered heterocyclyl of R 4 contains one to two heteroatoms or independently contains a group selected from S, N, O, and S(O)2. In some embodiments, each R b is independently selected from halo, hydroxyl, cyano, -NR a1 R a2 , C 1~4 alkyl, C 1~4 alkoxyl, and C 1~4 haloalkyl. In some embodiments, each R b is independently selected from F, Cl, CN, -OH, -CH3, -CH(CH3)2, -CF3, and -CH2CF3.

[0073] In some embodiments of formula (I), (II), (IIa), or (III), R 4 is a 6-membered heterocyclyl optionally substituted with one to three R b . In some embodiments, R 4 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0074] In some embodiments of formula (I), (II), (IIa), or (III), R 4 is

Chemical formula

Chemical formula

[0075] In some embodiments of formula (I), (II), (IIa), or (III), R 4 is -NR b1 R b2 . In some embodiments, each R b1 and R b2 is independently selected from H, C 1~6 alkyl, C 1~6 haloalkyl, and C 3~6 cycloalkyl. In some embodiments, R b1 is H and R b2 is C 1~6 haloalkyl. In some embodiments, R 4 is

Chemical formula

Chemical formula

[0076] In some embodiments of formula (I), (II), (IIa), or (III), R 4 is 5- to 10-membered heteroaryl optionally substituted with one to three R b , and each R b is independently selected from halo, C 1~4 alkyl, and C 1~4 haloalkyl. In some embodiments, R 4 is 5-membered heteroaryl optionally substituted with one to three R b . In some embodiments, R 4 is pyrrolyl optionally substituted with one to three R b . In some embodiments, R 4 is imidazolyl optionally substituted with one to three R b . In some embodiments, each R b is independently selected from -CH3, -CHF2, -CF3, and -CH2CF3. In some embodiments, R 4 is [Chemistry] is. In some embodiments, R 4 is [Chemistry] is. In some embodiments, R b is selected from -CH3, -CHF2, -CF3, and -CH2CF3.

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

[0078] In some embodiments of formula (III), (IIIa), or (IIIb), R c is selected from halo, C 1~4 alkyl, C 1~4 alkoxyl, C 1~4 haloalkyl, and C 1~4 haloalkoxyl. In some embodiments, R c is selected from F, Cl, CH3, -OCH3, -OCF3, and -CF3. In some embodiments, R c is -OCH3.

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

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

[0081] In some embodiments, the compounds of the present disclosure are selected from Examples 1 to 53.

[0082] In some embodiments, the compounds of the present disclosure are selected from Examples 54 to 93.

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

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

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

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

[0087] "Prodrugs" are biologically inactive derivatives of a drug that are converted into a biologically active parent drug upon administration into the human body via several chemical or enzymatic pathways. Accordingly,

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

[0089] When chirality is not specified but is present, embodiments are understood to be directed to either a particular diastereomerically or enantiomerically enriched form, or a racemic or scalemic mixture of such compound(s).

[0090] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. A mixture of enantiomers in a ratio other than 1:1 is a "scalemic" mixture.

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

[0092] "Atropisomers" are stereoisomers that result from hindrance to rotation around a single bond, and the barrier to rotation around the bond is high enough to permit isolation of the individual stereoisomers. Also provided are the atropisomers of the compounds described herein.

[0093] The compositions provided herein, which include the compounds described herein or pharmaceutically acceptable salts, isomers, or mixtures thereof, can include racemic mixtures, or mixtures containing one enantiomer with enantiomeric excess or a single diastereomer, or mixtures of diastereomers. All such isomeric forms of these compounds are expressly included herein as if each and every isomeric form were specifically and individually recited.

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

[0095] The methods described herein may be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, such as inside an animal or a human. In this context, the methods described herein may be used therapeutically in an individual. "Ex vivo" means outside of a living individual. Examples of cell populations ex vivo include in vitro cell cultures and biological samples including fluids 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 encompasses various purposes including treatment and experimentation It can be used for various purposes. For example, the present invention can be used ex vivo to determine the optimal schedule and / or dosage of administration of an α4β7 integrin inhibitor for a given indication, cell type, individual, and other parameters. Information collected from such use can be used for experimental purposes or to set protocols for in vivo treatment in a clinic. Other ex vivo uses for which the present invention may be suitable are described below or will be apparent to those skilled in the art. The selected compound can be further characterized to examine its safety or tolerable dosage in human or non-human subjects. Such characteristics can be examined using methods generally known to those skilled in the art.

[0096] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, or deuterated analogs thereof, may be used to treat a subject having or suspected of having a disease state, disorder, and condition (collectively also referred to as an "indication") that is responsive or thought to be responsive to inhibition of α4β7 integrin activity. In some embodiments, the compounds described herein can be used to inhibit the activity of α4β7 integrin. In some embodiments, the compounds described herein can be used to inhibit an immune response, growth, or proliferation that is excessive or destructive, such as in cancer cells, or to inhibit immunosuppression.

[0097] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, or deuterated analogs thereof, may be used to treat a subject having or suspected of having a disease state, disorder, and condition (collectively also referred to as "indications") that is responsive or thought to be responsive to inhibition of α4β7 integrin activity. In some embodiments, the compounds described herein may be used to inhibit the activity of α4β7 integrin. In some embodiments, the compounds described herein may be used to inhibit an immune response or growth or proliferation of cells, such as cancer cells, that are excessive or destructive, or to inhibit immunosuppression. Method

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

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

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

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

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

[0103] In some embodiments, provided are compounds described herein that are useful for treating a disease or condition in a patient suitable for treatment by inhibiting α4β7 integrin. Diseases or conditions that can be treated with the compounds described herein include solid tumors, diabetes, inflammatory diseases, graft-versus-host disease, primary sclerosing cholangitis, HIV, autoimmune diseases, inflammatory bowel disease (IBD), alcoholic hepatitis, fatty liver, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), systemic lupus erythematosus (SLE), and lupus nephritis. In some embodiments, provided are compounds described herein that are useful for treating an inflammatory disease or condition in a patient, at least in part, mediated by α4β7 integrin. "Administering" or "administration" refers to the delivery of one or more therapeutic agents to a patient. In some embodiments, administration is monotherapy, where the compound described herein is the only active ingredient administered to a patient in need of treatment. In another embodiment, administration is co-administration, where two or more therapeutic agents are delivered together during the course of treatment. In some embodiments, two or more therapeutic agents are co-formulated into a single dosage form or "combination dosage unit", such as in the case of intravenous or oral administration as a single-layer or bilayer tablet or capsule, or are formulated separately and then combined into a combined dosage form unit.

[0104]

[0105]

[0106] ​​In some embodiments, the compounds described herein are administered to a human patient in need thereof in an effective amount, such as from about 0.1 mg to about 1000 mg per dose of the compound. In some embodiments, the effective amount is from about 0.1 mg to about 400 mg per dose. In some embodiments, the effective amount is from about 0.1 mg to about 300 mg per dose. In some embodiments, the effective amount is from about 0.1 mg to about 200 mg per dose. In some embodiments, the effective amount is from about 1 mg to about 100 mg per dose. In other embodiments, the effective amount is, per dose, 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.

[0107] In some embodiments, the compounds described herein and at least one additional therapeutic agent are each administered to a human patient in need thereof in an effective amount, independently, from about 0.1 mg to about 1000 mg per dose of the compound, or in a dosage formulation per compound, per dose. In some embodiments, the effective amount of the combination treatment of the compounds described herein and an additional compound is, independently, from about 0.1 mg to about 200 mg per dose of the compound. In some embodiments, the effective amount of the combination treatment of the compounds described herein and an additional compound is, independently, from about 1 mg to about 100 mg per dose of the compound. In other embodiments, the effective amount of the combination treatment of the compounds described herein and an additional compound is, for each component, per dose, each of 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.

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

[0109] Co-administration may also involve administering the constituent drugs, e.g., one or more of the compounds described herein, and one or more additional (e.g., second, third, fourth, or fifth) therapeutic agent(s). Such combinations of one or more of the compounds described herein and one or more additional therapeutic agent(s) can be administered simultaneously or sequentially (alternately) within a suitable period for each administration (e.g., about 1 minute to 24 hours), depending on the pharmacokinetic and / or pharmacodynamic properties of each agent or combination. Co-administration may also include treatment with a fixed combination, and the agents of the treatment regimen can be combined in a fixed dosage or combined dosage form, e.g., as a solid, liquid, or aerosol. In some embodiments, a kit can be used to administer the drug or drug component.

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

[0111] "Intravenous administration" is the administration of a substance into a vein or "intravenously". Compared to other routes of administration, the intravenous (IV) route is for delivering fluids and drugs throughout the body It is a faster method. An infusion pump can enable precise control over the flow rate and total amount of the drug being delivered. However, if changes in flow rate do not have serious consequences or the pump is not available, the drip is often simply allowed to flow by placing the bag above the patient's height and adjusting the rate using a clamp. Alternatively, if the patient requires a high flow rate and the IV access device has a diameter large enough to accommodate it, a rapid infuser can be used. This is either an inflatable cuff placed around the fluid bag to force the fluid into the patient or a similar electrical device that can also heat the fluid being infused. If the patient requires the drug only at specific times, intermittent infusion, which does not require additional fluid, is used. This can use the same technology as a continuous IV drip (pump or gravity drip), but after the full dose of the drug has been given, the tubing is disconnected from the IV access device. Some drugs are also given by IV push or bolus. That is, a syringe is connected to the IV access device and the drug is injected directly (slowly if it irritates the vein or causes a rapid effect). When a pharmaceutical is injected into the fluid flow of an IV tube, there must be some means to ensure that it reaches the patient from the tube. Usually, this is achieved by allowing the fluid flow to occur normally, thereby carrying the pharmaceutical into the bloodstream. However, a second fluid injection may be used as a "flush" after the injection to more rapidly flush the pharmaceutical into the bloodstream. Thus, in some embodiments, the compound(s) or combination of compounds described herein can be administered by IV administration, either alone or in combination with the administration of specific components of a treatment regimen via oral or parenteral routes.

[0112] "Oral administration" is an administration route by which a substance is ingested through the mouth and does not involve direct contact of the drug with any part of the oral mucosa, such as via a tube, and includes buccal administration, sub labial administration, and sublingual administration, as well as enteral administration and administration through the airway It includes. Typical forms for oral administration of therapeutic agents include the use of tablets or capsules. Thus, in some embodiments, the compound(s) or combination of compounds described herein can be administered orally, either alone or in combination with the administration of specific components of a treatment regimen via the IV or parenteral route. Pharmaceutical preparation

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

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

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

[0116] When preparing a pharmaceutical composition comprising a compound described herein, optionally in combination with additional agents / therapies useful therefor and / or its pharmaceutically acceptable salts, the active ingredient is usually diluted by an excipient or carrier and / or enclosed or mixed in a carrier which can be in the form of a capsule, sachet, paper, or other container. When the excipient functions as a diluent, the excipient can be a solid, semi-solid, or liquid material (such as those described above) which acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, troches, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), for example, ointments containing up to 20% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solvents, and sterile packaged powders.

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

[0118] The compositions of the present disclosure may be formulated to provide immediate, sustained, or delayed release of the active ingredient(s) after administration to a patient by employing procedures known in the art. In some embodiments, sustained release formulations are used. Examples of controlled release drug delivery systems for oral administration include osmotic pump systems and solution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Certain compositions are preferably formulated in unit dosage form. The term "unit dosage form" or "combined dosage unit" refers to physically discrete units suitable as a single dosage for human subjects and other mammals, each unit containing a predetermined amount of one or more active materials (e.g., the compounds described herein, optionally in combination with additional therapeutic agents calculated to produce the desired effect), accompanied by suitable pharmaceutical excipients, e.g., in tablets, capsules, ampoules, or vials for injection. However, it will be understood that the actual amount of each agent administered will be determined by the physician in view of relevant circumstances including the condition being treated, the chosen route of administration, the actual compounds administered, and their relative activities, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0119] To prepare solid compositions such as tablets, the principal active ingredient(s) is / are mixed with pharmaceutical excipients to form a solid pre-formulation composition containing a homogeneous mixture of the compounds of the present disclosure. When these pre-formulation compositions are referred to as homogeneous, it means that the active ingredient(s) is / are uniformly dispersed throughout the composition, such that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0120]

[0121] ​Tablets or pills containing the compounds described herein, optionally in combination with a second agent, may be coated or otherwise formulated to provide a dosage form that affords the advantages of extended action or protects from the acidic conditions of the stomach. For example, a tablet or pill can include an inner dosage element and an outer dosage element, the latter being in the form of an envelope over the former. In some embodiments, the inner dosage element may contain the compounds described herein, and the outer dosage element may contain a second therapeutic agent or additional therapeutic agent, or vice versa. Alternatively, the combined dosage unit may be in a parallel configuration such as a capsule or tablet where one part or half of the tablet or capsule is filled with a formulation of the compounds described herein, while the other part or half of the tablet or capsule contains an additional therapeutic agent. The other part or half of the capsule contains an additional therapeutic agent, which may be in a parallel configuration such as a capsule or tablet.

[0122] Such enteric layers or enteric coatings may use a variety of materials, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate. Those skilled in the art are familiar with the techniques and materials used in the manufacture of dosages of the formulations disclosed herein.

[0123] A "sustained release formulation" or "extended release formulation" is a formulation designed to slowly release a therapeutic agent into the body over an extended period of time, whereas an "immediate release formulation" is a formulation designed to rapidly release a therapeutic agent into the body over a shortened period of time. In some cases, an immediate release formulation may be coated such that only the therapeutic agent is released when the therapeutic agent reaches a desired target in the body (e.g., the stomach). Those skilled in the art can develop sustained release formulations of the compounds of the present disclosure without undue experimentation. Thus, in some embodiments, the compound(s) or combination of compounds described herein can be delivered via a sustained release formulation, either alone or in combination with the administration of specific components of a treatment regimen via oral, IV, or parenteral routes.

[0124] Lyophilized formulations can also be used to administer the compounds described herein, either alone or in combination with additional therapeutic agents. Those skilled in the art are aware of methods for preparing and using lyophilized formulations of drug substances suitable for lyophilization.

[0125] Spray-dried formulations can also be used to administer the compounds described herein, either alone or in combination with additional therapeutic agents. Those skilled in the art are aware of methods for preparing and using spray-dried formulations of drug substances suitable for spray drying. Other known formulation techniques can also be utilized to formulate the compounds or combinations of compounds disclosed herein.

[0126] The compounds disclosed in this specification are useful, at least in part, for the treatment of diseases or conditions mediated by α4β7 integrin. Non-limiting examples of diseases or conditions mediated, at least in part, by α4β7 integrin include acne, acid-induced lung injury, Addison's disease, adrenal hyperplasia, 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 pectoris, angioedema, angiofibroma, anhidrotic ectodermal dysplasia, anti-glomerular basement membrane antibody disease, antigen-antibody complex-dependent diseases, ankylosing spondylitis, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, ascites, aspergillosis, asthma, atherosclerosis, atherosclerotic plaque, atopic dermatitis, atrophic thyroiditis, autoimmune diseases, autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria), autoimmune polyendocrine syndrome, autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia), autoimmune hepatitis, autoimmune thyroid disorders, autoinflammatory diseases, back pain, anthrax infection, Behçet's disease, bee sting-induced inflammation, Behçet's syndrome, Bell's palsy, beryllium disease, Braun's syndrome, bone pain, bronchiolitis, bullous pemphigoid (BP) asthma, burns, bursitis inflammation, cardiac hypertrophy, carpal tunnel syndrome, Castleman's disease, catabolic disorder )、cataract, celiac disease, cerebral aneurysm, chemical irritant-induced inflammation, chorioretinitis, lipodystrophy and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome ​syndrome, chronic heart failure, chronic lung disease of prematurity, chronic obstructive pulmonary disease (COPD), chronic pancreatitis, chronic prostatitis, chronic recurrent multifocal osteomyelitis, cicatricial alopecia, colitis, complex regional pain syndrome, complications of organ transplantation, conjunctivitis, connective tissue disease, contact dermatitis, corneal graft neovascularization, corneal ulcer, Crohn's disease, cryopyrin-associated periodic syndrome, cutaneous lupus erythematosus (CLE), cryptococcus disease, cystic fibrosis, deficiency of the interleukin-1 receptor antagonist (DIRA), dermatitis, dermatitis endotoxemia, dermatomyositis, diabetic macular edema, diverticulitis, eczema, encephalitis, endometriosis, endotoxemia, eosinophilic pneumonia, maxillary sinusitis, epidermolysis bullosa, erythema multiforme, erythroblastopenia, esophagitis, familial amyloidotic polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth retardation, fibromyalgia, fistulizing Crohn's disease, food allergy, giant cell arteritis, glaucoma, granuloma, glomerular disease, glomerular nephritis, glomerulonephritis, gluten-sensitive enteropathy, gout, gouty arthritis, graft-versus-host disease (GVHD), granulomatous hepatitis, Graves' disease, epiphyseal plate injury, Guillain-Barré syndrome, intestinal disease, hair loss, Hashimoto's thyroiditis, head trauma, headache, hearing impairment, heart disease, hemangioma, hemolytic anemia, hemophilic arthropathy, Henoch-Schönlein purpura, hepatitis, fatty liver, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hereditary periodic syndrome, hereditary disorders of connective tissue, herpes zoster and herpes simplex, hidradenitis suppurativa (HS), hip replacement, hoji disease, and so on. Gaucher disease, Huntington's disease, macular dystrophy, hyperactive inflammatory response, hyperammonemia, hypercalcemia, hypercholesterolemia, hypereosinophilic syndrome (HES), hyperimmunoglobulinemia D with recurrent fever (HIDS), hypersensitivity pneumonitis, hypertrophic osteogenesis, aplastic anemia and other anemias, ichthyosis, idiopathic demyelinating polyneuropathy, idiopathic inflammatory myopathy (dermatomyositis, polymyositis), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, immunoglobulin nephropathy, immune complex nephritis, immune thrombocytopenic purpura (ITP), incontinentia pigmenti (IP) (Bloch-Siemens syndrome), infectious mononucleosis, acquired immunodeficiency syndrome (HIV infection), hepatitis A, B, C, D and E, infectious diseases including viral diseases such as herpes, inflammation, inflammation of the central nervous system (CNS), inflammatory bowel disease (IBD), inflammatory diseases of the lower respiratory tract including bronchitis or chronic obstructive pulmonary disease, inflammatory diseases of the upper respiratory tract including the nose and paranasal sinuses such as rhinitis or sinusitis, inflammatory diseases of the airway, inflammatory ischemic events such as stroke or cardiac arrest, inflammatory lung diseases, inflammatory myopathies such as myocarditis, inflammatory liver diseases, inflammatory neuropathies, inflammatory pain, insect sting-induced inflammation, interstitial cystitis, interstitial lung diseases, iritis, irritant-induced inflammation, ischemia / reperfusion, joint replacement, juvenile arthritis, juvenile rheumatoid, keratitis, kidney disorders due to parasitic infections, transplanted kidney rejection, leptospirosis, leukocyte adhesion deficiency, lichen sclerosus (LS), Lambert-Eaton myasthenic syndrome response), hyperammonemia, hypercalcemia, hypercholesterolemia, hypereosinophilic syndrome (HES), hyperimmunoglobulinemia D with recurrent fever (HIDS), hypersensitivity pneumonitis, hypertrophic osteogenesis, aplastic anemia and other anemias, ichthyosis, idiopathic demyelinating polyneuropathy, idiopathic inflammatory myopathy (dermatomyositis, polymyositis), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, immunoglobulin nephropathy, immune complex nephritis, immune thrombocytopenic purpura (ITP), incontinentia pigmenti (IP) (Bloch-Siemens syndrome), infectious mononucleosis, acquired immunodeficiency syndrome (HIV infection), hepatitis A, B, C, D and E, infectious diseases including viral diseases such as herpes, inflammation, inflammation of the central nervous system (CNS), inflammatory bowel disease (IBD), inflammatory diseases of the lower respiratory tract including bronchitis or chronic obstructive pulmonary disease, inflammatory diseases of the upper respiratory tract including the nose and paranasal sinuses such as rhinitis or sinusitis, inflammatory diseases of the airway, inflammatory ischemic events such as stroke or cardiac arrest, inflammatory lung diseases, inflammatory myopathies such as myocarditis, inflammatory liver diseases, inflammatory neuropathies, inflammatory pain, insect sting-induced inflammation, interstitial cystitis, interstitial lung diseases, iritis, irritant-induced inflammation, ischemia / reperfusion, joint replacement, juvenile arthritis, juvenile rheumatoid, keratitis, kidney disorders due to parasitic infections, transplanted kidney rejection, leptospirosis, leukocyte adhesion deficiency, lichen sclerosus (LS), Lambert-Eaton myasthenic syndrome response), hyperammonemia, hypercalcemia, hypercholesterolemia, hypereosinophilic syndrome (HES), hyperimmunoglobulinemia D with recurrent fever (HIDS), hypersensitivity pneumonitis, hypertrophic osteogenesis, aplastic anemia and other anemias, ichthyosis, idiopathic demyelinating polyneuropathy, idiopathic inflammatory myopathy (dermatomyositis, polymyositis), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, immunoglobulin nephropathy, immune complex nephritis, immune thrombocytopenic purpura (ITP), incontinentia pigmenti (IP) (Bloch-Siemens syndrome), infectious mononucleosis, acquired immunodeficiency syndrome (HIV infection), hepatitis A, B, C, D and E, infectious diseases including viral diseases such as herpes, inflammation, inflammation of the central nervous system (CNS), inflammatory bowel disease (IBD), inflammatory diseases of the lower respiratory tract including bronchitis or chronic obstructive pulmonary disease, inflammatory diseases of the upper respiratory tract including the nose and paranasal sinuses such as rhinitis or sinusitis, inflammatory diseases of the airway, inflammatory ischemic events such as stroke or cardiac arrest, inflammatory lung diseases, inflammatory myopathies such as myocarditis, inflammatory liver diseases, inflammatory neuropathies, inflammatory pain, insect sting-induced inflammation, interstitial cystitis, interstitial lung diseases, iritis, irritant-induced inflammation, ischemia / reperfusion, joint replacement, juvenile arthritis, juvenile rheumatoid, keratitis, kidney disorders due to parasitic infections, transplanted kidney rejection, leptospirosis, leukocyte adhesion deficiency, lichen sclerosus (LS), Lambert-Eaton myasthenic syndrome Group, Reiter's syndrome, lupus, lupus nephritis, Lyme disease, Marfan syndrome (MFS), mast cell activation syndrome, mastocytosis, meningitis, meningioma, mesothelioma, mixed connective tissue disease, Macular Wells syndrome (urticaria deafness amyloidosis), mucositis, multiple organ dysfunction syndrome, multiple sclerosis, muscle wasting, muscular dystrophy, myasthenia gravis (MG), myelodysplastic syndrome, myocarditis, myositis, rhinosinusitis, necrotizing enteritis, neonatal onset multisystem inflammatory disease (NO MID), neovascular glaucoma, nephrotic syndrome, neuritis, neuropathological diseases, non-allergen-induced asthma, obesity, eye allergy, optic neuritis, organ transplant rejection, Osler-Weber syndrome, osteoarthritis, osteogenesis imperfecta, osteonecrosis, osteoporosis, osteoarthritis, otitis, congenital hypertrophy of nails, Paget's disease, bone Paget's disease, pancreatitis, Parkinson's disease, juvenile rheumatoid arthritis, pelvic inflammatory disease, pemphigus, pemphigus vulgaris (PV), bullous pemphigoid (BP), pericarditis, periodic fever, periodontitis, peritoneal endometriosis, malignant ​Anemia (Addison's disease), whooping cough, PFAPA (periodic fever, aphthous pharyngitis, and cervical adenitis), pharyngitis and adenitis (PFAPA syndrome), phytogenic irritant-induced inflammation, Pneumocystis infection, pneumonia, pneumonitis, Rhus / tox oil-induced inflammation, polyarteritis nodosa, polychondritis, polycystic kidney disease, polymyalgia rheumatica, giant cell arteritis, polymyositis, ileitis, pre-perfusion injury and graft rejection, primary biliary cirrhosis, primary pulmonary hypertension, primary sclerosing cholangitis (PSC), proctitis, psoriasis, psoriasis vulgaris, psoriatic arthritis, psoriatic epidermis, psychosocial stress disorder, lung disease, pulmonary fibrosis, pulmonary hypertension, pyoderma gangrenosum, fibroproliferative vitreoretinopathy after pyogenic granuloma, septic aseptic arthritis, Raynaud's syndrome, Reiter's disease, reactive arthritis, kidney disease, kidney graft rejection, reperfusion injury, respiratory distress syndrome, retinal disease, fibroproliferative vitreoretinopathy, Raynaud's syndrome, rheumatic carditis, rheumatic disease, rheumatic fever, rheumatoid arthritis, rhinitis, rhinitis psoriasis, rosacea, sarcoidosis, Schnitzler syndrome, episcleritis, sclerosis, scleroderma, spi nal curvature, seborrhea, sepsis, septic shock, severe pain, Sézary syndrome, sickle cell anemia, silica-induced disease (silicosis), Sjögren's syndrome, skin disease, skin irritation, skin rash, skin sensitization (contact dermatitis or allergic contact dermatitis), sleep apnea, spinal cord injury, spinal stenosis, spondylosis, sports injury, sprain and contusion, Stevens-Johnson syndrome (SJS), stroke, subarachnoid hemorrhage, sunburn, synovial inflammation, to tal systemic inflammatory response syndrome (SIRS), systemic lupus erythematosus, systemic mast cell disease (SMCD) systemic vasculitis, systemic-onset juvenile idiopathic arthritis, temporal arteritis, tendinitis, tenosynovitis, thrombocytopenia, thyroiditis, thyroiditis, Tissue transplantation, toxoplasmosis, trachoma, transplant rejection, traumatic brain injury, tuberculosis, renal tubules Interstitial nephritis, tumor necrosis factor (TNF) receptor-associated periodic syndrome Group (TNF receptor-associated periodic syndrome: TRAPS), type 1 diabetes, type 2 diabetes, complications of type 1 or type 2 diabetes, ulcerative colitis, urticaria, uterine leiomyoma, uveitis, uveitis, restenosis, vasculitis, vasculitis (NHLBI), vitiligo, Wegener's granulomatosis, and Whipple's disease, but not limited thereto.

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

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

[0129] In some embodiments, at least in part, a disorder or condition mediated by α4β7 integrin is inflammatory bowel disease (IBD). As used herein, the term "inflammatory bowel disease" or "IBD" is a collective term describing inflammatory disorders of the gastrointestinal tract, and the most common forms of inflammatory disorders of the gastrointestinal tract are ulcerative colitis and Crohn's disease. Other forms of IBD that can be treated using the compounds, compositions, and methods of the present disclosure include diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), indeterminate colitis ), Behçet's disease, gastroenterocolitis, jejunoileitis, ileitis, ileocolitis, colonic Crohn's disease (granulomatous colitis), irritable bowel syndrome, mucositis, radiation-induced enteritis, short bowel syndrome, celiac disease, gastric ulcer, diverticulitis, ileal pouchitis, proctitis, and chronic diarrhea.

[0130] Treating or preventing IBD may also involve improving or reducing one or more symptoms of IBD. As used herein, the term "symptoms of inflammatory bowel disease (IBD)" refers to detected symptoms such as abdominal pain, diarrhea, rectal bleeding, weight loss, fever, loss of appetite, and other more severe complications such as dehydration, anemia, and malnutrition. Some of these symptoms are subject to quantitative analysis (e.g., weight loss, fever, anemia, etc.). Some symptoms are readily determined from blood tests (e.g., anemia) or tests that detect the presence of blood (e.g., rectal bleeding). The term "the symptom is reduced" refers to a detectable qualitative or quantitative reduction of the symptom, including but not limited to a detectable effect on the rate of recovery from the disease (e.g., rate of weight gain). Diagnosis is typically determined by endoscopic observation of the mucosa and pathological examination of endoscopic biopsy samples.

[0131] The course of IBD varies and can often be associated with intermittent periods of disease remission and disease exacerbation. Various methods have been described to characterize the disease activity and severity of IBD, as well as the response to treatment in subjects suffering from IBD. Treatment by the present method is generally applicable to subjects suffering from IBD with some level or degree of disease activity.

[0132] In some embodiments, the diseases or conditions treated by administration of the compounds of the compositions described herein include acute gout and ankylosing spondylitis, allergic disorders, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), amyotrophic lateral Sclerosis and multiple sclerosis, atherosclerosis, bacterial infections, pain due to bone cancer and endometriosis, BRAF-resistant melanoma, brainstem glioma or pituitary adenoma, burns, bursitis, cancer of the anal region, cancer of the endocrine system, kidney cancer or ureteral cancer (e.g., renal cell carcinoma and renal pelvic carcinoma), 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 pelvic cancer, vaginal cancer or vulvar cancer, chronic myeloid leukemia, chronic or acute leukemia, chronic pain, classical Bartter syndrome, infectious conjunctivitis, coronary heart disease, cutaneous melanoma or uveal melanoma, dermatitis, dysmenorrhea, eczema, endometriosis, familial adenomatous polyposis, fibromyalgia, fungal infections, gout, gynecological tumors, uterine sarcoma, fallopian tube cancer, headache, hemophilic arthropathy, Parkinson's disease, acquired immunodeficiency syndrome, herpes zoster, Hodgkin's disease, Huntington's disease, high prostaglandin E syndrome, influenza, iritis, juvenile arthritis, juvenile idiopathic arthritis, juvenile rheumatoid arthritis, low back pain and neck pain, lymphocytic lymphoma, fascial disorders, myositis, neuralgia, neurodegenerative disorders such as Alzheimer's disease, neuroinflammatory disorders, neuropathic pain, vulvar cancer, Parkinson's disease, pediatric malignancies, pulmonary fibrosis rectal cancer, rhinitis, sarcoidosis, soft tissue sarcoma, scleritis, skin cancer, pediatric solid tumors, spinal cord tumors, sprains and contusions, stomach 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 there is wound healing.

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

[0134] The treatment methods disclosed in this specification can also be applied at any point in the course of the disease. In some embodiments, the method is applied to a subject suffering from IBD during a remission period (i.e., inactive disease). In such embodiments, the method provides a benefit by extending the remission period (e.g., extending the period of inactive disease) or by preventing, reducing, or delaying the onset of active disease. In other embodiments, the method may be applied to a subject suffering from IBD during an active disease episode. Such a method provides a benefit by shortening the duration of the active disease episode, reducing or improving one or more symptoms of IBD, or treating IBD.

[0135] Measures for determining the effectiveness of treating IBD in clinical practice are described, and such measures include, for example, the following, namely, symptom management, fistula closure, the degree of corticosteroid therapy required, and improvement in quality of life. The Heath-related quality of life (HRQL) can be evaluated using the Inflammatory Bowel Disease Questionnaire (IBDQ), which is widely used in clinical practice to evaluate the quality of life in subjects suffering from IBD. (See Guyatt et al. (1989) Gastroenterology 96:804-810.) In some embodiments, the disease or condition is an immune-mediated liver disorder, disease, or condition. See Guyatt et al. (1989) Gastroenterology 96:804-810. In some embodiments, the disease or condition is an immune-mediated liver disorder, disease, or condition.

[0136] In some embodiments, at least in part, the disease or condition mediated by α4β7 integrin is alcoholic hepatitis. Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver failure that develops in subjects with chronic and active alcohol abuse. (See Akriviadis E. et al., "Ann Gastroenterol." (April - June 2016), Vol. 29, No. 2, pp. 236 - 237). Alcoholic hepatitis can cause cirrhosis and hepatic fibrosis. Glucocorticoids (e.g., prednisone) and phosphodiesterase inhibitors (e.g., pentoxifylline) can be used to treat alcoholic hepatitis. The compounds of this specification can be used as an independent treatment or in combination with current treatments for alcoholic hepatitis.

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

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

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

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

[0141] Thus, in some embodiments, a method of treating a disease or condition mediated at least in part by α4β7 integrin, and / or a disease or condition mediated at least in part by α4β7 integrin, such as an allergic disorder, and / or an autoimmune disease and / or an inflammatory disease, and / or a disease or symptom that coexists with, or is exacerbated or caused by, an acute inflammatory response, comprises administering to a patient in need thereof an effective amount of a compound described herein, optionally in combination with an additional agent (e.g., a second, third, fourth, or fifth agent), wherein combining with the additional agent is useful for treating an allergic disorder and / or an autoimmune disease, and / or an inflammatory disease, and / or an acute inflammatory response that is associated with or coexists with a disease or condition mediated at least in part by α4β7, a disease or condition mediated at least in part by α4β7 integrin. Treatment with the second, third, fourth, or fifth agent can be performed before, simultaneously with, or after treatment with the compound described herein. In some embodiments, the compounds described herein are combined with another agent in a single dosage form. Suitable therapeutic agents that can be used in combination with the compounds described herein include the therapeutic agents provided herein, or at least Combinations including at least one therapeutic agent are included, but not limited to these.

[0142] Treatment methods in which the compounds described herein are administered in combination with an agent for the treatment of an inflammatory disease or condition are included herein. Examples of agents for the treatment of inflammatory diseases or conditions that can be used in combination with the compounds described herein include alpha-fetoprotein modulators, adenosine A3 receptor antagonists, adrenomedullin ligands, AKT1 gene inhibitors, antibiotics, antifungal agents, ASK1 inhibitors, ATPase inhibitors, beta-adrenergic receptor antagonists, BTK inhibitors, calcineurin inhibitors, carbohydrate metabolism modulators, cathepsin S inhibitors, CCR9 chemokine antagonists, CD233 modulators, CD29 modulators, CD3 antagonists, CD40 ligand inhibitors, CD40 ligand receptor antagonists, chemokine CXC ligand inhibitors, CHST15 gene inhibitors, collagen modulators, CSF-1 antagonists, CX3CR1 chemokine modulators, ecobiotics, eotaxin ligand inhibitors, EP4 prostanoid receptor agonists, F1F0 ATP synthase modulators, farnesoid X receptor agonists, fecal microbiota transplantation: FMT), fructoalkyne ligand inhibitors, free fatty acid receptor 2 Antagonist, GATA3 transcription factor inhibitor, glucagon-like peptide 2 agonist, glucocorticoid agonist, glucocorticoid receptor modulator, guanylate cyclase receptor agonist, HIF prolyl hydroxylase inhibitor, histone deacetylase inhibitor, HLA class II antigen modulator, hypoxia-inducing factor-1 stimulator, ICAM1 gene inhibitor, IL-1β ligand modulator, IL-12 antagonist, IL-13 antagonist, IL-18 antagonist, IL-22 agonist, IL-23 antagonist, IL-23A inhibitor, IL-6 antagonist, IL-7 receptor antagonist, IL-8 receptor antagonist, integrin α-4 / β-1 antagonist, integrin α-4 / β-7 antagonist, integrin antagonist, interleukin ligand inhibitor, interleukin receptor 17A antagonist, interleukin-1β ligand, interleukin 1-like receptor 2 inhibitor, IL-6 receptor modulator, JAK tyrosine kinase inhibitor, Jak1 tyrosine kinase inhibitor, Jak3 tyrosine kinase inhibitor, lactoferrin stimulator, LanC-like protein 2 modulator, leukocyte elastase inhibitor, leukocyte proteinase-3 inhibitor, MAdCAM inhibitor, melanin-concentrating hormone (MCH-1) antagonist, melanocortin agonist, metalloprotease 9 inhibitor, microbiome-targeted therapeutic agent, natriuretic peptide receptor C agonist, neuregulin 4 ligand, NLPR3 inhibitor, NKG2D-activated NK receptor antagonist, NR1H4 receptor (FXR) agonist or modulator, nuclear factor κB inhibitor, opioid receptor antagonist, OX40 ligand inhibitor, oxidoreductase inhibitor, P2X7 purinergic receptor modulator, PDE4 inhibitor, Pellino homolog 1 inhibitor, PPARα / δ 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-phosphate phosphatase 1 stimulator, sphingosine-1-phosphate receptor-1 agonistSphingosine-1-phosphate receptor-5 agonist, sphingosine-1-phosphate receptor-1 antagonist, sphingosine-1-phosphate receptor-1 modulator, stem cell antigen 1 inhibitor, superoxide dismutase modulator, SYK inhibitor, TLR-3 antagonist, TLR-4 antagonist, Toll-like receptor 8 (TLR8) inhibitor, TLR-9 agonist, TNFα ligand inhibitor, TNF ligand inhibitor, TNFα ligand modulator, TNF antagonist, TPL-2 inhibitor, tumor necrosis factor 14 ligand modulator, tumor necrosis factor 15 ligand inhibitor, Tyk2 tyrosine kinase inhibitor, type I IL-1 receptor antagonist, vanilloid VR1 agonist, and zonulin inhibitor, and combinations thereof are included.

[0143] The adenosine A3 receptor antagonist includes PBF-677.

[0144] The adrenomedullin ligand includes adrenomedullin.

[0145] The antibiotics include ciprofloxacin, metronidazole, vancomycin, and rifaximin.

[0146] The ASK1 inhibitor includes GS-4997.

[0147] The α-fetoprotein modulator includes ACT-101.

[0148] The anti-CD28 inhibitor includes JNJ-3133.

[0149] [[ID= / / ]] The β-adrenergic receptor antagonist includes NM-001.

[0150] The BTK inhibitor includes GS-4059.

[0151] The calcineurin inhibitors include tacrolimus and cyclosporine.

[0152] The carbohydrate metabolism modulator includes ASD-003.

[0153] The cathepsin S inhibitor includes VBY-129.

[0154] The CCR9 chemokine antagonist includes CCX-507.

[0155] The CD233 modulator includes GSK-2831781.

[0156] The CD29 modulator includes PF-06687234.

[0157] The CD3 antagonist includes NI-0401.

[0158] The CD4 antagonist includes IT-1208.

[0159] The CD40 ligand inhibitor includes SAR-441344 and rituximab.

[0160] The CD40 gene inhibitor includes NJA-730.

[0161] The CD40 ligand receptor antagonist includes FFP-104, BI-655064.

[0162] The chemokine CXC ligand inhibitor includes LY-3041658.

[0163] The CHST15 gene inhibitor includes STNM-01.

[0164] The collagen modulator includes ECCS-50 (DCCT-10).

[0165] The COT protein kinase inhibitor includes GS-4875.

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

[0167] CX3CR1 chemokine modulators include E-6130.

[0168] Ecoviotics include SER-287.

[0169] Eotaxin ligand inhibitors include belimumab.

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

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

[0172] Fractalkine ligand inhibitors include E-6011.

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

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

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

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

[0177] Glucocorticoid receptor modulators / TNF ligand inhibitors include ABBV-3373. [[ID=4�]]

[0178] Guanylate cyclase receptor agonists include dovanatide.

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

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

[0181] Histone deacetylase inhibitors include givinostat.

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

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

[0184] ICAM1 gene inhibitors include alicaforsen.

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

[0186] IL-13 antagonists include tralokinumab.

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

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

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

[0190] IL-23A inhibitors include guselkumab.

[0191] IL-6 antagonists include orolizumab.

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

[0193] The IL-8 receptor antagonists include clotrimazole.

[0194] The integrin α-4 / β-1 antagonists include natalizumab.

[0195] The integrin α-4 / β-7 antagonists include etrolizumab (α4β7 / αEb7), vedolizumab, carotegast methyl, TRK-170 (α4β7 / α4β1), PN-10943, and PTG-100.

[0196] The integrin antagonists include E-6007.

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

[0198] The interleukin receptor 17A antagonists include brodalumab.

[0199] The interleukin-1β ligand includes K(D)PT.

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

[0201] The IL-6 receptor modulators include olamkicept.

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

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

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

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

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

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

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

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

[0210] The metalloprotease 9 inhibitor includes GS-5745.

[0211] The natriuretic peptide receptor C agonist includes precanatide.

[0212] The neuregulin-4 ligand includes NRG-4.

[0213] The NKG2D-activated NK receptor antagonist includes JNJ-4500.

[0214] The NLPR3 inhibitor includes dapansutrile, BMS-986299, SB-414, MCC-950, IFM-514, JT-194, PELA-167, and NBC-6.

[0215] The NR1H4 receptor (FXR) agonist or modulator includes tropifexor and GS-9674.

[0216] The nuclear factor κB inhibitor includes Thetanix.

[0217] The opioid receptor antagonist includes naltrexone and IRT-103.

[0218] The OX40 ligand inhibitor includes KHK-4083.

[0219] The oxidoreductase inhibitor includes olsalazine.

[0220] The Pellino homolog 1 inhibitor includes BBT-401.

[0221] The P2X7 purinergic receptor modulator includes SGM-1019.

[0222] The PDE4 inhibitor includes apremilast.

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

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

[0225] Protein fimH inhibitors include EB-8018.

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

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

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

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

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

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

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

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

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

[0235] The stem cell antigen 1 inhibitor includes Ampion (DMI-9523).

[0236] The superoxide dismutase modulator includes Midisumase.

[0237] The Syk inhibitor includes GS-9876.

[0238] The TLR-3 antagonist includes PRV-300.

[0239] The TLR-4 antagonist includes JKB-122.

[0240] The Toll-like receptor 8 (TLR8) inhibitor includes E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, Motolimod, Resiquimod, VTX-1463, and VTX-763.

[0241] The TLR-9 agonist includes Cobitolimod, IMO-2055, IMO-2125, Lefitolimod, Litenimod, MGN-1601, and PUL-042.

[0242] The TNFα ligand inhibitor includes Adalimumab, Certolizumab pegol, Infliximab, Golimumab, DLX-105, Debio-0512, HMPL-004, CYT-020-TNFQb, Hemay-007, and V-565.

[0243] The TNF antagonist includes AVX-470, Tulinercept, and Etanercept.

[0244] The TPL-2 inhibitor includes GS-4875.

[0245] The tumor necrosis factor 14 ligand modulator includes AEVI-002.

[0246] The tumor necrosis factor 15 ligand inhibitor includes PF-06480605.

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

[0248] The type I IL-1 receptor antagonist includes anakinra.

[0249] The zonulin inhibitor includes larazotide acetate.

[0250] Treatment methods in which the compounds described herein are administered in combination with an anti-inflammatory agent are included herein. Anti-inflammatory agents include, but are not limited to, NSAIDs, non-specific and COX-2 specific cyclooxygenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptor antagonists, immunosuppressants, and methotrexate.

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

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

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

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

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

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

[0257] Treatment methods in which the compounds described herein are administered in combination with an immunosuppressant are included herein. In some embodiments, the immunosuppressant is methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, or mycophenolate mofetil.

[0258] Treatment methods in which the compounds described herein are administered in combination with a class of agents for the treatment of IBD are included herein. Examples of classes of agents for the treatment of IBD that can be used in combination with the compounds described herein include ASK1 inhibitors, β adrena Phosphate receptor antagonist, BTK inhibitor, β-glucuronidase inhibitor, bradykinin receptor modulator, calcineurin inhibitor, calcium channel inhibitor, cathepsin S inhibitor, CCR3 chemokine antagonist, CD40 ligand receptor antagonist, chemokine CXC ligand inhibitor, CHST15 gene inhibitor, collagen modulator, CSF-1 antagonist, cyclooxygenase inhibitor, cytochrome P450 3A4 inhibitor, eotaxin ligand inhibitor, EP4 prostanoid receptor agonist, fractalkine ligand inhibitor, free fatty acid receptor 2 antagonist, GATA3 transcription factor inhibitor, glucagon-like peptide 2 agonist, glucocorticoid agonist, guanylate cyclase receptor agonist, histone deacetylase inhibitor, HLA class II antigen modulator, IL-12 antagonist, IL-13 antagonist, IL-23 antagonist, IL-6 antagonist, IL-6 receptor modulator, interleukin-7 receptor modulator, IL-7 antagonist, IL-8 antagonist, integrin α-4 / β-1 antagonist, integrin α-4 / β-7 antagonist, integrin α-E antagonist, integrin antagonist, integrin β-7 antagonist, interleukin ligand inhibitor, interleukin receptor 17A antagonist, interleukin-1β ligand, interleukin-1β ligand modulator, IRAK4 inhibitor, JAK tyrosine kinase inhibitor, Jak1 tyrosine kinase inhibitor, Jak3 tyrosine kinase inhibitor, LanC-like protein 2 modulator, lipoxygenase modulator, MAdCAM inhibitor, matrix metalloprotease inhibitor, melanocortin agonist, metalloprotease 9 inhibitor, natriuretic peptide receptor C agonist, neuregulin 4 ligand, NKG2D-activated NK receptor antagonist, opioid receptor antagonist, opioid receptor δ antagonist, oxidoreductase inhibitor, P2X7 purinergic receptor agonist, PDE4 inhibitor, orexigenic peptide modulator, potassium channel inhibitor, PPARα agonist, PPARδ agonist, PPARγ agonist, fimH protein inhibitor, P-selectin glycoprotein ligand 1 inhibitor, RNA polymerase inhibitor, sphingosine-1-phosphate phosphatase 1 stimulator, sphingosine-1-phosphate phosphatase modulator, sphingosine-1-phosphate receptor 1 agonist, sphingosine-1-phosphate receptor 1 antagonist, sphingosine-1-phosphate receptor 1 modulator, sphingosine-1-phosphate receptor 5 modulator, STAT3 gene inhibitor, stem cell antigen 1 inhibitor, superoxide dismutase modulator, superoxide dismutase stimulator, SYK inhibitor, TGFβ1 ligand inhibitor, timulin agonist, TLR antagonist, TLR agonist, TNFα ligand inhibitor, TNF antagonist, tumor necrosis factor 14 ligand modulator, type II TNF receptor modulator, Tpl 2 inhibitor, and zonulin inhibitor.

[0259] Also included herein are methods of treatment in which the compounds described herein are administered in combination with an agent for the treatment of IBD. Examples of agents for the treatment of IBD that can be used in combination with the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, or deuterated analogs thereof, include agents provided herein for the treatment of inflammatory diseases or conditions, and ABX-464, adalimumab, alicaforsen, ALLO-ASC-CD, AMG-966, anakinra, apremilast, Alequel, AMG-139, amiselimod, ASD-003, ASP-3291, AX-1505, BBT-401, balsalazide, beclometasone 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, mesalazine, HLD-400, LYC-30937 EC, IONIS-JBI1-2.5Rx, JNJ-64304500, JNJ-4447, naltrexone, natalizumab, neihulizumab, olsalazine, PH-46-A , propionyl-L-carnitine, PTG-100, remestemcel-L, tacrolimus, teduglutide, tofacitinib, ASP-1002, ustekinumab Mab, Vedolizumab, AVX-470, INN-108, SGM-1019, PF-06480605, PF-06651600, PF-06687234, RBX-8225, SER-287, Thetanix, TOP-1288, VBY-129, 99mTc-Annexin V-128, Bralimomab, DLX-105, Dolcanatide, E-6011, FFP-104, Filgotinib, Foralumab, GED-0507-34-Levo, Gibinostat, GLPG-0974, Iberogast, JNJ-40346527, K(D)PT, KAG-308, KHK-4083, KRP-203, Larazotide Acetate, LY-3074828, Midisase, Oloxizumab, OvaSave, P-28-GST, PF-547659, Prednisolone, QBECO, RBX-2660, JKB-122, SB-012, STNM-01, Debio-0512, TRK-170, Zucapsaicin, ABT-494, Ampion, BI-655066, Cartegas Trimethyl, Cobitolimod, Elafibranor, Etrolizumab, GS-5745, HMPL-004, LP-02, Ozanimod, Peficitinib, RHB-104, Rifaximin, Tildrakizumab, Tralokinumab, Brodalumab, Lacanimod, Precanatide, Vidofludimus, and AZD-058 are included.

[0260] Also included herein are methods of treatment in which the compounds described herein are administered in combination with an agent for the treatment of graft-versus-host disease. Examples of agents for the treatment of graft-versus-host disease that can be used in combination with the compounds described herein include the agents provided herein for the treatment of inflammatory diseases or conditions, as well as [18F]F-AraG, AM-01, AAT-IV, Allocetra, AMG-592, arsenic trioxide, ATIR-101, basiliximab, belatacept, belimumab, bortezomib, brentuximab vedotin, brimonidine, brimonidine tartrate, cannabidiol, CE-1145, cyclosporine, clazakizumab, CSL-964, CYP-001, defibrotide, diranubecel, dornase alfa, DSM-9843, eculizumab, EDP-1066, everolimus, Furestem, GSK-1070806, ibrutinib, IMSUT-CORD, IRX-4204, KD-025, MaaT-013, miratuzumab, 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, Saracatinib, SCM-CGH, Sirolimus, T-allo10, Telmisartan, T-Guard, TOP-1288, TZ-101, Tacrolimus, CCR5 chemokine antagonist, PRO-140, CD40 ligand receptor antagonist, Iscalimab, Complement C1s small component inhibitor: Stimulizumab, Cinryze, BIVV-009, B-lymphocyte antigen CD20 inhibitor: Ofatumumab, CASP9 gene stimulator: Rivogenlecleucel, CD3 antagonist or CD7 inhibitor: T-Guard, Complement C5a factor inhibitor: Olaratumab, Dipeptidyl peptidase IV inhibitor: Velaverumab, JAK1 / 2 tyrosine kinase inhibitor: Ruxolitinib, Jak1 tyrosine kinase inhibitor: Itacitinib, Interleukin-2 ligand: Aldesleukin, Interleukin 22 ligand: F-652, IL-2 receptor α subunit inhibitor: Inolimomab, IL-6 receptor agonist: PLX-1, IL-6 receptor antagonist: Clazakizumab, OX40 ligand inhibitor, KY-1005, examples of such OX40 inhibitors are the compounds disclosed in U.S. Patent No. 8,450,460, the entire content of which is incorporated herein by reference, Signal transducer CD24 modulator: CD24-IgFc, Somatostatin receptor agonist: Timoglubulin, and Sphingosine-1-phosphate receptor-1 agonist: Ponatinib.

[0261] Also included herein is a treatment method in which the compounds described in this specification are administered in combination with a medicament for the treatment of primary sclerosing cholangitis. Examples of medicaments for treating primary sclerosing cholangitis that can be used in combination with the compounds described in this specification include the medicaments provided herein for the treatment of inflammatory diseases or conditions, as well as BTT-1023, CM-101, Doconexent, GRI-0124, HTD-1801, HTD-2802, chamechromone, IDN-7314, NGM-282, norursodeoxycholic acid, ORBCEL-C, SCT-5-27, STP-705, farnesoid X receptor agonist: obeticholic acid, GS-9674, and MET-409, liver X receptor antagonist: DUR-928, and CCR5 / CCR2 chemokine antagonist: cenicriviroc.

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

[0263] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of an HIV protease inhibitor compound, a non-nucleoside inhibitor of HIV reverse transcriptase, a non-nucleotide inhibitor of HIV reverse transcriptase, a nucleoside inhibitor of HIV reverse transcriptase, a nucleotide inhibitor of HIV reverse transcriptase, an HIV integrase inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a capsid polymerization inhibitor, a pharmacokinetic enhancer, and other drugs for treating HIV, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

[0264] In some embodiments, the one or more additional therapeutic agents are immunomodulators, such as immunostimulants or immunosuppressants. In certain other embodiments, the immunomodulator is an agent that can alter the function of immune checkpoints, including, for example, the CTLA-4, LAG-3, B7-H3, B7-H4, Tim3, BTLA, KIR, A2aR, CD200, and / or PD-1 pathways. In other embodiments, the immunomodulator is an immune checkpoint modulator. Exemplary immune checkpoint modulators include anti-CTLA-4 antibodies (e.g., ipilimumab), anti-LAG-3 antibodies, anti-B7-H3 antibodies, anti-B7-H4 antibodies, anti-Tim3 antibodies , anti-BTLA antibodies, anti-KIR antibodies, anti-A2aR antibodies, anti-CD200 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CD28 antibodies, anti-CD80 antibodies or anti-CD86 antibodies, anti-B7RP1 antibodies, anti-B7-H3 antibodies, anti-HVEM antibodies, anti-CD137 or anti-CD137L antibodies, anti-OX40 antibodies or anti-OX40L antibodies, anti-CD40 antibodies or anti-CD40L antibodies, anti-GAL9 antibodies, anti-IL-10 antibodies, and A2aR drugs. For certain such immune pathway gene products, the use of either an antagonist or an agonist of such gene products, as well as small molecule modulators of such gene products, is contemplated. In some embodiments, the immunomodulator includes an agent that can alter the function of mediators in cytokine-mediated signaling pathways.

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

[0266] The compounds described herein can be combined with the agents provided herein in any dosage of the compound (e.g., 50 mg to 500 mg of the compound), in the same manner as when each combination of dosages is specifically and individually listed.

[0267] In some embodiments, there is provided a kit comprising a pharmaceutical composition comprising a compound described herein, or a compound described herein and at least one additional therapeutic agent, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, there is provided a kit comprising a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analog thereof, in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, or 1 to 3, or 1 to 4) additional therapeutic agents. Any pharmaceutical composition provided by the present disclosure can be used in a kit, in the same manner as when each composition is specifically and individually listed for use in the kit. In some embodiments, the kit includes instructions for use in the treatment of an inflammatory disease or condition. In some embodiments, the instructions of the kit are directed to the use of a pharmaceutical composition for the treatment of IBD.

Table 1-1

Table 1-2

Table 1-3

[0268] The compounds of the present disclosure may be prepared using the methods disclosed herein and their routine modifications, which will be apparent considering the disclosure herein and methods well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods may be used. Typical compounds of formula (I), for example, compounds having the structures described by one or more of formula (I), or other formulas or compounds disclosed herein, or their pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, or deuterated analogs, may be synthesized as described in the following examples. General Scheme

[0269] Typical embodiments of the compounds according to the present disclosure may be synthesized using the general reaction schemes and / or examples described below. Considering the description herein, it will be apparent that the general scheme can be modified by substituting the starting materials with other materials having similar structures, resulting in different products accordingly. The description of the synthesis then provides many examples of how the starting materials can be varied to provide the corresponding products. The starting materials are typically obtained from commercial sources or synthesized using published methods for synthesizing compounds that are embodiments of the present disclosure, and inspection of the structure of the compound being synthesized provides the identity of each substituent. The identity of the final product will generally be revealed by a simple inspection process of the identity of the required starting materials considering the examples herein.

Chemical formula

[0270] General Scheme 1 illustrates the general route used to prepare the compounds of formula (I). An amino acid ester (AA2) can be prepared from intermediate AA1 having a hydroxyl group or a halogen group as Q and a halogen group as X under various conditions (e.g., Schollkopf, Maruoka, etc.). The free amine is protected with a protecting The group (PG), for example, after being appropriately protected with trityl, Boc, etc., AA2 was converted to a boronic acid or boronic acid ester (AA3) under standard conditions (for example, Miyaura). R was introduced under various cross-coupling conditions to obtain AA4. After removing the amine protecting group (PG) under appropriate conditions, the amine was combined with an acid to obtain AA5. In some embodiments, AA4 is prepared as outlined in General Scheme 2, which describes another general route for preparing the compound of formula (I). From intermediate AA6 having a halogen group as Q and an amino group, the R group on AA7 can be prepared by several chemical steps such as urea formation and ring closure. The amino acid ester (AA4) can be prepared from AA7 under various conditions (for example, Schollkopf, Maruoka, etc.). After appropriately removing the amine protecting group (PG) under appropriate conditions, the amine was combined with an acid to obtain the heterocyclic compound AA5. 1 After appropriately removing the amine protecting group (PG) under appropriate conditions, the amine was combined with an acid to obtain AA5.

Chemical formula

[0271] In some embodiments, AA4 is prepared as outlined in General Scheme 2, which describes another general route for preparing the compound of formula (I). From intermediate AA6 having a halogen group as Q and an amino group, the R group on AA7 can be prepared by several chemical steps such as urea formation and ring closure. 1 The amino acid ester (AA4) can be prepared from AA7 under various conditions (for example, Schollkopf, Maruoka, etc.). After appropriately removing the amine protecting group (PG) under appropriate conditions, the amine was combined with an acid to obtain the heterocyclic compound AA5.

Chemical formula

[0272] Synthesis of tert-butyl 4-bromo-2,6-difluorobenzoate (A1): To a stirred solution of 4-bromo-2,6-difluorobenzoic acid (5 g, 21.1 mmol) and tert-butyl alcohol (50 mL) in DCM (50 mL), di-tert-butyl dicarbonate (9.2 g, 42.2 mol) was added, followed by 4-dimethylaminopyridine (0.8 g, 6.3 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction The mixture was concentrated under reduced pressure, dissolved in EA (100 mL), and washed with a 10% aqueous solution of citric acid (100 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude material. This material was suspended in hexane, the solid was filtered off, and the filtrate was evaporated under reduced pressure to obtain Compound A1.

[0273] Synthesis of tert-butyl (R)-2,6-difluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoate (A2): To a stirred suspension of A1 (250 mg, 0.55 mmol), (R)-1,1,1-trifluorobutan-2-amine (85 mg, 0.67 mmol), and cesium carbonate (904 mg, 2.8 mmol) in toluene (5 mL) was added XPhos Pd G3 (42 mg, 0.06 mmol). The reaction mixture was sparged with nitrogen and then heated to 90 °C for 12 h. The mixture was cooled to room temperature and diluted with EA (50 mL). The resulting suspension was filtered through a pad of celite, and the filtrate was evaporated under reduced pressure to obtain Compound A2.

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

Chemical Structure

[0275] (Synthesis of (R)-2,6-difluoro-4-(3-(trifluoromethyl)morpholino)benzoic acid (B)): In a 150 mL pressure vessel equipped with a stir 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. Subsequently, the reaction vessel was sealed and heated at 90 °C overnight. The reaction mixture was cooled to room temperature, filtered through a pad of celite, rinsed with EA, and the filtrate was evaporated to dryness under reduced pressure. The material was purified by silica gel chromatography using EA in hexane as the eluent. To this material, THF (6 mL) and aqueous LiOH (6.2 mL, 1.0 M) were added. The reaction mixture was stirred at 60 °C for 20 h. The reaction mixture was cooled to room temperature and acidified with 1.0 M HCl before extraction with EA. The organic layers were combined and dried over Na2SO4. The solvent was removed under reduced pressure to afford Intermediate B.

Chemical formula

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

Chemical formula

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

Chemical formula

[0278] tert-Butyl (R)-2,3,6-trifluoro-4-((1,1,1-trifluoro Synthesis of tert-butyl (R)-2,3,6-trifluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoate (E1): To a stirred suspension of tert-butyl 4-bromo-2,3,6-trifluorobenzoate (250 mg, 0.55 mmol), (R)-1,1,1-trifluorobutan-2-amine (85 mg, 0.67 mmol), and cesium carbonate (904 mg, 2.8 mmol) in toluene (5 mL) was added XPhos Pd G3 (42 mg, 0.06 mmol). The reaction mixture was sparged with nitrogen and then heated to 90 °C for 2 h. The mixture was cooled to room temperature and diluted with EA (50 mL). The resulting suspension was filtered through a pad of celite, and the filtrate was evaporated under reduced pressure to give compound E1.

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

Chemical formula

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

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

[0282] Synthesis of (R)-4-(cyclopropyl(1,1,1-trifluorobutan-2-yl)amino)-2,6-difluorobenzoic acid (F): To F2 (360 mg, 1.07 mmol) in THF was added 1.0 M LiOH (5 mL). The reaction was stirred at 40 °C overnight. 2.0 M HCl was added (20 mL) and the mixture was extracted 3 times with EA. The combined organics were washed with brine and concentrated in vacuo to give the intermediate F without further purification.

Chemical Structure

[0283] Synthesis of 5-iodo-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one (G): A solution of 6-methyl-4-(trifluoromethyl)pyridin-2(1H)-one (1.26 g, 7.11 mmol), TFA (16.0 g, 140 mmol), and TFAA (3.2 g, 15 mmol) in DME (3.80 mL) was heated at 60 °C for 5 minutes, and then NIS (2.04 g, 9.0 mmol) was added. The mixture was then heated at 60 °C for an additional 12 hours, after which the solvent was removed under reduced pressure. The residue was dissolved in EA, washed with water, and then washed with saturated aqueous NaHCO3. The organic layer was concentrated under reduced pressure, and the crude product was suspended in DME (3.80 mL). To this mixture, K2CO3 (0.98 g, 7.0 mmol) and MeI (1.0 g, 7.0 mmol) were added, and the mixture was heated at 95 °C for 2 hours. When complete, the reaction was diluted with EA, 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% - 100%) to afford Intermediate G. [Chemical formula]

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

[0285] Synthesis of 3-iodo-1,4-dimethyl-5-(trifluoromethyl)pyridin-2(1H)-one (H): To a stirred solution of H1 (0.72 g, 4 mmol) as a stock solution in TFA (16 mL), TFAA (1.6 g, 8 mmol) was added. The reaction mixture was heated in a sealed vial up to 100 °C for 5 minutes, then NIS (1.08 g, 5 mmol) was added and heating was continued 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 brine. The organic layer was filtered and then concentrated to give intermediate G without further purification. The reaction mixture was heated in a sealed vial up to 100 °C for 5 minutes, then NIS (1.08 g, 5 mmol) was added and heating was continued 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 brine. The organic layer was filtered and then concentrated to give intermediate G without further purification. [Chemical formula]

[0286] (2S,5R)-2-(4-bromo-3-methylbenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (I1) synthesis: To a solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1.36 g, 7.39 mmol) in THF (28.0 mL) at -78 °C, a solution of n-BuLi in hexane (4.62 g, 7.96 mmol) was added. The mixture was stirred at -78 °C for 20 minutes, then a solution of 1-bromo-4-(bromomethyl)-2-methylbenzene (1.5 g, 5.68 mmol) in THF (37 mL) was added dropwise. The reaction was stirred at -78 °C for 40 minutes and quenched with water (10 mL). The cold bath was removed, the reaction was warmed to room temperature, extracted with EA, washed with brine, 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 hexane (10% - 100%) to give compound I1.

[0287] Synthesis of (2S,5S)-2-isopropyl-3,6-dimethoxy-5-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-2,5-dihydropyrazine (I2): To a solution of compound I1 (297 mg, 0.809 mmol) in DMA (5.40 mL) were added bis(pinacolato)diboron (262 mg, 1.03 mmol) and KOAc (238 mg, 2.42 mmol), and the mixture was purged with nitrogen gas for 6 minutes. CataCXium A Pd G3 (29.5 mg, 0.04 mmol) was added, and the mixture was heated at 90 °C for 1 hour. Upon completion, the reaction was quenched with water, extracted with EA, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain compound I2, which was used without further purification.

[0288] Synthesis of 3-(4-(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)methyl)-2-methylphenyl)-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one (I3): To a solution of compound I2 (130 mg, 0.157 mmol) and 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 gas for 6 minutes. Then, XPhos Pd G3 (13.0 mg, 0.016 mmol) was added, and the mixture was purged with nitrogen gas for an additional 3 minutes and heated thermally at 77 °C for 45 minutes. Then, the solvent was removed under reduced pressure, the mixture was dissolved in EA, washed with H2O, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude material. The crude material was purified using flash chromatography eluting with EA in hexane (20% - 100%), then MeOH in EA (0% - 35%) to obtain I3.

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

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

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

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

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

Chemical formula

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

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

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

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

Chemical formula

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

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

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

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

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

Chemical Structure

[0303] Synthesis of Methyl 3-(3-(6-iodopyridin-3-yl)ureido)isonicotinate (M1): Into a 500 mL RB flask, 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. The reaction mixture was heated to 50 °C for 10 minutes. Then, diphenylphosphoryl azide (6.37 mL, 29.5 mmol, 1.3 eq.) was added dropwise to the reaction mixture. The reaction was stirred for 60 minutes. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water (200 mL each). The organic layer was separated, washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The crude was purified by column chromatography on silica gel using 0 - 20% methanol in DCM as the eluent to obtain the title compound (M1).

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

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

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

Chemical Structure

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

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

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

Chemical Structure

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

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

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

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

Chemical Structure

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

[0315] (S)-4-(3-(2,2-Difluoroethyl)morpholino)-2-fluoro-6-methylbenzoic acid (Q) synthesis: To a pressure vessel equipped with a 150 mL stir bar, add 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). Then, seal the reaction vessel and heat at 90 °C overnight. Cool the reaction mixture to room temperature, filter through a pad of celite, rinse with EA, and evaporate the filtrate to dryness under reduced pressure. Purify the material by silica gel chromatography using EA in hexane as the eluent. To this material, add THF (6 mL) and aqueous LiOH( 6.2 mL, 1.0 M). Stir the reaction mixture at 60 °C for 20 h. Cool the reaction mixture to room temperature and acidify with 1.0 M HCl before extraction with EA. Combine the organic layers and dry over Na2SO4. Remove the solvent under reduced pressure to obtain Q. Intermediate R

[0316] Synthesis of methyl (S)-4-(3-(4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)phenyl)ureido)-5,6-dihydro-2H-pyran-3-carboxylate (R1): To a solution of methyl 4-amino-5,6-dihydro-2H-pyran-3-carboxylate (114 mg, 0.725 mmol) in dichloromethane (4 mL), add 20% phosgene in toluene (0.352 mL, 0.67 mmol) and stir the reaction at room temperature for 30 min. Cool this to 0 °C, then add Hunig's base (0.237 mL, 1.36 mmol), followed by Methyl (S)-3-(4-aminophenyl)-2-((tert-butoxycarbonyl)amino)propanoate (100 mg, 0.34 mmol) was added. The reaction mixture was warmed 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. This was purified by flash chromatography (linear gradient of 5 - 100% ethyl acetate / hexane) to obtain R1. [Chemical formula]

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

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

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

Chemical formula

[0320] Synthesis of ethyl 5-amino-3,6-dihydro-2H-pyran-4-carboxylate (S1): To a solution of ethyl 3-oxotetrahydro-2H-pyran-4-carboxylate (2.0 g, 12 mmol) in methanol (71 mL), ammonium acetate (4.57 g, 59 mmol) was added, and the reaction mixture 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 obtain S1.

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

Chemical formula

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

Chemical formula

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

Chemical formula

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

Chemical formula

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

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

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

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

Chemical Structure

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

[0330] (S)-2-(2,6-Difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamide)-3-(4-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)phenyl)propanoic acid (1) synthesis: 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 obtain the crude material. The crude product was purified using flash chromatography eluting with EA in hexane (12% - 100%). , an ester was obtained. 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 minutes. Upon completion, the mixture was acidified with TFA, and the volatiles were removed under reduced pressure. The crude material was dissolved in DMSO and chromatographed on C-18 modified silica gel eluting with acetonitrile in water (0.4% TFA) to give Compound 1. MS (m / z) 620.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 7.7 Hz, 1H), 7.28 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 6.76 (d, J = 10.4 Hz, 1H), 6.50 (s, 1H), 6.45 (d, J = 11.4 Hz, 2H), 4.58 - 4.50 (m, 1H), 4.37 - 4.26 (m, 1H), 3.48 (s, 3H), 3.13 (dd, J = 14.1, 5.8 Hz, 1H), 2.97 (dd, J = 13.7, 10.1 Hz, 1H), 2.47 (s, 3H), 1.81 - 1.74 (m, 1H), 1.59 - 1.48 (m, 1H), 0.93 (t, J = 7.5 Hz, 3H). Example 2

Chemical Structure

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

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

[0333] (S)-2-(2,6-Difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamide)-3-(4-(1,2-dimethyl-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenyl)propanoic acid (2) Synthesis: The title compound was prepared according to the method presented for the synthesis of 1 starting from 2B and Intermediate A. MS (m / z) 620.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 8.1 Hz, 1H), 7.35 - 7.30 (m, 2H), 7.09 (t, J = 7.4 Hz, 2H), 6.74 (d, J = 10.9 Hz, 1H), 6.73 (s, 1H), 6.43 (d, J = 11.3 Hz, 2H), 4.66 - 4.57 (m, 1H), 4.37 - 4.24 (m, 1H), 3.54 (s, 3H), 3.18 (dd, J = 14.1, 4.4 Hz, 1H), 2.94 (dd, J = 14.3, 10.2 Hz, 1H), 2.03 (s, 3H), 1.80 (s, 1H), 1.58 - 1.47 (m, 1H), 0.93 (t, J = 7.2 Hz, 3H). Example 3 [Chemical formula]

[0334] (S)-2-(2,6-Difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-3-(4-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)phenyl)propanoic acid (3) Synthesis: 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 (400 MHz, DMSO-d6) δ 8.84 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 11.6 Hz, 2H), 6.49 (s, 2H), 4.91 (m, 1H), 4.57 (m, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.96 (dd, J = 11.5, 3.8 Hz, 1H), 3.78 - 3.70 (m, 1H), 3.56 (td, J = 11.6, 2.9 Hz, 1H), 3.48 (s, 3H), 3.43 (d, J = 12.9 Hz, 1H), 3.24 (t, J = 12.2 Hz, 1H), 3.15 (dd, J = 14.2, 4.7 Hz, 1H), 2.99 (dd, J = 14.1, 9.8 Hz, 1H), 2.47 (s, 3H). Example 4

[0335] Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1,4-dimethyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)phenyl)propanoate (4A): A solution of (S)-(4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)phenyl)boronic acid (100 mg, 0.310 mmol) and Intermediate H (124 mg, 0.390 mmol) in DME (1.6 mL) was purged with nitrogen gas for 5 minutes. To this mixture, an aqueous solution of XPhosPdG3 (26.0 mg, 0.031 mmol) and K3PO4 (230 mg, 1.00 mmol) in 1 M was added, and the reaction was purged with nitrogen gas for an additional 5 minutes. The mixture was then heated with stirring at 77 °C for 7 minutes. Upon completion, the solvent was removed under reduced pressure It was removed, the mixture was dissolved in EA, washed with water, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude material. The crude product was purified using flash chromatography eluting with EA (20% - 100%) in hexane to obtain Compound 4A.

Chemical formula

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

[0337] (S)-2-(2,6-Difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-3-(4-(1,4-dimethyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)phenyl)propanoic acid (4) synthesis: The title compound was prepared according to the method presented for the synthesis of 1 starting from Compound 4B and Intermediate B. MS (m / z) 648.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J = 8.0 Hz, 1H), 8.30 (s, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 8.2 Hz, 2H), 6.76 (d, J = 11.6 Hz, 2H), 4.90 (td, J = 8.5, 3.2 Hz, 1H), 4.62 - 4.55 (m, 1H), 4.16 (d, J = 12.7 Hz, 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 = 12.3 Hz, 1H), 3.29 - 3.23 (m, 1H), 3.17 (dd, J = 14.0, 4.6 Hz, 1H), 2.98 (dd, J = 13.9, 10.1 Hz, 1H), 2.00 (s, 3H). Example 5

Chemical formula

[0338] (S)-3-(4-(1,6-Dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-3-methylphenyl)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamide)propanoic acid (5) Synthesis: The title compound was prepared according to the method presented for the synthesis of 1 starting from Intermediate I and Intermediate C. MS (m / z) 658.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (dd, J = 8.0, 4.0 Hz, 1H), 7.17 (d, J = 12.1 Hz, 1H), 7.10 (t, J = 8.5 Hz, 1H), 6.89 - 6.83 (m, 1H), 6.69 (d, J = 14.1 Hz, 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 = 12.6 Hz, 1H), 3.94 (dd, J = 11.2, 3.2 Hz, 1H), 3.73 (d, J = 11.9 Hz, 1H), 3.59 - 3.51 (m, 1H), 3.50 (s, 3H), 3.35 (d, J = 11.5 Hz, 1H), 3.27 (d, J = 12.8 Hz, 1H), 3.13 (dd, J = 14.2, 3.9 Hz, 1H), 2.97 - 2.89 (m, 1H), 2.49 (s, 3H), 2.04 (d, J = 1.6 Hz, 3H), 1.97 (d, J = 4.0 Hz, 3H). Example 6

Chemical Structure

[0339] (S)-2-(2,6-Difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-3-(4-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-3-fluorophenyl)propanoic acid (6) Synthesis: The title compound was prepared according to the method presented for the synthesis of 1 starting from Intermediate J and Intermediate B. MS (m / z) 666.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (dd, J=7.9, 2.4 Hz, 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=12.7 Hz, 1H), 3.95 (dd, J=11.3, 3.5 Hz , 1H), 3.74 (d, J=14.9 Hz, 1H), 3.56 (td, J=11.9, 2.8 Hz, 1H), 3.50 (s, 3H), 3.43 (d, J=13.9 Hz, 1H), 3.22 (ddd, J=31.6, 12.8, 4.0 Hz, 2H), 3.00 (t, J=13.3 Hz, 1H). Example 7

Chemical Structure

[0340] (2S,5R)-2-(3-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-5-isopropyl-3,6-dimethoxydihydropyrazine (7A) Synthesis: To a solution of (R)-2-isopropyl-3,6-dimethoxydihydropyrazine (361 mg, 1.96 mmol) in THF (9.80 mL) at -78 °C was added a solution of n-BuLi in hexane (2.11 g, 2.11 mmol). The mixture was stirred at -78 °C for 20 minutes, followed by the dropwise addition of a solution of 2-(4-(bromomethyl)-2-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg, 1.51 mmol) in THF (7.50 mL). The reaction was stirred at -78 °C for 40 minutes and quenched with water. The cold bath was removed, the reaction was warmed to room temperature, extracted with EA, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give compound 7A. This was used without further purification.

[0341] 3-(2-Chloro-4-(((2S,5R)-5-isopropyl-3,6-dimethoxydihydropyrazin-2-yl)methyl)phenyl)-1,5,6-trimethylpyrazin-2(1H)-one (7B) Synthesis: To a solution of compound 7A (200 mg, 0.276 mmol) and 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 gas for 6 minutes. Then, XPhosPdG3 (11.7 mg, 0.014 mmol) was added, the mixture was purged with nitrogen gas for an additional 4 minutes, and heated at 90 °C for 30 minutes. The solvent was then removed under reduced pressure, 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 hexane (20% - 100%) and then MeOH in EA (0% - 25%) to give compound 7B.

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

[0343] (S)-3-(3-Chloro-4-(4,5,6-trimethyl-3-oxo-3,4-dihydropyrazin-2-yl)phenyl)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamide)propanoic acid (7) synthesis: The title compound was prepared according to the method presented for the synthesis of 1 using 7C and Intermediate C. MS (m / z) 625.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 7.8 Hz, 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 = 7.9 Hz, 1H), 3.95 (d, J = 11.7 Hz, 1H), 3.73 (d, J = 13.9 Hz, 1H), 3.56 (d, J = 12.2 Hz, 1H), 3.52 (s, 3H), 3.36 (d, J = 11.3 Hz, 1H), 3.27 (d, J = 11.9 Hz, 1H), 3.18 (d, J = 11.2 Hz, 1H), 3.03 - 2.93 (m, 1H), 2.37 (s, 3H), 2.30 (s, 3H), 2.09 (s, 3H). Example 8 [Chemical formula]

[0344] Synthesis of methyl (S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamide)-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 (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.93 (d, J = 7.6 Hz, 1H), 8.56 (d, J = 5.0 Hz, 1H), 8.47 (d, J = 2.3 Hz, 1H), 7.96 - 7.85 (m, 2H), 7.40 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 9.4 Hz, 1H), 6.46 (d, J = 11.6 Hz, 2H), 4.72 - 4.56 (m, 1H), 4.31 (d, J = 10.0 Hz, 1H), 3.20 (dd, J = 14.2, 5.1 Hz, 1H), 3.16 - 2.99 (m, 2H), 2.67 (d, J = 0.7 Hz, 2H), 1.76 (ddd, J = 13.7, 7.3, 3.3 Hz, 1H), 1.52 (ddd, J = 13.8, 10.5, 7.2 Hz, 1H), 1.32 - 1.21 (m, 6H), 1.09 (d, J = 0.7 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H). Example 9

Chemical Structure

[0345] (S)-2-(2,6-Difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamide)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoic acid (9) synthesis: To 8 (12.5 mg, 0.02 mmol) dissolved in THF, 1.0 M LiOH (0.04 mL, 0.04 mmol) was added and the mixture was stirred at room temperature for 1 hour. Then, 4.0 M in dioxane (0.1 mL, 0.4 mmol) HCl was added and the mixture was stirred overnight. The reaction mixture was concentrated, filtered, and purified via reverse-phase HPLC (MeCN / H2O) to obtain 9. Example 10

Chemical Structure

[0346] Synthesis of methyl (S)-2-(2-fluoro-6-methyl-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamide)-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 (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.81 (d, J = 7.8 Hz, 1H), 8.57 (dd, J = 5.1, 1.8 Hz, 1H), 8.49 (s, 1H), 8.16 (s, 2H), 7.92 (dd, J = 12.9, 6.5 Hz, 2H), 7.42 (d, J = 8.1 Hz, 1H), 6.40 (d, J = 7.4 Hz, 2H), 6.32 (d, J = 9.3 Hz, 1H), 4.72 (d, J = 6.2 Hz, 1H), 4.20 (s, 1H), 3.68 (d, J = 2.0 Hz, 3H), 3.32 (d, J = 1.9 Hz, 4H), 3.24 (dd, J = 14.9, 4.6 Hz, 1H), 3.19 - 3.01 (m, 4H), 2.00 (s, 3H), 1.75 (d, J = 10.1 Hz, 1H), 1.55 (d, J = 15.8 Hz, 1H), 0.93 (t, J = 7.3 Hz, 3H). Example 11

Chemical Structure

[0347] (S)-2-(2-Fluoro-6-methyl-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamide)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoic acid (11) Synthesis: The title compound was prepared according to the method presented for the synthesis of Example 9 starting from 10. MS (m / z) 603.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J = 1.9 Hz, 1H), 8.67 (d, J = 8.1 Hz, 1H), 8.62 - 8.52 (m, 1H), 8.50 (s, 1H), 8.02 - 7.80 (m, 2H), 7.41 (dd, J = 8.2, 2.0 Hz, 1H), 6.53 - 6.34 (m, 3H), 6.30 (d, J = 9.2 Hz, 1H), 5.76 (d, J = 1.8 Hz, 1H), 4.65 (d, J = 11.1 Hz, 1H), 4.03 (d, J = 7.0 Hz, 1H), 3.61 (s, 3H), 3.26 (d, J = 13.9 Hz, 1H), 3.03 (t, J = 12.6 Hz, 1H), 2.00 (d, J = 2.3 Hz, 4H), 1.89 - 1.63 (m, 2H), 1.52 (dd, J = 14.8, 8.1 Hz, 1H), 0.93 (t, J = 7.4 Hz, 3H). Example 12

Chemical Structure

[0348] Synthesis of methyl (S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-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 (400 MHz, DMSO-d6) δ 9.09 (d, J = 7.6 Hz, 1H), 9.00 (s, 1H), 8.57 (dd, J = 5.0, 1.5 Hz, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.01 - 7.80 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 11.8 Hz, 2H), 5.09 - 4.81 (m , 1H), 4.70 (td, J = 9.0, 5.7 Hz, 1H), 4.17 (d, J = 12.7 Hz, 1H), 4.07 - 3.88 (m, 1H), 3.75 (d, J = 12.9 Hz, 1H), 3.67 (d, J = 1.6 Hz, 3H), 3.61 (d, J = 1.6 Hz, 3H), 3.58 - 3.51 (m, 1H), 3.44 (d, J = 12.7 Hz, 1H), 3.29 - 3.19 (m, 2H), 3.12 (dd, J = 14.2, 9.9 Hz, 1H). Example 13

Chemical Structure

[0349] (S)-2-(2,6-Difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoic acid (13) Synthesis: The title compound was prepared according to the method presented for the synthesis of Example 9 starting from 12. MS (m / z) 635.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.95 (d, J = 7.9 Hz, 1H), 8.57 (d, J = 5.0 Hz, 1H), 8.50 (d, J = 2.3 Hz, 1H), 7.96 - 7.85 (m, 2H), 7.41 (d, J = 8.1 Hz, 1H), 6.78 (d, J = 11.6 Hz, 2H), 4.92 (s, 1H), 4.70 - 4.55 (m, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.96 (dd, J = 11.3, 3.9 Hz, 1H), 3.74 (d, J = 12.6 Hz, 1H), 3.61 (s, 3H), 3.55 (d, J = 10.6 Hz, 1H), 3.44 (d, J = 12.5 Hz, 1H), 3.25 (dd, J = 14.3, 4.6 Hz, 2H), 3.08 (dd, J = 14.3, 10.0 Hz, 1H). Example 14

Chemical Structure

[0350] Synthesis of methyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-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 of 1 using Intermediate K and Intermediate C Prepared according to the method presented for the synthesis. MS (m / z) 644.8 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.93 (d, J = 7.9 Hz, 1H), 8.57 (dd, J = 5.0, 1.6 Hz, 1H), 8.50 (s, 1H), 7.93 (dd, J = 16.9, 6.6 Hz, 2H), 7.42 (d, J = 8.1 Hz, 1H), 6.87 - 6.48 (m, 2H), 4.93 - 4.69 (m, 2H), 4.15 (d, J = 12.7 Hz, 2H), 3.97 (s, 12H), 3.77 - 3.71 (m, 1H), 3.69 (d, J = 1.7 Hz, 3H), 3.61 (d, J = 1.7 Hz, 3H), 3.59 - 3.48 (m, 1H), 3.36 (d, J = 12.4 Hz, 1H), 3.26 (dd, J = 14.1, 4.9 Hz, 2H), 3.14 - 3.01 (m, 1H), 2.06 (s, 3H). Example 15 [Chemical formula]

[0351] (S)-2-(2-Fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoic acid (15) Synthesis: The title compound was prepared according to the method presented for the synthesis of Example 9 starting from 14. MS (m / z) 631.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.79 (d, J = 8.1 Hz, 1H), 8.57 (d, J = 5.0 Hz, 1H), 8.50 (s, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 5.1 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 6.75 - 6.61 (m, 2H), 4.85 (d, J = 9.6 Hz, 1H), 4.69 (d, J = 8.4 Hz, 1H), 4.15 (d, J = 12.6 Hz, 1H), 4.07 - 3.90 (m, 1H), 3.73 (d, J = 12.6 Hz, 1H), 3.61 (s, 3H), 3.59 - 3.49 (m, 1H), 3.43 - 3.19 (m, 3H), 3.13 - 2.95 (m, 1H), 2.04 (s, 3H). Example 16

Chemical Structure

[0352] Synthesis of methyl (S)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)-2-(2,3,6-trifluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamide)propanoate (16): The title compound was prepared according to the method presented for the synthesis of 1 using Intermediate K and Intermediate E. MS (m / z) 639.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 7.8 Hz, 1H), 9.00 (s, 1H), 8.60 - 8.54 (m, 1H), 8.49 (s, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.48 - 7.35 (m, 1H), 6.99 - 6.78 (m, 1H), 6.73 (d, J = 9.3 Hz, 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 = 7.3 Hz, 2H), 0.93 (t, J = 6.8 Hz, 3H). Example 17

Chemical Structure

[0353] (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)benzamide)propanoic acid (17): The title compound was prepared according to the method presented for the synthesis of Example 9 starting from 16. MS (m / z) 625.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.02 - 8.91 (m, 2H), 8.57 (d, J = 5.4 Hz, 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 = 9.2 Hz, 1H), 4.64 (s, 1H), 3.61 (s, 3H), 3.26 (d, J = 14.1 Hz, 1H), 3.15 - 2.95 (m, 1H), 1.77 (d, J = 8.4 Hz, 2H), 0.93 (t, J = 7.1 Hz, 3H). Example 18

Chemical Structure

[0354] Synthesis of Methyl (S)-2-(4-(Cyclopropyl((R)-1,1,1-trifluorobutan-2-yl)amino)-2,6-difluorobenzamide)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate (18): The title compound was prepared according to the method presented for the synthesis of 1 using Intermediate K and Intermediate F. MS (m / z) 661.3 [M + H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 7.6 Hz, 1H), 9.00 (s, 1H), 8.57 (d, J = 5.0 Hz, 1H), 8.52 - 8.45 (m, 1H), 7.96 - 7.87 (m, 2H), 7.42 (dd, J = 8.1, 0.7 Hz, 1H), 6.68 (d, J = 12.1 Hz, 2H), 5.68 (ddd, J = 22.3, 10.1, 4.9 Hz, 1H), 5.25 - 5.15 (m, 2H), 4.81 (s, 1H), 4.69 (ddd, J = 10.1, 7.6, 5.1 Hz, 1H), 4.01 (s, 2H), 3.67 (s, 3H), 3.61 (s, 3H), 3.23 (dd, J = 14.2, 5.1 Hz, 1H), 3.09 (dd, J = 14.2, 10.0 Hz, 1H), 1.92 (ddd, J = 14.3, 10.4, 7.1 Hz, 1H), 1.78 (dtd, J = 13.8, 7.0, 3.8 Hz, 1H), 0.87 (t, J = 7.3 Hz, 3H). Example 19 [Chemistry]

[0355] (S)-2-(4-(Cyclopropyl((R)-1,1,1-trifluorobutan-2-yl)amino)-2,6-difluorobenzamide)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoic acid (19) Synthesis: The title compound was prepared according to the method presented for the synthesis of Example 9 starting from 18. MS (m / z) 647.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.23 - 12.44 (s, 1H), 9.00 (s, 1H), 8.91 (d, J = 7.9 Hz, 1H), 8.57 (d, J = 4.9 Hz, 1H), 8.50 (d, J = 2.3 Hz, 1H), 7.97 - 7.86 (m, 2H), 7.45 - 7.38 (m, 1H), 6.67 (d, J = 12.0 Hz, 2H), 5.78 - 5.59 (m, 1H), 5.28 - 5.12 (m, 2H), 4.81 (s, 1H), 4.61 (ddd, J = 10.1, 7.8, 4.5 Hz, 1H), 4.01 (s, 2H), 3.61 (s, 3H), 3.24 (dd, J = 14.2, 4.5 Hz, 1H), 3.06 (dd, J = 14.2, 10.2 Hz, 1H), 1.99 - 1.85 (m, 1H), 1.85 - 1.73 (m, 1H), 0.86 (t, J = 7.3 Hz, 3H). Example 20

[0356] Synthesis of Cyclopropyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate (20): The title compound was prepared according to the method presented for the synthesis of 1 using Intermediate L and Intermediate C. MS (m / z) 671.2 [M +H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.92 (d, J = 7.7 Hz, 1H), 8.57 (d, J = 4.9 Hz, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.00 - 7.86 (m, 2H), 7.42 (d, J = 8.1 Hz, 1H), 6.82 - 6.60 (m, 2H), 4.85 (d, J = 9.7 Hz, 1H), 4.71 (ddd, J = 10.3, 7.6, 5.2 Hz, 1H), 4.14 (ddd, J = 9.3, 4.7, 2.3 Hz, 2H), 3.99 - 3.92 (m, 1H), 3.61 (s, 3H), 3.36 (d, J = 12.4 Hz, 1H), 3.23 (dd, J = 14.2, 5.3 Hz, 1H), 3.08 (dd, J = 14.2, 10.3 Hz, 1H), 2.06 (s, 3H), 0.77 - 0.52 (m, 3H).

Chem.

Chem.

[0357] Synthesis of ethyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate (21): To 15 (600 mg, 0.8 mmol) in DCM (13 mL) 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 minutes. The reaction mixture was concentrated in vacuo and then purified by column chromatography on silica gel eluting with EA in 0 - 100% hexane to give 21. MS (m / z) 659.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.92 (d, J = 7.7 Hz, 1H), 8.57 (d, J = 4.9 Hz, 1H), 8.50 (d, J = 2.3 Hz, 1H), 7.95 (dd, J = 8.2, 2.4 Hz, 1H), 7.91 (dd, J = 5.0, 0.8 Hz, 1H), 7.47 - 7.35 (m, 1H), 6.77 - 6.59 (m, 2H), 4.85 (dd, J = 8.8, 3.5 Hz, 1H), 4.74 (ddd, J = 10.4, 7.8, 5.2 Hz, 1H), 4.20 - 4.08 (m, 3H), 3.95 (dd, J = 11.4, 3.6 Hz, 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, 10.4 Hz, 1H), 2.07 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). Example 22

Chemical Structure

[0358] Synthesis of methyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-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 (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.86 (d, J = 7.7 Hz, 1H), 8.58 (d, J = 5.0 Hz, 1H), 8.48 (d, J = 2.5 Hz, 1H), 7.92 (d, J = 4.9 Hz, 1H), 7.74 (dd, J = 8.2, 2.5 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 6.77 - 6.61 (m, 2H), 4.97 (ddd, J = 9.8, 7.7, 5.2 Hz, 1H), 4.85 (dd, J = 8.9, 3.6 Hz, 1H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (dd, J = 11.5, 3.6 Hz, 1H), 3.74 (d, J = 12.7 Hz, 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, 9.8 Hz, 2H), 2.06 (s, 3H). Example 23 [Chemical formula]

[0359] (S)-2-(2-Fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-3-(5-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-2-yl)propanoic acid (23) Synthesis: The title compound was prepared according to the method presented for the synthesis of Example 9 starting from 22. MS (m / z) 631.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.71 (d, J = 8.0 Hz, 1H), 8.58 (d, J = 4.9 Hz, 1H), 8.48 (d, J = 2.5 Hz, 1H), 7.92 (d, J = 4.9 Hz, 1H), 7.74 (dd, J = 8.2, 2.5 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 6.74 - 6.61 (m, 2H ), 4.98 - 4.78 (m, 2H), 4.14 (d, J = 12.6 Hz, 1H), 3.95 (dd, J = 11.6, 3.6 Hz, 1H), 3.73 (d, J = 12.8 Hz, 1H), 3.62 (s, 3H), 3.60 - 3.49 (m, 1H), 3.42 - 3.29 (m, 2H), 3.31 - 3.09 (m, 2H), 2.05 (s, 3H). Example 24

Chemical Structure

[0360] Synthesis of methyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-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 (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.89 (d, J = 7.7 Hz, 1H), 8.55 (d, J = 5.0 Hz, 1H), 7.90 (d, J = 5.0 Hz, 1H), 7.39 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 6.70 (dd, J = 12.9, 2.3 Hz, 1H), 6.67 (d, J = 2.3 Hz, 1H), 4.84 (dt, J = 9.8, 5.1 Hz, 1H), 4.70 (ddd, J = 10.4, 7.7, 4.8 Hz, 1H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (dd, J = 11.5, 3.7 Hz, 1H), 3.74 (dd, J = 12.1, 3.4 Hz, 1H), 3.67 (s, 3H), 3.60 (s, 3H), 3.59 - 3.50 (m, 1H), 3.36 (d, J = 11.8 Hz, 1H), 3.27 (d, J = 12.2 Hz, 1H), 3.19 (dd, J = 14.2, 5.0 Hz, 1H), 3.05 (dd, J = 14.1, 10.4 Hz, 1H), 2.07 (s, 3H). Example 25

Chemical Structure

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

[0362] Synthesis of methyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-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 (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.91 (d, J = 7.7 Hz, 1H), 8.56 (d, J = 4.9 Hz, 1H), 7.94 - 7.84 (m, 1H), 7.21 - 7.09 (m, 2H), 6.96 (dd, J = 8.0, 1.7 Hz, 1H), 6.77 - 6.63 (m, 2H), 4.84 (td, J = 8.8, 3.5 Hz, 1H), 4.72 (ddd, J = 10.6, 7.7, 4.7 Hz, 1H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (dd, J = 11.4, 3.6 Hz, 1H), 3.84 - 3.72 (m, 1H), 3.69 (d, J = 3.9 Hz, 6H), 3.64 - 3.58 (m, 4H), 3.31 - 3.00 (m, 6H), 2.09 (s, 3H). Example 27 [Chemical Structure Diagram]

[0363] (S)-2-(2-Fluoro-6-methyl-4-((R)-3-(trifluoromethyl) )Morpholino)benzamide)-3-(3-methoxy-4-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)phenyl)propanoic acid (27) Synthesis: The title compound was prepared according to the method presented for the synthesis of Example 9 starting from 26. MS (m / z) 660.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.76 (d, J = 8.0 Hz, 1H), 8.56 (d, J = 5.0 Hz, 1H), 7.89 (dd, J = 5.0, 1.4 Hz, 1H), 7.20 - 7.12 (m, 2H), 6.97 (dd, J = 8.0, 1.6 Hz, 1H), 6.74 - 6.61 (m, 2H), 4.84 (dd, J = 8.9, 3.5 Hz, 1H), 4.67 (ddd, J = 11.6, 7.9, 4.1 Hz, 1H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (dd, J = 11.5, 3.7 Hz, 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, 10.8 Hz, 1H), 2.08 (s, 3H). Example 54 [Chemical Structure]

[0364] Synthesis of ethyl (S)-2-(2-chloro-6-fluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate (54): The title compound was prepared according to the method presented for the synthesis of 8 using ethyl esters of intermediate K and intermediate P. MS (m / z) 679.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.16 (d, J = 7.9 Hz, 1H), 9.00 (s, 1H), 8.57 (d, J = 5.0 Hz, 1H), 8.50 (d, J = 2.3 Hz, 1H), 7.94 (dd, J = 8.1, 2.4 Hz, 1H), 7.90 (d, J = 5.0 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 6.98 - 6.88 (m, 2H), 4.93 (dd, J = 8.9, 3.5 Hz, 1H), 4.74 (ddd, J = 10.3, 7.9, 5.1 Hz, 1H), 4.20 - 4.08 (m, 3H), 3.95 (dd, J = 11.6, 3.7 Hz, 1H), 3.74 (d, J = 12.7 Hz, 1H), 3.61 (s, 3H), 3.54 (t, J = 9.14 Hz, 1H), 3.41 (d, J = 12.5 Hz, 1H), 3.25 (m, 2H), 3.09 (dd, J = 14.2, 10.2 Hz, 1H), 1.20 (t, J = 7.1 Hz, 3H). Example 55 [Chemical Structure Diagram]

[0365] (S)-2-(2-Chloro-6-fluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoic acid (55) Synthesis: The title compound was prepared according to the method presented for the synthesis of Example 9 starting from 54. MS (m / z) 651.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.32 - 12.45 (s, 1H), 9.04 (d, J = 8.2 Hz, 1H), 9.00 (s, 1H), 8.57 (d, J = 5.0 Hz, 1H), 8.50 (d, J = 2.3 Hz, 1H), 7.94 (dd, J = 8.1, 2.4 Hz, 1H), 7.90 (d, J = 5.0 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 6.96 - 6.87 (m, 2H), 5.00 - 4.84 (m, 1H), 4.76 - 4.63 (m, 1H), 4.15 (d, J = 12.7 Hz, 1H), 3.95 (dd, J = 11.5, 3.7 Hz, 1H), 3.74 (d, J = 12.7 Hz, 1H), 3.61 (s, 3H), 3.60 - 3.49 (m, 1H), 3.40 (d, J = 12.7 Hz, 1H), 3.27 (m, 2H), 3.04 (dd, J = 14.3, 10.6 Hz, 1H). Example 56 [Chemical Structure Diagram]

[0366] Synthesis of methyl (S)-2-(4-((S)-3-(2,2-difluoroethyl)morpholino)-2-fluoro-6-methylbenzamide)-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 esters of intermediate R and intermediate Q. MS (m / z) 645.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 7.7 Hz, 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, 4.9 Hz, 1H), 4.28 (d, J = 1.8 Hz, 2H), 4.02 (d, J = 9.3 Hz, 1H), 3.93 - 3.80 (m, 4H), 3.66 (s, 3H), 3.63 (s, 1H), 3.52 (td, J = 11.7, 3.2 Hz, 1H), 3.34 (s, 1H), 3.16 (dd, J = 14.1, 4.9 Hz, 1H), 3.09 - 2.95 (m, 2H), 2.72 (d, J = 5.8 Hz, 2H), 2.37 (d, J = 14.0 Hz, 1H), 2.05 (s, 3H), 1.77 (q, J = 17.5 Hz, 1H). Example 57 [Chemical Structure Diagram]

[0367] (S)-2-(4-((S)-3-(2,2-Difluoroethyl)morpholino)-2-fluoro-6-methylbenzamide)-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) Synthesis: The title compound was prepared according to the method presented for the synthesis of Example 9 starting from 56. MS(m / z) 631.4 [M+H]+. 1H NMR(400MHz, DMSO-d6) δ 12.87 - 12.58(s, 1H), 8.68(d, J = 8.1Hz, 1H), 7.36(d, J = 8.2Hz, 2H), 7.10(d, J = 8.2Hz, 2H), 6.53(d, J = 8.7Hz, 2H), 6.34 - 5.94(m, 1H), 4.70 - 4.54(m, 1H), 4.28(s, 2H), 4.01(s, 1H) 394 - 379(m 4H) 364(d, J = 11.2Hz, 1H), 352(d, J = 3.3Hz, 1H), 3.33(s, 1H), 3.31(s, 3H), 3.22 - 3.14(m, 1H), 3.09 - 2.93(m, 2H), 2.71(s, 2H), 2.43 - 2.34(m, 1H), 2.04(s, 3H), 1.79(s, 1H). Example 58

Chemical Structure

[0368] Synthesis of Methyl (S)-2-(2-Fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-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 esters of Intermediate R and Intermediate C. MS(m / z) 649.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 7.7 Hz, 1H), 7.35 (d, J = 8.3 Hz, 2H), 7.14 - 7.07 (m, 2H), 6.69 (d, J = 13.5 Hz, 1H), 6.66 (d, J = 2.3 Hz, 1H), 4.84 (d, J = 9.0 Hz, 1H), 4.68 (ddd, J = 12.4, 7.8, 4.9 Hz, 1H), 4.29 (s, 2H), 4.15 (d, J = 12.6 Hz, 1H), 4.00 - 3.92 (m, 1H), 3.88 (t, J = 5.6 Hz, 2H), 3.73 (d, J = 12.6 Hz, 1H), 3.66 (s, 3H), 3.54 (t, J = 10.2 Hz, 1H), 3.35 (d, J = 13.3 Hz, 2H), 3.31 (s, 2H), 3.16 (dd, J = 14.2, 5.0 Hz, 1H), 3.02 (dd, J = 14.1, 10.2 Hz, 1H), 2.71 (m, 2H), 2.05 (s, 3H). Example 59

Chemical Structure

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

Chemical Structure

[0370] Synthesis of methyl (S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-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 intermediate S and the ethyl ester of intermediate B. MS (m / z) 653.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 7.5 Hz, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.3 Hz, 2H), 6.79 (d, J = 11.6 Hz, 2H), 4.91 (dt, J = 12.0, 6.0 Hz, 1H), 4.68 - 4.56 (m, 3H), 4.17 (d, J = 12.7 Hz, 1H), 3.96 (dd, J = 11.4, 3.8 Hz, 1H), 3.8^{4}-3.7^{0}(m, 3H), 3.64 (s, 3H), 3.61 - 3.51 (m, 1H), 3.44 (d, J = 12.7 Hz, 1H), 3.26 (d, J = 13.2 Hz, 1H), 3.21 (s, 3H), 3.17 (d, J = 5.3 Hz, 1H), 3.15 - 3.01 (m, 2H), 2.39 - 2.24 (m, 2H). Example 61 [Chemical Structure]

[0371] (S)-2-(2,6-Difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-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) Synthesis: The title compound was prepared according to the method presented for the synthesis of Example 9 starting from 60. MS (m / z) 639.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 7.8 Hz, 1H), 7.35 (dd, J = 8.5, 2.0 Hz, 2H), 7.16 - 7.00 (m, 2H), 6.78 (d, J = 11.6 Hz, 2H), 5.04 - 4.82 (m, 1H), 4.64 - 4.49 (m, 3H), 4.16 (d, J = 12.7 Hz, 1H), 3.96 (dd, J = 11.5, 3.7 Hz, 1H), 3.83 - 3.70 (m, 3H), 3.62 - 3.49 (m, 1H), 3.43 (d, J = 12.7 Hz, 1H), 3.26 (d, J = 12.5 Hz, 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). Example 62 [Chemical Structure Diagram]

[0372] Synthesis of methyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-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 intermediate S and the ethyl ester of intermediate C. MS (m / z) 671.2 [M+Na]. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 7.7 Hz, 1H), 7.35 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 8.2 Hz, 2H), 6.70 (d, J = 13.5 Hz, 1H), 6.66 (s, 1H), 4.84 (d, J = 7.7 Hz, 1H), 4.76 - 4.64 (m, 1H), 4.60 (s, 2H), 4.15 (d, J = 12.6 Hz, 1H), 4.03 - 3.90 (m, 1H), 3.86 - 3.70 (m, 3H), 3.66 (s, 3H), 3.55 (t, J = 10.7 Hz, 1H), 3.21 (s, 4H), 3.03 (dd, J = 14.1, 10.3 Hz, 1H), 2.33 (d, J = 2.5 Hz, 3H), 2.06 (s, 3H). Example 63

Chemical Structure

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

[0374] (S)-2-(2-Fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-3-(4-(1-methyl-2,4-dioxo-1,2,4,5,6,7-hexahydro-3H-cyclopenta[d]pyrimidin-3-yl)phenyl)propanoic acid (64) Synthesis: The title compound was prepared according to the method presented for the synthesis of 1 using ethyl esters of intermediate T and intermediate C. MS (m / z) 619.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 8.0 Hz, 1H), 7.35 (dd, J = 8.5, 2.0 Hz, 2H), 7.11 - 7.00 (m, 2H), 6.68 (dd, J = 12.9, 2.4 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H), 4.84 (dd, J = 8.8, 3.5 Hz, 1H), 4.63 (ddd, J = 10.6, 8.0, 4.2 Hz, 1H), 4.14 (d, J = 12.6 Hz, 1H), 3.94 (dd, J = 11.4, 3.6 Hz, 1H), 3.73 (d, J = 12.7 Hz, 1H), 3.54 (td, J = 11.7, 3.5 Hz, 1H), 3.35 (d, J = 12.2 Hz, 1H), 3.29 (s, 3H), 3.18 (dd, J = 14.3, 4.3 Hz, 1H), 3.05 - 2.89 (m, 3H), 2.61 (t, J = 7.4 Hz, 2H), 2.04 (s, 3H). Example 65 [Chemical formula]

[0375] Synthesis of ethyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-3-(4-(1-methyl-2,4-dioxo-1,2,4,5,6,7-hexahydro-3H-cyclopenta[d]pyrimidin-3-yl)phenyl)propanoate (65): To 64 (30 mg, 0.05 mmol), TPP (38 mg, 0.145 mmol), and EtOH (0.03 mL, 0.48 mmol) in DCM, DIAD (0.05 mL, 0.24 mmol) was added. The mixture was stirred for 6 It was stirred at room temperature for 0 minutes. Upon completion, the mixture was acidified with TFA, and the volatiles were removed under reduced pressure. The crude material was dissolved in DMSO and chromatographed on C-18 modified silica gel eluting with acetonitrile in water (0.4% TFA) to afford Compound 65. MS (m / z) 647.3 [M+H]+. 1H NMR (400 MHz, DMSO-dd6) δ 8.86 (d, J = 7.6 Hz, 1H), 7.39 - 7.28 (m, 2H), 7.12 - 7.01 (m, 2H), 6.75 - 6.67 (m, 1H), 6.66 (d, J = 2.3 Hz, 1H), 4.92 - 4.76 (m, 1H), 4.65 (ddd, J = 9.9, 7.6, 5.2 Hz, 1H), 4.19 - 4.06 (m, 3H), 3.95 (dd, J = 11.4, 3.7 Hz, 1H), 3.73 (d, J = 12.7 Hz, 1H), 3.62 - 3.43 (m, 1H), 3.36 (d, J = 12.4 Hz, 1H), 3.29 (s, 4H), 3.15 (dd, J = 14.1, 5.3 Hz, 1H), 3.10 - 3.00 (m, 1H), 2.97 (q, J = 7.6, 6.6 Hz, 2H), 2.61 (t, J = 7.5 Hz, 2H), 2.13 - 1.92 (m, 5H), 1.17 (t, J = 7.1 Hz, 3H). Example 66

[0376] (S)-2-(2-Fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-3-(4-(1-methyl-2,4-dioxo-1,2,5,7-tetrahydrofuro[3,4-d]pyrimidin-3(4H)-yl)phenyl)propanoic acid (66) Synthesis: The title compound was prepared according to the method presented for the synthesis of 1 using the ethyl esters of Intermediate U and Intermediate C. MS (m / z) 621.2 [M+H 1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 8.0 Hz, 1H), 7.42 - 7.30 (m, 2H), 7.16 - 7.03 (m, 2H), 6.68 (dd, J = 12.9, 2.3 Hz, 1H), 6.64 (d, J = 2.3 Hz, 1H), 5.06 (t, J = 3.6 Hz, 2H), 4.86 (t, J = 3.6 Hz, 3H), 4.64 (ddd, J = 10.7, 8.0, 4.2 Hz, 1H), 4.14 (d, J = 12.6 Hz, 1H), 3.94 (dd, J = 11.4, 3.6 Hz, 1H), 3.73 (d, J = 12.5 Hz, 1H), 3.63 - 3.47 (m, 1H), 3.35 (d, J = 12.2 Hz, 1H), 3.23 (s, 5H), 2.99 (dd, J = 14.2, 10.7 Hz, 1H), 2.03 (s, 3H).

Chemical Structure

Chemical Structure

[0377] Synthesis of ethyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-3-(6-(1-methyl-2,4-dioxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-d]pyrimidin-3(4H)-yl)pyridin-3-yl)propanoate (67): The title compound was prepared according to the method presented for the synthesis of 8 using intermediate V and the ethyl ester of intermediate C. MS (m / z) 664.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J = 7.7 Hz, 1H), 8.45 (d, J = 2.3 Hz, 1H), 7.95 (s, 1H), 7.89 (dd, J = 8.2, 2.4 Hz, 1H), 7.30 (dd, J = 8.1, 0.7 Hz, 1H), 6.75 - 6.64 (m, 2H), 4.84 (dd, J = 8.8, 3.5 Hz, 1H), 4.71 (ddd, J = 10.4, 7.8, 5.2 Hz, 1H), 4.29 (s, 2H), 4.19 - 4.06 (m, 3H), 3.99 - 3.84 (m, 3H), 3.73 (d, J = 12.5 Hz, 1H), 3.59 - 3.49 (m, 1H), 3.31 (s, 4H), 3.28 - 3.16 (m, 2H), 3.07 (dd, J = 14.3, 10.3 Hz, 1H), 2.89 (s, 2H), 2.77 - 2.66 (m, 4H), 2.06 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H). Example 68

Chemical Structure

[0378] (S)-2-(2-Fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamide)-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) Synthesis: The title compound was prepared according to the method presented for the synthesis of Example 9 starting from 67. MS (m / z) 636.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 8.1 Hz, 1H), 8.46 (d, J = 2.3 Hz, 1H), 7.88 (dd, J = 8.2, , 2.4 Hz, 1H), 7.33 - 7.26 (m, 1H), 6.73 - 6.62 (m, 2H), 4.84 (dd, J = 8.8, 3.6 Hz, 1H), 4.67 (ddd, J = 11.9, 8.0, 4.2 Hz, 1H), 4.29 (s, 2H), 4.14 (d, J = 12.6 Hz Example 69

Chemical Structure

[0379] (S)-2-(4-((S)-3-(2,2-Difluoroethyl)morpholino)-2-fluoro-6-methylbenzamide)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoic acid (69) Synthesis: The title compound was prepared according to the method presented for the synthesis of 1 using the ethyl esters of intermediate K and intermediate Q. MS (m / z) 627.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.75 (d, J = 8.2 Hz, 1H), 8.57 (d, J = 5.0 Hz, 1H), 8.50 (d, J = 2.4 Hz, 1H), 7.94 (dd, J = 8.3, 2.4 Hz, 1H), 7.92 - 7.89 (m, 1H), 7.42 (d, J = 8.0 Hz, 1H), 6.53 (t, J = 6.1 Hz, 2H), 6.36 - 5.96 (m, 1H), 4.75 - 4.61 (m, 1H), 4.03 (m, 1H), 3.90 (d, J = 9.1 Hz, 1H), 3.84 (d, J = 11.8 Hz, 1H), 3.61 (s, 3H), 3.58 - 3.46 (m, 1H), 3.35 - 3.13 (m, 2H), 3.04 (dd, J = 14.4, 10.9 Hz, 2H), 2.03 (s, 3H). Example 70 [Chemical Structure Diagram]

[0380] (S)-2-(4-((S)-3-(2,2-Difluoroethyl)morpholino)-2-fluoro-6-methylbenzamide)-3-(4-(1-methyl-2,4-dioxo-1,2,5,7-tetrahydrofuro[3,4-d]pyrimidin-3(4H)-yl)phenyl (R)-Propanoic acid (70): The title compound was prepared according to the method presented for the synthesis of 1 using ethyl esters of intermediate W and intermediate Q. MS (m / z) 617.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 8.0 Hz, 1H), 7.42 - 7.30 (m, 2H), 7.16 - 7.04 (m, 2H), 6.61 - 6.44 (m, 2H), 6.16 (tt, J = 56.3, 4.5 Hz, 1H), 5.06 (t, J = 3.6 Hz, 2H), 4.86 (t, J = 3.6 Hz, 2H), 4.64 (ddd, J = 11.9, 8.1, 4.2 Hz, 1H), 4.01 (d, J = 9.3 Hz, 1H), 3.89 (dd, J = 11.2, 3.5 Hz, 1H), 3.84 (d, J = 11.6 Hz, 1H), 3.69 - 3.58 (m, 1H), 3.52 (td, J = 11.6, 3.1 Hz, 1H), 3.31 (d, J = 12.6 Hz, 1H), 3.23 (s, 3H), 3.19 (dd, J = 14.3, 4.3 Hz, 1H), 3.08 - 2.85 (m, 2H), 2.43 - 2.25 (m, 1H), 2.03 (s, 3H), 1.75 (dd, J = 19.1, 14.8 Hz, 1H). α4β7 integrin cell capture assay

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

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

[0383] RPMI 8866 cells were spun down and 0.5×10 6Resuspended in assay medium (DMEM + 0.5% FBS + 0.5 mM MnCl2) at a density of cells / mL. Then, the cells were dispensed into a 384-well plate (Greiner 781280) that had been pre-spotted with 60 nL of the test compound per well (60 μL / well). The plate was incubated at 37 °C for 1 hour. 50 μL of the 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 (final concentration of 2% glutaraldehyde and 0.01 mg / mL). The plate was incubated at room temperature for 90 minutes. Then, the plate was washed three times with 70 μL of PBS per well and imaged with a Cellomics ArrayScan instrument. The cells bound to the plate were counted and plotted against the compound concentration to determine the EC 50 of the test compound. The results are shown in Tables 1 and 2. α4β1 cell capture assay

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

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

[0386] Jurkat cells were spun down and resuspended in assay medium (DMEM + 0.5% FBS + 0.5 mM MnCl2) at a density of 0.5×10 6 cells / mL. Then, the cells were pre-spotted with 60 nL of the test compound per well into a 384-well plate (Gr Dispensed into (60 μL / well) of a 781280). The plate was incubated at 37 °C for 1 hour. 50 μL of cells were transferred to the blocked VCAM-1 coated plate and incubated at 37 °C for 30 minutes. 10 μL of 12% glutaraldehyde containing Hoechst 33342 (0.06 mg / mL) was added to the cells (final concentration of 2% glutaraldehyde and 0.01 mg / mL of Hoechst 33342). The plate was incubated at room temperature for 90 minutes. Then, the plate was washed 3 times with 70 μL of PBS per well and imaged with a Cellomics ArrayScan instrument. The cells bound to the plate were counted and plotted against the compound concentration to determine the EC 50 of the test compound was determined. The results are shown in Tables 1 and 2.

Table 2

Table 3-1

Table 3-2

Table 3-3

Table 3-4

Table 3-5

Table 3-6

Table 3-7

Table 3-8

Table 3-9

Table 3-10

Table 3-11

Table 3-12

Table 3-13

Table 3-14

Table 3-15

Table 3-16

Table 3-17

Table 3-18

Table 3-19

Table 3-20

Table 3-21

[0387] All references, including publications, patents, and patent documents, are hereby incorporated by reference into this specification as if each were individually incorporated by reference. This disclosure refers to various embodiments and techniques. However, it should be understood that many variations and modifications can be made while staying within the spirit and scope of this disclosure. The description should be regarded as illustrative of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience only and should in no way be construed as limiting the scope of the claims. The embodiments shown under any heading can be combined with the embodiments shown under any other heading.

[0388] According to a preferred embodiment of the present invention, for example, the following is provided. (Item 1) A compound of formula (I),

Chemical formula

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Claims

1. A compound of formula (III), 【Chemical 8】 or a pharmaceutically acceptable salt thereof, wherein R １ is 【Chemical Formula 1-1】 selected from, where R ｄ is H, C １～４ alkyl, and C １～４ haloalkyl, and where each R １ is independently optionally substituted with one to three R ａ and where each R ａ is independently halo, cyano, hydroxyl, -NR ａ１ R ａ２ , C １～４ alkyl, C １～４ alkoxyl, C １～４ haloalkyl, C １～４ haloalkoxyl, -C １～４ alkylene - O - C １～４ alkyl, and C ３～１０ cycloalkyl, Or R １ is 【Chemical 1-2】 selected from, where R ｄ is -CH ３ and R ｃ is selected from H, halo, cyano, hydroxyl, -NR ａ１ R ａ２ , C １～４ alkyl, C １～４ alkoxyl, C １～４ haloalkyl, and C １～４ haloalkoxyl, and Each R ２ , and R ６ is independently selected from H, halo, cyano, hydroxyl, -NR ａ１ R ａ２ , C １～４ alkyl, C １～４ alkoxyl, C １～４ haloalkyl, and C １～４ haloalkoxyl, R ４ is 【Chemical 1-3】 , and -NR ｂ１ R ｂ２ selected from, Here, R ４ is 【Chemical Formula 1-4】 When it is, it has 1 to 4 Rs ｂ which may be optionally substituted in the case, and each R ｂ is independently selected from halo, cyano, hydroxyl, -NR ａ１ R ａ２ , C １～６ alkyl, C １～６ alkoxyl, C １～８ haloalkyl, and C １～８ haloalkoxyl, and is selected from Each R ｂ１ and R ｂ２ is 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 is H, C １－１０ alkyl, C １～１０ haloalkyl, C ３～１０ cycloalkyl, 3- to 14-membered heterocyclyl, C ６～１０ aryl, 5- to 10-membered heteroaryl, -C １～４ alkylene-NR ａ１ R ａ２ , -C １～４ alkylene-C(O)NR ａ１ R ａ２ , -C １～４ alkylene-C ３～１０ cycloalkyl, -C １～４ alkylene-3- to 14-membered heterocyclyl, -C １～４ alkylene-C ６～１０ aryl, -C １～４ alkylene-5- to 10-membered heteroaryl, and -L １ -R ９ selected from L １ is selected from -C １～４ alkylene-O-,-C １～４ alkylene-C(O)-,-C １～４ alkylene-O-C(O)-,-C １～４ alkylene-O-C(O)-C １～４ alkylene-,-C １～４ alkylene-C(O)-O-,-C １～４ alkylene-C(O)-O-C １～４ alkylene-,-C １～４ alkylene-O-C(O)-O-,-C １～４ alkylene-O-C(O)-O-C １～４ alkylene-,-C １～４ alkylene-NR ａ１ C(O)-O- and -C １～４ alkylene-O-C(O)-NR ａ１ - and is selected from R ９ is selected from C １～６ alkyl, C １～６ haloalkyl, C ３～１０ cycloalkyl, 3- to 14-membered heterocyclyl, C ６～１０ aryl, and 5- to 10-membered heteroaryl, R ７ and R ９ each C ３～１０ cycloalkyl, 3- to 14-membered heterocyclyl, C ６～１０ aryl, and 5- to 10-membered heteroaryl is independently halo, hydroxyl, C １～４ alkyl, C １～４ alkoxyl, C １～４ haloalkyl, C １～４ haloalkoxyl, -NR ａ１ R ａ２ and -C １～４ alkylene-NR ａ１ R ａ２ optionally substituted with 1 to 4 groups selected from, Each R ａ１ and R ａ２ are independently selected from H, C １～６ alkyl, C １～６ haloalkyl, and C ３～１０ cycloalkyl, However, when R ４ is -NH ２ in the case, R １ is 【Chemical Formula 1-5】 is not,[[]]END]] the compound or a pharmaceutically acceptable salt thereof.[[]]END]]

2. The compound is a compound of formula (IIIa), 【Chemical Formula 9】 wherein, X １ is N, X ２ is O, and R ｘ１ is selected from H and R ｂ and R ｘ２ is selected from H, C １～４ alkyl, and C １～４ haloalkyl, and m is selected from 0, 1, and 2, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.[[]]END]]

3. The compound is a compound of formula (IIIb), 【Chemical 10】 In the formula, R ｂ is C １～４ alkyl, or C １～６ haloalkyl, the compound according to any one of claims 1 and 2 or a pharmaceutically acceptable salt thereof.

4. R １ is 【Chemical 11】 selected from, wherein R ｄ is H, C １～４ alkyl, and C １～４ haloalkyl, and each R １ is independently optionally substituted with 1 to 3 R ａ The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. R １ is 【Chemical Formula 12】 and in the formula, R ｄ is C １～４ alkyl, and r is selected from 0, 1, 2, and 3, the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

6. R １ is 【Chemical 13】 is, the compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.[[]]END]]

7. R １ is 【Chemical Formula 14】 selected from, where R ｄ is -CH ３ The compound according to any one of claims 1 to 3, wherein is.

8. R １ is 【Chemical Formula 15】 is, the compound according to any one of claims 1 to 3.[[]]END]]

9. Each R ２ and R ６ is independently selected from H, halo, C １～４ alkyl, C １～４ alkoxyl, C １～４ haloalkyl, and C １～４ haloalkoxyl, and the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

10. Each R ２ and R ６ is independently selected from F and -CH ３ The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. R ２ is F, and R ６ is -CH ３ is as defined in any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. R ４ where R is one to three R ｂ optionally substituted with 【Chemical Formula 12-1】 and each R ｂ independently is halo, C １～４ alkyl, and C １～４ haloalkyl, a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

13. R ｂ is -CH ３ , -CHF ２ , and -CF ３ selected from, a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.

14. R ｂ is -CF ３ and is a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

15. R ４ is R ｂ optionally substituted with 【Chemical 16】 and R ｂ is -CH ３ , -CHF ２ , -CF ３ , -CH ２ CHF ２ , and -CH ２ CF ３ The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, selected from

16. R ４ is 【Chemical 17】 is, the compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.[[]]END]]

17. R ４ is 【Chemical 18】 selected from, the compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.[[]]END]]

18. R ４ is -NR ｂ１ R ｂ２ and R ｂ１ and R ｂ２ are independently selected from H, C １～４ alkyl, C １～６ haloalkyl, and C ３～６ cycloalkyl, a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.

19. R ４ is 【Chemical 19】 is, the compound according to any one of claims 1 to 14 and 18, or a pharmaceutically acceptable salt thereof.[[]]END]]

20. X １ is N, and X ２ is O, the compound according to claim 2 or a pharmaceutically acceptable salt thereof.

21. R ｃ is halo, C １～４ alkyl, C １～４ alkoxyl, C １～４ haloalkyl, and C １～４ haloalkoxyl, and the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof.

22. R ｃ is F, Cl, CH ３ , -OCH ３ , -OCF ３ , and -CF ３ selected from, the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.

23. R ７ is H, C １～６ alkyl, and C ３～６ cycloalkyl, and the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof.

24. R ７ is H, methyl, ethyl, propyl, butyl, cyclopropyl, -CH ２ -O-C(O)C(CH) ３ and phenyl, the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof.

25. R ７ wherein R is selected from H, methyl, ethyl, and cyclopropyl, of claims 1 to 24 the compound according to any one of claims, or a pharmaceutically acceptable salt thereof.[[]]END]]

26. R ７ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, wherein R is H.

27. R ７ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, wherein R is methyl.

28. R ７ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, wherein R is ethyl.

29. a compound or a pharmaceutically acceptable salt thereof, wherein the compound is 【Chemical Formula 29-1】 【Chemical Formula 29-2】 【Chemical Formula 29-3】 【Chemical Formula 29-4】 【Chemical 29-5】 selected from, the compound or a pharmaceutically acceptable salt thereof.[[]]END]]

30. a compound or a pharmaceutically acceptable salt thereof, wherein the compound is 【Chemical 31】 selected from, the compound or a pharmaceutically acceptable salt thereof.[[]]END]]

31. A pharmaceutical composition comprising the compound according to any one of claims 1 to 30 and at least one pharmaceutically acceptable carrier.[[]]END]]

32. A composition comprising the compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, or the composition according to claim 31, for treating a disease or condition associated with α4β7 integrin.[[]]END]]

33. The composition according to claim 32, wherein the disease or condition is an inflammatory disease.[[]]END]]

34. The composition according to any one of claims 32 to 33, 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).

35. The composition according to any one of claims 32 to 33, which is administered in combination with an additional therapeutic compound.

36. Use of a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or condition mediated by α4β7 integrin.

37. Use of a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating an inflammatory disease.

38. Use of a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating inflammatory bowel disease (IBD).

39. A composition comprising a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof for use in treating a disease or condition mediated by α4β7 integrin.

40. A composition comprising a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof for use in treating an inflammatory disease.

41. A composition comprising a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof for use in treating inflammatory bowel disease (IBD).

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