LPA receptor antagonists and uses thereof

Abstract

The present disclosure generally relates to compounds that bind to lysophosphatidic acid receptor 1 (LPAR1) and act as antagonists of LPAR1. The present disclosure also relates to the use of these compounds for the preparation of medicaments for treating diseases and / or conditions (including fibrosis and liver diseases such as non-alcoholic steatohepatitis (NASH)) by binding to LPAR1.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 034,190, filed on June 3, 2020, under 35 U.S.C. §119(e), which is hereby incorporated by reference in its entirety for all purposes. Technical Field

[0003] The present disclosure relates to compounds that bind to lysophosphatidic acid (LPA) receptors (such as LPAR1) and act as antagonists thereof. The present disclosure also relates to the use of compounds for treating and / or preventing diseases and / or conditions associated with one or more LPA receptors (e.g., LPAR1-associated diseases or conditions). Background Art

[0004] Lysophosphatidic acid (monoacyl-glycerol-3-phosphate, LPA) is a class of biologically active phospholipids that can be made, for example, from lysophosphatidylcholine (LPC) by the enzyme autotaxin. Typical LPA has glycerol, fatty acids ester-linked at the sn-1 position, and a phosphate head group at the sn-3 position. LPAs with various fatty acids have been identified, including palmitoyl LPA (16:0), stearoyl LPA (18:0), oleoyl LPA (18:1), linoleoyl LPA (18:2), and arachidonoyl LPA (20:4). LPA exerts a wide range of cellular responses, such as proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis, through the rhodopsin-like G protein-coupled receptor (GPCR) family. Six LPA receptors have been characterized, and it has been found that their tissue distribution and downstream signaling pathways are different. These six LPA receptors are usually interchangeably referred to as LPAR1-6 (genes) or LPA1-6 (proteins). LPA receptor-mediated signaling has been shown to influence many biological processes such as wound healing, immunity, carcinogenesis, angiogenesis, and neurogenesis.

[0005] In vivo studies involving LPA receptor-deficient mice or certain tool compounds have demonstrated the potential of the LPA receptor as a possible drug target in a variety of diseases, including cancer, fibrosis, inflammation, pain, and cardiovascular disease. Recently, LPAR1 antagonists have been studied clinically in conjunction with fibrotic disease states, such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis.

[0006] However, there remains a need for LPA antagonists with desired selectivity, potency, metabolic stability or reduced deleterious effects. Summary of the invention

[0007] The present disclosure provides compounds useful as inhibitors of lysophosphatidic acid receptor 1 (LPAR1). The present disclosure also relates to the use of compounds for treating and / or preventing diseases and / or disorders by binding of the compounds to LPAR1.

[0008] In one embodiment, provided herein is a compound of formula (I),

[0009]

[0010] or a pharmaceutically acceptable salt thereof,

[0011] in:

[0012] R 1 is hydrogen or C optionally substituted by 1 to 3 substituents 1-6 Alkyl, these substituents may be the same or different, each independently selected from halogen, cyano, C 1-4 Alkoxy and C 3-10 Cycloalkyl; or

[0013] R 1 is C optionally substituted by 1 to 3 substituents 3-6 Cycloalkyl, these substituents may be the same or different, each independently selected from halogen, cyano, C 1-4 Alkoxy and C 1-6 alkyl;

[0014] Can be the same or different for each R 2 are independently selected from hydrogen, halogen, cyano, oxo, C 1-4 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, -N(R 2A1 )(R 2A2 ),-OR 2A1 、-SR 2A1 , –C(O)N(R 2A1 )(R 2A2 ),–NR 2A1 C(O)R 2A2 、-NR 2A1 C(O)N(R 2A2 )(R 2A3 ),–S(O) 0-2 R 2A1 , –S(O) 2 N(R 2A1 )(R 2A2 ) and –NR 2A1 S(O) 2 R2A2 , where each R 2A1 , R 2A2 and R 2A3 are independently hydrogen or C 1-6 Alkyl, where each R 2 Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1 to 4 R which may be the same or different. 2B Substitute, where each R 2B Independently for C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy, halogen or cyano;

[0015] Can be the same or different for each R 3 independently selected from deuterium, halogen, C 1-6 Alkyl, C 3-10 Cycloalkyl or C 1-4 Alkoxy, each C 1-6 Alkyl and C 3-10 Cycloalkyl is optionally substituted with 1 to 3 halogens;

[0016] R 4 is C optionally substituted by 1 to 3 substituents 1-6 Alkyl, these substituents may be the same or different, each independently selected from halogen, cyano, C 1-4 Alkoxy, -C(O)N(R 4A1 ) and -N(R 4A1 )(R 4A2 ), where each R 4A1 and R 4A2 Independently H, C 1-6 Alkyl or C 3-10 Cycloalkyl; or

[0017] R 4 C 3-6 Cycloalkyl or 3 to 6 membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1 to 3 substituents which may be the same or different and are independently selected from halogen, cyano, C 1-4 Alkyl and C 1-4 Alkoxy;

[0018] m is 0, 1, 2, 3 or 4;

[0019] n is 0, 1, 2 or 3;

[0020] o is 0, 1, 2, or 3;

[0021] X 1 , X 2 and X 3 are each independently selected from CH and N;

[0022] Each U is independently -CH=, -CH 2 -, -N=, -NH- or -O-;

[0023] Each Y 1 and Y 2 is independently hydrogen, deuterium or C optionally substituted by 1 to 3 substituents 1-6 Alkyl, these substituents may be the same or different, each independently selected from deuterium, halogen, cyano, C 2-3 Alkynyl, C 1-4 Alkoxy and -C(O)NH-(C 1- 4 H 3-9 );and

[0024] Z is C 1-8 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-12 aryl, 3 to 12 membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5 to 12 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the alkyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl are each optionally substituted with 1 to 3 substituents which may be the same or different and are each independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1 to 3 substituents which may be the same or different and are each selected from C 1-4 Alkoxy and halogen; or

[0025] Y 1 and Z together with the carbon to which they are attached form C 3-6 Cycloalkyl, C 6-12 aryl, 3 to 12 membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5 to 12 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, aryl, heterocyclyl or heteroaryl are each optionally substituted with 1 to 3 substituents which may be the same or different and are each independently selected from cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 6-10 Aryl and halogen, wherein the C 1-4 The alkyl group is optionally substituted by 1 to 3 substituents, which may be the same or different and are each independently selected from C 1-4 alkoxy and halogen, and wherein the C 6-10The aryl group is optionally substituted by 1 to 3 substituents which may be the same or different and are each independently selected from C 1-4 Alkyl, C 1-4 Alkoxy and halogen, and Y 2 is hydrogen or deuterium.

[0026] In some embodiments, provided herein are pharmaceutical compositions comprising a compound provided herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0027] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions further comprise a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof.

[0028] In some embodiments, the present disclosure provides methods of inhibiting LPAR1 activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg), (VIa)-(Vj)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0029] In some embodiments, the present disclosure provides methods for treating a patient suffering from an LPAR1-mediated disorder, comprising administering to the patient a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg), (VIa)-(Vj)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein. DETAILED DESCRIPTION

[0030] The present disclosure relates to LPA receptor antagonists, such as antagonists of LPAR1. The present disclosure also relates to compositions and methods related to LPAR1 antagonists, and the use of such compounds for treating and / or preventing LPAR1-mediated diseases and conditions. The present disclosure also relates to compositions and methods for treating and / or preventing liver disease, including LPAR1 antagonists in combination with one or more additional therapeutic agents.

[0031] It is generally believed that patients with certain LPAR1 mediated diseases, such as cancer, fibrosis, inflammation, pain, cardiovascular disease or liver disease, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), may benefit from treatment with an LPAR1 antagonist and, optionally, one or more additional therapeutic agents.

[0032] Definition and general parameters

[0033] It should be understood that the present disclosure is considered to be an illustration of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments described. The titles used throughout the present disclosure are provided for convenience and should not be interpreted as limiting the claims in any way. The embodiments illustrated under any title may be combined with the embodiments illustrated under any other title.

[0034] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. It must be noted that, as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "an assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art, and so forth.

[0035] As used in this specification, the following terms and phrases are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0036] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -CONH 2 Attached through carbon atoms. Dashes at the front or end of a chemical group are for convenience; a chemical group can be depicted without one or more dashes without losing its ordinary meaning. A wavy line drawn through a line in a structure indicates the point of attachment of a group. Directionality is not indicated or implied by the order in which chemical groups are written or named unless required by chemistry or structure. A solid line extending from the center of a ring indicates that the point of attachment of a substituent on the ring can be at any ring atom. For example, R in the following structure a can be attached to any of the five carbon ring atoms, or R a Can replace hydrogen attached to nitrogen ring atoms:

[0037]

[0038] The prefix "C u-v " indicates that the following group has u to v carbon atoms. For example, "C 1-6"Alkyl" indicates that the alkyl group has 1 to 6 carbon atoms. Likewise, the term "xy membered" ring (wherein x and y are numerical ranges, such as "3- to 12-membered heterocyclyl") refers to a ring containing xy atoms (e.g., 3-12), of which up to 80% may be heteroatoms, such as N, O, S, P, and the remaining atoms are carbon.

[0039] Moreover, some commonly used alternative chemical names may or may not be used. For example, divalent groups (such as divalent "alkyl" groups, divalent "aryl" groups, etc.) may also be referred to as "alkylene" groups ("alkylene" groups or "alkylenyl" groups or alkylyl groups), "arylene" groups ("arylenyl" groups or "arylyl" groups or arylyl groups), respectively.

[0040] "Compounds disclosed herein" or "compounds of the present disclosure" or "compounds provided herein" or "compounds described herein" refer to compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg), (VIa)-(Vj). Also included are specific compounds 1 to 32 provided herein (e.g., Examples 1 to 33).

[0041] The "about" value or parameter mentioned herein includes (and describes) embodiments involving the value or parameter itself. In certain embodiments, the term "about" includes an indication of ±10%. In other embodiments, the term "about" includes an indication of ±5%. In certain other embodiments, the term "about" includes an indication of ±1%. Moreover, for the term "about X", a description of "X" is included. Moreover, unless the context clearly provides otherwise, the singular forms "a", "an" and "the" include plural references. Therefore, for example, reference to "compound" includes a variety of such compounds, and reference to "determination" includes reference to one or more determinations known to those skilled in the art and their equivalents.

[0042] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group has 1 to 20 carbon atoms (i.e., C 1-20 Alkyl), 1 to 8 carbon atoms (i.e. C 1-8 Alkyl), 1 to 6 carbon atoms (i.e. C 1-6 alkyl), 1 to 4 carbon atoms (i.e., C 1-4 Alkyl) or 1 to 3 carbon atoms (i.e. C 1-3Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a particular number of carbon atoms is designated by a chemical name or identified by a molecular formula, all positional isomers having that number of carbon atoms are contemplated; thus, for example, "butyl" includes n-butyl (i.e., -(CH 2 ) 3 CH 3 ), sec-butyl (i.e. -CH(CH 3 )CH 2 CH 3 ), isobutyl (i.e. -CH 2 CH(CH 3 ) 2 ) and tert-butyl (i.e. -C(CH 3 ) 3 ); and "propyl" includes n-propyl (i.e. -(CH 2 ) 2 CH 3 ) and isopropyl (i.e. -CH(CH 3 ) 2 ).

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

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

[0045] “Alkoxy” refers to the group “alkyl-O—.” Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

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

[0047] "Amino" refers to the group -NR y R z , where R y and R z independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; each of which can be optionally substituted.

[0048] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) comprising a fused system. As used herein, an aryl group has 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 Aryl) or 6 to 10 carbon ring atoms (i.e. C 6-10 Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthracenyl. However, aryl does not encompass or overlap in any way with heteroaryl as defined below. If one or more aryl groups are fused to a heteroaryl ring, the resulting ring system is a heteroaryl.

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

[0050] "Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, a cycloalkyl group has 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e. C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e. C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e. C 3-8 Cycloalkyl) or 3 to 6 ring carbon atoms (i.e. C 3-6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0051] "Fused" means that one ring is bound to an adjacent ring. In some embodiments, the fused ring system is a heterocyclyl. In some embodiments, the fused ring system is an oxabicyclohexyl. In some embodiments, the fused ring system is

[0052] "Bridged" refers to ring fusions in which non-adjacent atoms on the ring are connected by a divalent substituent (such as an alkylene group, an alkylene group containing one or two heteroatoms) or a single heteroatom. Quinuclidinyl and adamantyl are examples of bridged ring systems. In some embodiments, the bridged ring is dicyclopentyl (dicyclo[1.1.1]pentyl]) or dicyclooctyl (dicyclo[2.2.2]octyl). In some embodiments, the bridged ring is

[0053] "Spiro" refers to a ring substituent connected by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, where cyclopentane and piperidine are spiro substituents, respectively. In some embodiments, the spiro substituent is spiropentyl (spiro[ab]pentyl), spirohexyl, spiroheptyl, or spirodecanyl. In some embodiments, the spiro substituent is

[0054]

[0055] "Halogen" or "halo" includes fluorine, chlorine, bromine and iodine.

[0056] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group includes 1 to 20 carbon ring atoms (i.e., C 1-20 heteroaryl), 3 to 12 carbon ring atoms (i.e., C 3-12 heteroaryl) or 3 to 8 carbon ring atoms (i.e. C 3-8 and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridinyl, pyridazinyl, benzothiazolyl and pyrazolyl. Heteroaryl does not encompass or overlap with aryl as defined above.

[0057] "Heterocyclyl" or "heterocycle" refers to a non-aromatic cyclic alkyl group in which one or more ring heteroatoms are independently selected from nitrogen, oxygen and sulfur. As used herein, unless otherwise indicated, "heterocyclyl" or "heterocycle" refers to a saturated or partially saturated ring, for example, in some embodiments, "heterocyclyl" or "heterocycle" refers to a partially saturated ring in the specified case. The term "heterocyclyl" or "heterocycle" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond). A heterocyclyl group can be a single ring or multiple rings, wherein the multiple rings can be fused, bridged or spiro. As used herein, a heterocyclyl group has 2 to 20 carbon ring atoms (i.e., C 2-20 heterocyclic group), 2 to 12 carbon ring atoms (i.e., C 2-12 Heterocyclic groups), 2 to 10 carbon ring atoms (i.e., C 2-10 Heterocyclic groups), 2 to 8 carbon ring atoms (i.e., C 2-8 heterocyclic group), 3 to 12 carbon ring atoms (i.e., C 3-12 heterocyclic group), 3 to 8 carbon ring atoms (i.e., C 3-8 heterocyclic group) or 3 to 6 carbon ring atoms (i.e. C 3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl and morpholinyl. As used herein, the terms "heterocycle", "heterocyclyl" and "heterocycle" are used interchangeably.

[0058] "Hydroxy" or "hydroxyl" refers to the group -OH.

[0059] "Oxo" refers to the group (=O) or (O).

[0060] "Sulfonyl" refers to the group -S(O) 2 R c , where R c is an alkyl group, a heterocyclic group, a cycloalkyl group, a heteroaryl group or an aryl group. Examples of the sulfonyl group are a methylsulfonyl group, an ethylsulfonyl group, a phenylsulfonyl group and a toluenesulfonyl group.

[0061] Unless otherwise indicated, whenever a radical ends at a singly bonded nitrogen atom, the radical represents -NH 2 Similarly, unless otherwise expressed, hydrogen atoms are implied and assumed to be present where necessary to complete valency or provide stability, based on the knowledge of one skilled in the art.

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

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

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

[0065] In some embodiments, substituted cycloalkyl, substituted heterocyclyl, substituted aryl and / or substituted heteroaryl include cycloalkyl, heterocyclyl, aryl and / or heteroaryl groups having substituents on the ring atoms, which are attached to the rest of the compound. For example, in the following moiety, the cyclopropyl group is substituted with a methyl group:

[0066]

[0067] The disclosure illustratively described herein may be suitably practiced in the absence of any one or more elements, one or more limitations not specifically disclosed herein. Thus, for example, the terms "comprising," "including," "containing," and the like are to be understood broadly and without limitation. In addition, the terms and expressions employed herein have been used as terms of description rather than limitation, and it is not intended that such terms and expressions be used to exclude any equivalents of the features shown and described, or portions thereof, but it should be recognized that various modifications within the scope of the disclosure claimed are possible.

[0068] The compounds of the present disclosure may be in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid (including an inorganic base or an inorganic acid and an organic base or an organic acid). The compounds of the present disclosure may be in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid (including an inorganic base or an inorganic acid and an organic base or an organic acid). In the case where the compounds of the present disclosure contain one or more acidic or basic groups, the present disclosure also includes its corresponding pharmaceutically or toxicologically acceptable salts, particularly its pharmaceutically available salts. Therefore, the compounds of the present disclosure containing acidic groups may be present on these groups and may be used as, for example, alkali metal salts, alkaline earth metal salts or ammonium salts according to the present disclosure. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines (such as ethylamine, ethanolamine, triethanolamine), amino acids or other bases known to those skilled in the art. Compounds of the present disclosure containing one or more basic groups (i.e., protonable groups) may exist in the form of addition salts thereof with inorganic or organic acids and may be used in accordance with the present disclosure. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalene disulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art.

[0069] If the compounds of the present disclosure contain both acidic and basic groups in the molecule, the present disclosure also includes internal salts or betaines (zwitterions) in addition to the salt forms mentioned. The corresponding salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting these with organic or inorganic acids or bases in solvents or dispersants, or by anion exchange or cation exchange with other salts.

[0070] The present disclosure also includes all salts of the compounds of the present disclosure, which are not directly suitable for use in drugs due to low physiological compatibility, but which can be used, for example, as intermediates for chemical reactions or for preparing pharmaceutically acceptable salts. Acids and bases that can be used to react with the following compounds to form pharmaceutically acceptable salts (acid addition salts or base addition salts, respectively) are known to those skilled in the art. Similarly, methods for preparing pharmaceutically acceptable salts from the following compounds (after disclosure) are known to those skilled in the art and are disclosed in, for example, Berge et al., Journal of Pharmaceutical Science, January 1977, Vol. 66, No. 1, and other sources.

[0071] In addition, the compounds disclosed herein may undergo tautomerism. Where tautomerism (e.g., keto-enol tautomerism) of a compound or its prodrug may occur, individual forms (e.g., keto and enol forms) are each within the scope of the present disclosure as well as mixtures of any ratio thereof. The same applies to stereoisomers, such as enantiomers, cis / trans isomers, diastereomers, conformers, etc.

[0072] The term "protecting group" refers to a compound moiety that masks or changes the properties of a functional group or the properties of the entire compound. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See, for example, "Protective Groups in Organic Chemistry", Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often used to mask the reactivity of certain functional groups to aid in the efficiency of a desired chemical reaction, such as forming and breaking chemical bonds in an orderly and planned manner. The term "deprotection" refers to the removal of a protecting group.

[0073] The skilled artisan will understand that when a list of alternative substituents includes members that cannot be used to replace a particular group due to their valency requirements or other reasons, the list is intended to be interpreted with the skilled artisan's knowledge to include only those members of the list that are suitable for replacing the particular group.

[0074] Additionally, the compounds of the present disclosure may exist in the form of solvates, such as those that include water as a solvate, or a pharmaceutically acceptable solvate, such as an alcohol, particularly ethanol."Solvate" is formed by the interaction of a solvent and a compound.

[0075] In certain embodiments, there is provided an optical isomer, racemate or other mixture of a compound described herein or a pharmaceutically acceptable salt thereof or a mixture thereof. If desired, isomers can be separated by methods well known in the art, such as by liquid chromatography. In these cases, a single enantiomer or diastereomer, i.e., an optically active form, can be obtained by asymmetric synthesis or by splitting. For example, splitting can be achieved by conventional methods, such as crystallization in the presence of a splitting agent, or using, for example, a chiral high pressure liquid chromatography (HPLC) column chromatography.

[0076] "Stereoisomers" refer to compounds composed of the same atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. The present invention encompasses various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of one another.

[0077] In some embodiments, the compounds disclosed herein and their pharmaceutically acceptable salts may include asymmetric centers, and thus may produce enantiomers, diastereomers, and other stereoisomeric forms that may be defined as (R)- or (S)-, or as (D)- or (L)- for amino acids, according to absolute stereochemistry. Some embodiments include all such possible isomers and their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometric asymmetric centers, and unless otherwise indicated, it is intended that the compounds include both E and Z geometric isomers.

[0078] Compositions provided herein including compounds described herein or their pharmaceutically acceptable salts, isomers or mixtures thereof may include racemic mixtures or mixtures containing an enantiomeric excess of one enantiomer or a single diastereomer or a mixture of diastereomers. All such isomeric forms of these compounds are expressly included herein, as if each and every isomeric form were specifically and individually listed.

[0079] Any formula or structure given herein is also intended to represent unlabeled forms of the compound as well as isotopically labeled forms. An isotopically labeled compound has a structure depicted by a formula given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N. 18 F. 31 P. 32 P. 35 S. 36 Cl and 125 I. Various isotopically labeled compounds of the present disclosure, for example, wherein a radioactive isotope such as 3 H. 13 C and 14C is incorporated. Such isotopically labeled compounds are useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including tissue distribution assays of drugs or substrates, or in radiation therapy of patients. Isotopically labeled compounds of the present disclosure and prodrugs thereof can generally be prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent and carrying out the procedures disclosed in the schemes or examples and formulations described below.

[0080] The present disclosure also includes "deuterated analogs" of the compounds disclosed herein, in which 1 to n hydrogens attached to a carbon atom are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and thus may be used to extend the half-life of any compound of formula (I) when administered to a mammal (e.g., a human). See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci. Vol. 5 (No. 12): pp. 524-527 (1984). Such compounds are synthesized by methods well known in the art, for example, by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0081] Deuterium-labeled or substituted therapeutic compounds of the present disclosure may have beneficial DMPK (drug metabolism and pharmacokinetics) properties, which relate to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes (such as deuterium) may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements and / or improved therapeutic index. 18 F-labeled compounds can be used in PET or SPECT studies.

[0082] The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen", then that position is understood to be a hydrogen having its natural abundance isotopic composition. Therefore, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0083] In addition, the present disclosure provides a pharmaceutical composition comprising, as an active ingredient, a compound of the present disclosure, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0084] "Pharmaceutical composition" means one or more active ingredients, and one or more inert ingredients constituting a carrier, as well as any product obtained directly or indirectly from the combination, complexation or aggregation of any two or more ingredients, or from the dissociation of one or more ingredients, or from other types of reactions or interactions of one or more ingredients. Therefore, the pharmaceutical composition of the present disclosure may encompass any composition made by mixing at least one compound of the present disclosure and a pharmaceutically acceptable carrier.

[0085] As used herein, "pharmaceutically acceptable carriers" include excipients or agents that are not harmful to the disclosed compounds or their uses, such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The use of such carriers and agents to prepare compositions of pharmaceutically active substances is well known in the art (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA, 17th edition, 1985; and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd edition (GS Banker & C. T. Rhodes, ed.)).

[0086] “IC 50 ” or “EC 50 ” refers to the inhibitory concentration required to achieve 50% of the maximal desired effect. In many cases, the maximal desired effect herein is the inhibition of LPA-induced LPAR1 activation. The term is obtained using in vitro assays that assess concentration-dependent inhibition of LPA-induced LPAR1 activity, such as a calcium mobilization assay.

[0087] "Treatment" or "treating" is a method for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results include one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the extent of the disease or condition); b) slowing or preventing the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the deterioration or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis of the disease or condition); and / or c) alleviating the disease, i.e., causing regression of clinical symptoms (e.g., improving the disease state, providing partial or total remission of the disease or condition, enhancing the effect of another drug, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival). In some embodiments, the term "treating" means administering a compound or pharmaceutically acceptable salt of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg), (VIa)-(Vj) for the purpose of: (i) delaying the onset of a disease, i.e., preventing the development of clinical symptoms of the disease; (ii) inhibiting the disease, i.e., preventing the development of clinical symptoms; and / or (iii) ameliorating the disease, i.e., causing regression of clinical symptoms or their severity.

[0088] "Prevention" or "preventing" means any treatment of a disease or condition that results in the clinical symptoms of the disease or condition not developing. In some embodiments, the compounds may be administered to subjects (including humans) who are at risk or have a family history of the disease or condition.

[0089] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation, or experiment. The methods described herein can be used for human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0090] The term "therapeutically effective amount" or "effective amount" of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analog thereof refers to an amount sufficient to achieve treatment when administered to a subject to provide a therapeutic benefit, such as improving symptoms or slowing disease progression. For example, a therapeutically effective amount can be an amount sufficient to alleviate the symptoms of a disease or condition that is responsive to an LPAR1 antagonist. The therapeutically effective amount can vary depending on the subject, the disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the mode of administration, which can be readily determined by one skilled in the art.

[0091] List of abbreviations and acronyms

[0092] Abbreviation meaning

[0093] ACN or MeCN Acetonitrile

[0094] aq. containing water

[0095] Bn Benzyl

[0096] COPD Chronic Obstructive Pulmonary Disease

[0097] DCM Dichloromethane

[0098] DIEA N,N-Diisopropylethylamine

[0099] DMF N,N-Dimethylformamide

[0100] DMSO Dimethyl sulfoxide

[0101] DPPA Diphenylphosphorylazide

[0102] EA Ethyl acetate

[0103] EDTA Ethylenediaminetetraacetic acid

[0104] ESI Electrospray ionization

[0105] Et Ethyl

[0106] Et 2 O Ether

[0107] EtOAc Ethyl acetate

[0108] h or hr hour

[0109] HBSS Hank's Balanced Salt Solution

[0110] HCC Hepatocellular carcinoma

[0111] HPLC High Performance Liquid Chromatography

[0112] LCMS or LC / MS Liquid chromatography mass spectrometry

[0113] LPA Lysophosphatidic acid

[0114] LPC Lysophosphatidylcholine

[0115] Me Methyl

[0116] MeOH Methanol

[0117] MS

[0118] m / z mass-to-charge ratio

[0119] NADPH dihydronicotinamide-adenine dinucleotide phosphate

[0120] NAFLD Nonalcoholic fatty liver disease

[0121] NASH Nonalcoholic steatohepatitis

[0122] NMR Nuclear Magnetic Resonance Spectroscopy

[0123] PBC Primary biliary cirrhosis

[0124] PE Petroleum Ether

[0125] PSC Primary sclerosing cholangitis

[0126] rpm revolutions per minute

[0127] RT or rt Room temperature

[0128] sat. saturated

[0129] TEMPO 2,2,6,6-Tetramethylpiperidinyl 1-oxyl

[0130] TFA Trifluoroacetic acid

[0131] THF Tetrahydrofuran

[0132] T3P Propanephosphonic anhydride

[0133] As used herein, "LPAR1 antagonist" refers to any agent that is capable of binding to and inhibiting LPAR1. LPAR1 is also known as LPA 1 , is a GPCR that binds the lipid signaling molecule lysophosphatidic acid (LPA). Exemplary reference sequences of LPAR1 include NCBI reference sequences NP_001392 (human protein), NP_001277415 (mouse protein), NM_001401 (human mRNA), and NM_001290486 (mouse mRNA). LPAR1 antagonists can act as competitive inhibitors of full or partial LPAR1 agonists, or act as inverse agonists. The activity of LPAR antagonists can be measured by methods known in the art, such as those described and cited below: Castelino et al., 2010 Arthritis Rheum. 2011 May; 63(5): 1405–1415 or Swaney et al., J Pharmacol Exp Ther. 2011 March; 336(3): 693-700.

[0134] As used herein, "ACC inhibitor" refers to any agent capable of binding and inhibiting acetyl-CoA carboxylase (ACC). ACC inhibitors can act as inhibitors or partial inhibitors of ACC. Agents can be chemical compounds or biomolecules (e.g., proteins or antibodies). The activity of ACC inhibitors can be measured by methods known in the art (such as those described and cited in U.S. Patent No. 8,969,557 and / or U.S. Patent No. 10,208,063, both of which are incorporated herein by reference in their entirety).

[0135] As referred to herein, an "ASK1 inhibitor" can be any agent capable of inactivating apoptosis signal-regulating kinase 1 (ASK1) protein. The agent can be a chemical compound or a biomolecule (e.g., a protein or an antibody). ASK1 protein activity can be measured by several different methods. For example, the activity of the ASK1 protein can be determined based on the ability of the ASK1 protein to phosphorylate a substrate protein. Methods for identifying ASK1 inhibitors are known (see, e.g., US2007 / 0276050). Exemplary ASK1 substrate proteins include MAPKK3, MAPKK4, MAPKK6, MAPKK7, or fragments thereof. ASK1 protein activity can also be measured by the phosphorylation level of the ASK1 protein (e.g., the phosphorylation level of the threonine residue in the ASK1 protein corresponding to threonine 838 (T838) of the human full-length ASK1 protein or threonine 845 (T845) of the mouse full-length ASK1 protein). For example, in the case where the ASK1 protein comprises a full-length human ASK1 protein sequence, the ASK1 inhibitor can attenuate the phosphorylation of T838 in the full-length human ASK1 protein sequence. Site-specific antibodies against human ASK1 T838 or mouse ASK1 T845 can be used to detect the phosphorylation level.

[0136] As used herein, "FXR agonist" refers to any agent capable of binding to and activating the farnesoid X receptor (FXR), which may be referred to as the bile acid receptor (BAR) or NR1H4 (nuclear receptor subfamily 1, group H, member 4) receptor. FXR agonists may act as agonists or partial agonists of FXR. The agent may be a chemical compound or a biomolecule (e.g., a protein or antibody). The activity of an FXR agonist may be measured by several different methods, for example, in an in vitro assay using a fluorescence resonance energy transfer (FRET) cell-free assay as described in Pellicciari et al., Journal of Medicinal Chemistry, 2002 Vol. 15, No. 45: 3569-72.

[0137] Compound

[0138] In one embodiment, provided herein is a compound of formula (I),

[0139]

[0140] or a pharmaceutically acceptable salt thereof,

[0141] in:

[0142] R 1 is hydrogen or C optionally substituted by 1 to 3 substituents 1-6 Alkyl, these substituents may be the same or different, each independently selected from halogen, cyano, C 1-4 Alkoxy and C 3-10 Cycloalkyl; or

[0143] R 1 is C optionally substituted by 1 to 3 substituents 3-6 Cycloalkyl, these substituents may be the same or different, each independently selected from halogen, cyano, C 1-4 Alkoxy and C 1-6 alkyl;

[0144] Can be the same or different for each R 2 are independently selected from hydrogen, halogen, cyano, oxo, C 1-4 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, -N(R 2A1 )(R 2A2 ),-OR 2A1 、-SR 2A1 , –C(O)N(R 2A1 )(R 2A2 ),–NR 2A1 C(O)R 2A2 、-NR 2A1 C(O)N(R 2A2 )(R 2A3 ),–S(O) 0-2 R 2A1 , –S(O) 2 N(R 2A1 )(R 2A2 ) and –NR 2A1 S(O) 2 R 2A2 , where each R 2A1 , R 2A2 and R 2A3 are independently hydrogen or C 1-6 Alkyl, where each R 2 Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1 to 4 R which may be the same or different.2B Substitute, where each R 2B Independently for C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy, halogen or cyano;

[0145] Can be the same or different for each R 3 independently selected from deuterium, halogen, C 1-6 Alkyl, C 3-10 Cycloalkyl or C 1-4 Alkoxy, each C 1-6 Alkyl and C 3-10 Cycloalkyl is optionally substituted with 1 to 3 halogens;

[0146] R 4 is C optionally substituted by 1 to 3 substituents 1-6 Alkyl, these substituents may be the same or different, each independently selected from halogen, cyano, C 1-4 Alkoxy, -C(O)N(R 4A1 ) and -N(R 4A1 )(R 4A2 ), where each R 4A1 and R 4A2 Independently H, C 1-6 Alkyl or C 3-10 Cycloalkyl; or

[0147] R 4 C 3-6 Cycloalkyl or 3 to 6 membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1 to 3 substituents which may be the same or different and are independently selected from halogen, cyano, C 1-4 Alkyl and C 1-4 Alkoxy;

[0148] m is 0, 1, 2, 3 or 4;

[0149] n is 0, 1, 2 or 3;

[0150] o is 0, 1, 2, or 3;

[0151] X 1 , X 2 and X 3 are each independently selected from CH and N;

[0152] Each U is independently -CH=, -CH 2 -, -N=, -NH- or -O-;

[0153] Each Y 1 and Y 2is independently hydrogen, deuterium or C optionally substituted by 1 to 3 substituents 1-6 Alkyl, these substituents may be the same or different, each independently selected from deuterium, halogen, cyano, C 2-3 Alkynyl, C 1-4 Alkoxy and -C(O)NH-(C 1- 4 H 3-9 );and

[0154] Z is C 1-8 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-12 aryl, 3 to 12 membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5 to 12 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the alkyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl are each optionally substituted with 1 to 3 substituents which may be the same or different and are each independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1 to 3 substituents which may be the same or different and are each selected from C 1-4 Alkoxy and halogen; or

[0155] Y 1 and Z together with the carbon to which they are attached form C 3-6 Cycloalkyl, C 6-12 aryl, 3 to 12 membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5 to 12 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, aryl, heterocyclyl or heteroaryl are each optionally substituted with 1 to 3 substituents which may be the same or different and are each independently selected from cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 6-10 Aryl and halogen, wherein the C 1-4 The alkyl group is optionally substituted by 1 to 3 substituents, which may be the same or different and are each independently selected from C 1-4 alkoxy and halogen, and wherein the C 6-10 The aryl group is optionally substituted by 1 to 3 substituents which may be the same or different and are each independently selected from C 1-4 Alkyl, C 1-4 Alkoxy and halogen, and Y 2 is hydrogen or deuterium.

[0156] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ia)

[0157]

[0158] or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments of the compound of Formula (I) or (Ia), R 1 For hydrogen.

[0160] In some embodiments of the compound of Formula (I) or (Ia), R 4 is C optionally substituted by 1 to 3 substituents 1-3 Alkyl, these substituents may be the same or different, and are independently selected from -CN and -F. In some embodiments of the compounds of formula (I) or (Ia), R 4 -CH 3 .

[0161] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II):

[0162]

[0163] or a pharmaceutically acceptable salt thereof;

[0164] in:

[0165] R 1 is hydrogen;

[0166] Each R 2 are independently selected from deuterium, cyano, hydroxyl, halogen, C 1-6 Alkyl, C 3-10 Cycloalkyl or C 1-4 Alkoxy, wherein the C 1-6 Alkyl or C 3-10 Cycloalkyl is optionally substituted with 1 to 3 halogens;

[0167] W 1 -CH 2 -;

[0168] W 2 -CH=、-CH 2 -or-O-;

[0169] W 3 -CH=、-CH 2 -, -O- or -NH-; and

[0170] p and q are each independently 0 or 1.

[0171] In some embodiments, the compound of Formula (I), (Ia) or (II) or a pharmaceutically acceptable salt thereof is a compound of Formula (IIa):

[0172]

[0173] In some embodiments of the compound of Formula (I), (Ia), (II) or (IIa), p is 0 and q is 0. In some embodiments of the compound of Formula (I), (Ia), (II) or (IIa), p is 0 and q is 1. In some embodiments of the compound of Formula (I), (Ia), (II) or (IIa), p is 1 and q is 1.

[0174] In some embodiments, the compound of Formula (I), (Ia), (II) or (IIa) or a pharmaceutically acceptable salt thereof is a compound of Formula (IIIa):

[0175]

[0176] or a pharmaceutically acceptable salt thereof;

[0177] in:

[0178] m is 0, 1 or 2; and

[0179] o is 0, 1, 2, or 3.

[0180] In some embodiments, the compound of Formula (I), (Ia), (II) or (IIa) or a pharmaceutically acceptable salt thereof is a compound of Formula (IIIb):

[0181]

[0182] or a pharmaceutically acceptable salt thereof;

[0183] in:

[0184] m is 0, 1, 2, 3 or 4; and

[0185] o is 0, 1, 2, or 3.

[0186] In some embodiments, the compound of Formula (I), (Ia), (II) or (IIa) or a pharmaceutically acceptable salt thereof is a compound of Formula (IIIc):

[0187]

[0188] or a pharmaceutically acceptable salt thereof;

[0189] in:

[0190] m is 0, 1 or 2; and

[0191] o is 0, 1, 2, or 3.

[0192] In some embodiments, the compound of Formula (I), (Ia), (II) or (IIa) or a pharmaceutically acceptable salt thereof is a compound of Formula (IIId):

[0193]

[0194] or a pharmaceutically acceptable salt thereof;

[0195] in:

[0196] m is 0, 1 or 2; and

[0197] o is 0, 1, 2, or 3.

[0198] In some embodiments, the compound of Formula (I), (Ia), (II) or (IIa) or a pharmaceutically acceptable salt thereof is a compound of Formula (IIIe):

[0199]

[0200] or a pharmaceutically acceptable salt thereof;

[0201] in:

[0202] m is 0, 1 or 2; and

[0203] o is 0, 1, 2, or 3.

[0204] In some embodiments, the compound of Formula (I), (Ia), (II) or (IIa) or a pharmaceutically acceptable salt thereof is a compound of Formula (IIIf):

[0205]

[0206]

[0207] or a pharmaceutically acceptable salt thereof;

[0208] in:

[0209] m is 0, 1, 2 or 3; and

[0210] o is 0, 1, 2, or 3.

[0211] In some embodiments, the compound of Formula (I), (Ia), (II) or (IIa) or a pharmaceutically acceptable salt thereof is a compound of Formula (IIIg):

[0212]

[0213] or a pharmaceutically acceptable salt thereof;

[0214] in:

[0215] m is 0, 1, 2, 3 or 4; and

[0216] o is 0, 1, 2, or 3.

[0217] In some embodiments, the compound of Formula (I), (Ia), (II) or (IIa) or a pharmaceutically acceptable salt thereof is a compound of Formula (IVa):

[0218]

[0219] or a pharmaceutically acceptable salt thereof;

[0220] in

[0221] m is 0, 1 or 2; and

[0222] o is 0, 1, 2, or 3.

[0223] In some embodiments, the compound of Formula (I), (Ia), (II) or (IIa) or a pharmaceutically acceptable salt thereof is a compound of Formula (IVb):

[0224]

[0225] or a pharmaceutically acceptable salt thereof;

[0226] in

[0227] m is 0, 1, 2, 3 or 4; and

[0228] o is 0, 1, 2, or 3.

[0229] In some embodiments, the compound of Formula (I), (Ia), (II) or (IIa) or a pharmaceutically acceptable salt thereof is a compound of Formula (IVc):

[0230]

[0231] or a pharmaceutically acceptable salt thereof;

[0232] in

[0233] m is 0, 1 or 2; and

[0234] o is 0, 1, 2, or 3.

[0235] In some embodiments, the compound of Formula (I), (Ia), (II) or (IIa) or a pharmaceutically acceptable salt thereof is a compound of Formula (IVd):

[0236]

[0237] or a pharmaceutically acceptable salt thereof;

[0238] in

[0239] m is 0, 1 or 2; and

[0240] o is 0, 1, 2, or 3.

[0241] In some embodiments, the compound of Formula (I), (Ia), (II) or (IIa) or a pharmaceutically acceptable salt thereof is a compound of Formula (IVe):

[0242]

[0243] or a pharmaceutically acceptable salt thereof;

[0244] in

[0245] m is 0, 1 or 2; and

[0246] o is 0, 1, or 2.

[0247] In some embodiments, the compound of Formula (I), (Ia), (II) or (IIa) or a pharmaceutically acceptable salt thereof is a compound of Formula (IVf):

[0248]

[0249] or a pharmaceutically acceptable salt thereof;

[0250] in

[0251] m is 0, 1 or 2; and

[0252] o is 0, 1, 2, or 3.

[0253] In some embodiments, the compound of Formula (I), (Ia), (II) or (IIa) or a pharmaceutically acceptable salt thereof is a compound of Formula (IVg):

[0254]

[0255] or a pharmaceutically acceptable salt thereof;

[0256] in

[0257] m is 0, 1 or 2; and

[0258] o is 0, 1, or 2.

[0259] In some embodiments, the compound of Formula (I), (Ia), (II) or (IIa) or a pharmaceutically acceptable salt thereof is a compound of Formula (IVh):

[0260]

[0261] or a pharmaceutically acceptable salt thereof;

[0262] in

[0263] m is 0, 1 or 2; and

[0264] o is 0, 1, or 2.

[0265] In some embodiments, the compound of Formula (I), (Ia), (II) or (IIa) or a pharmaceutically acceptable salt thereof is a compound of Formula (IVi):

[0266]

[0267] or a pharmaceutically acceptable salt thereof;

[0268] in

[0269] m is 0, 1 or 2;

[0270] o is 0, 1, 2, or 3.

[0271] In some embodiments, the compound of Formula (I), (Ia), (II) or (IIa) or a pharmaceutically acceptable salt thereof is a compound of Formula (IVj):

[0272]

[0273] or a pharmaceutically acceptable salt thereof;

[0274] in

[0275] m is 0, 1, 2, 3 or 4; and

[0276] o is 0, 1, 2, or 3.

[0277] In some embodiments of the compounds of Formula (IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable salts thereof, m is 0, 1 or 2. In some embodiments of the compounds of Formula (IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable salts thereof, o is 0 or 1. In some embodiments of the compounds of Formula (IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable salts thereof, m is 0 and o is 0. In some embodiments of the compounds of Formula (IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable salts thereof, m is 1 and o is 0. In some embodiments of the compounds of Formula (IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable salts thereof, m is 2 and o is 0. In some embodiments of the compounds of Formula (IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable salts thereof, m is 0 and o is 1.

[0278] In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or pharmaceutically acceptable salts thereof, each R, which may be the same or different, 2 are independently selected from hydrogen, halogen, cyano, oxo, C 1-4 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, -N(R 2A1 )(R 2A2 ),-OR 2A1 、-SR 2A1 , –C(O)N(R 2A1 )(R 2A2 ),–NR 2A1 C(O)R 2A2 、-NR 2A1 C(O)N(R 2A2 )(R 2A3 ),–S(O) 0-2 R 2A1 , –S(O) 2 N(R 2A1 )(R 2A2 ) and –NR 2A1 S(O) 2 R 2A2 , where each R 2A1 , R 2A2 and R 2A3 are independently hydrogen or C 1-6 Alkyl, where each R2 Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1 to 4 R which may be the same or different. 2B Substitute, where each R 2B Independently for C 1-4 Alkyl, C 1-4 In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or pharmaceutically acceptable salts thereof, each R, which may be the same or different, 2 Independently for C 1-4 Alkyl, 6- to 10-membered aryl, C 1-4 Alkoxy or halogen, where each C 1-4 The alkyl group is optionally substituted with 1 to 4 halogens. In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or pharmaceutically acceptable salts thereof, each R, which may be the same or different, 2 Independently selected from C 1-4 Alkyl, C 1-4 In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or pharmaceutically acceptable salts thereof, each R, which may be the same or different, 2 independently -CH 3 , -CF 3 , -C 2 H 5 In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or pharmaceutically acceptable salts thereof, each R 2 In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or pharmaceutically acceptable salts thereof, each R 2 is -F.

[0279] In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or pharmaceutically acceptable salts thereof, each R may be the same or different. 3 independently selected from deuterium, halogen, C 1-6 Alkyl, C 3-10 Cycloalkyl or C 1-4 Alkoxy, each C 1-6 Alkyl and C3-10 Cycloalkyl is optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable salts thereof, each R 3 In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or pharmaceutically acceptable salts thereof, each R 3 is -F.

[0280] In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or pharmaceutically acceptable salts thereof, Y 1 is hydrogen, deuterium or C optionally substituted by 1 to 3 substituents 1-6 Alkyl, these substituents may be the same or different, each independently selected from deuterium, halogen, cyano, C 2-3 Alkynyl, C 1-4 Alkoxy and -C(O)NH-(C 1-4 H 3-9 In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or pharmaceutically acceptable salts thereof, Y 1 is C optionally substituted by 1 to 3 substituents 1-4 Alkyl, these substituents may be the same or different, each independently selected from halogen, cyano and C 1-4 In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or pharmaceutically acceptable salts thereof, Y 1 is a methyl group optionally substituted by 1 to 3 substituents, which may be the same or different and are each independently selected from -F, -Cl, -CN and -O-CH 3 In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or pharmaceutically acceptable salts thereof, Y 1 -CH 3 or -CH 2 F.

[0281] In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or pharmaceutically acceptable salts thereof, Z is C 1-8Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-12 aryl, 3 to 12 membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5 to 12 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the alkyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl are each optionally substituted with 1 to 3 substituents which may be the same or different and are each independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1 to 3 substituents which may be the same or different and are each selected from C 1-4 In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or pharmaceutically acceptable salts thereof, Z is phenyl optionally substituted with 1 to 3 substituents, which may be the same or different, each independently selected from halogen and C 1-4 In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or their pharmaceutically acceptable salts, Z is phenyl optionally substituted with 1 to 3 substituents, which may be the same or different, each independently selected from -F and -Cl. In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or their pharmaceutically acceptable salts, Z is In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj), or pharmaceutically acceptable salts thereof, Z is a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heteroaryl is optionally substituted with 1 to 3 substituents which may be the same or different and are independently selected from halogen and C 1-4 In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or pharmaceutically acceptable salts thereof, Z is pyridinyl optionally substituted with 1 to 3 substituents, which may be the same or different and are independently selected from -F, -Cl, -Br and -CH 3In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or pharmaceutically acceptable salts thereof, Z is

[0282] In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or pharmaceutically acceptable salts thereof, Y 1 -CH 3 , and Z is

[0283] In some embodiments of the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or pharmaceutically acceptable salts thereof, Y 1 -CH 3 , and Z is

[0284] In some embodiments, the compound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg), or (IVa)-(IVj), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

[0285]

[0286] or a pharmaceutically acceptable salt thereof.

[0287] In some embodiments, the compound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg), or (IVa)-(IVj), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0288] In some embodiments, the compound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or a pharmaceutically acceptable salt thereof is:

[0289]

[0290] or a pharmaceutically acceptable salt thereof.

[0291] In some embodiments, the compound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or a pharmaceutically acceptable salt thereof is:

[0292]

[0293] or a pharmaceutically acceptable salt thereof.

[0294] In some embodiments, the compound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or a pharmaceutically acceptable salt thereof is:

[0295]

[0296] or a pharmaceutically acceptable salt thereof.

[0297] In some embodiments, the compound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or a pharmaceutically acceptable salt thereof is:

[0298]

[0299] or a pharmaceutically acceptable salt thereof.

[0300] Pharmaceutical composition and mode of administration

[0301] In addition, the present disclosure provides a pharmaceutical composition comprising, as an active ingredient, at least one compound of the present disclosure, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0302] The pharmaceutical compositions of the present disclosure may additionally comprise one or more other compounds as active ingredients, such as prodrug compounds or other enzyme inhibitors.

[0303] The compositions are suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation) or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the condition to be treated and the nature of the active ingredient. They may conveniently be presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical art.

[0304] In actual use, the compounds of the present disclosure can be closely blended and combined with drug carriers as active ingredients according to conventional drug compounding techniques. Depending on the form of the preparation required for administration, such as oral or parenteral (including intravenous), the carrier can take a variety of forms. When preparing a composition for oral dosage forms, any common pharmaceutical medium can be used, such as water, glycols, oils, alcohols, flavoring agents, preservatives, colorants, etc. in the case of oral liquid preparations (such as suspensions, elixirs, and solutions); or in the case of oral solid preparations (such as powders, hard and soft capsules and tablets), carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc., wherein solid oral preparations are superior to liquid preparations.

[0305] Because they are easy to apply, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets can be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1% of the active compound. Of course, the percentage of the active compound in these compositions can vary and can conveniently be between about 2% and about 60% of the unit weight. The amount of the active compound in such therapeutically useful compositions is such that an effective dose will be obtained. The active compound can also be administered intranasally, for example, as drops or sprays.

[0306] Tablets, pills, capsules, etc. may also contain a binder such as gum tragacanth, gum arabic, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrant such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetener such as sucrose, lactose or saccharin. When the dosage unit form is a capsule, it may contain a liquid carrier such as a fatty oil in addition to the above-mentioned types of materials.

[0307] Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. In addition to the active ingredient, a syrup or elixir may contain sucrose as a sweetener, methyl and propylparabens as preservatives, dyes, and flavorings (such as cherry or orange flavoring).

[0308] In some embodiments, the compounds of the present disclosure may also be used as salts with various counter cations to produce orally acceptable formulations.

[0309] Compounds of the present disclosure may also be administered parenterally. Solutions or suspensions of these active compounds may be prepared in water appropriately mixed with a surfactant such as hydroxypropylcellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under general storage and use conditions, these preparations contain preservatives to prevent the growth of microorganisms.

[0310] The pharmaceutical form suitable for injectable purposes includes sterile aqueous solution or dispersion and the sterile powder for the temporary preparation of sterile injectable solution or dispersion. In all cases, the form must be sterile and must be a fluid that reaches the degree of easy injection. It must be stable under manufacturing and storage conditions, and must prevent the contamination of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (for example, glycerol, propylene glycol and liquid polyethylene glycol), their suitable mixture and vegetable oil.

[0311] Any suitable route of administration can be used to provide an effective dose of the compounds of the present disclosure to mammals, especially humans. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, etc. can be used. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc. In some embodiments, the compounds of the present disclosure are administered orally.

[0312] Reagent test kit

[0313] Also provided herein are kits comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer, a mixture of stereoisomers, a prodrug or a deuterated analogue, and suitable packaging. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit comprises a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer, a mixture of stereoisomers, a prodrug or a deuterated analogue, and a label and / or instructions for using the compound in a therapeutic indication (including a disease or condition described herein).

[0314] Also provided herein are articles of manufacture comprising a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analog thereof in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe and intravenous bag.

[0315] Treatments and uses

[0316] The present disclosure also relates to the use of the compounds disclosed herein for treating and / or preventing diseases and / or conditions by binding to LPAR1. The present disclosure also relates to the use of the compounds for preparing a medicament for treating and / or preventing diseases and / or conditions by binding to LPAR1.

[0317] The medicaments mentioned herein can be prepared by conventional methods, comprising a combination of a compound according to the present disclosure and a pharmaceutically acceptable carrier.

[0318] In some embodiments, provided herein is a method for treating and / or preventing an LPAR1-mediated disease or condition in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or a pharmaceutically acceptable salt thereof.

[0319] In some embodiments, LPAR1-mediated diseases or conditions include those in which an absolute or relative excess of LPA is present and / or observed.

[0320] In some embodiments, the LPAR1-mediated disease or condition comprises fibrosis, wound healing, cancer, pain, respiratory disease, allergic disease, neurological disease, cardiovascular disease, or inflammatory disease.

[0321] In some embodiments, the LPAR1 mediated disease or condition comprises fibrosis. In some embodiments, fibrosis comprises pulmonary fibrosis, renal fibrosis, liver fibrosis, ocular fibrosis, or myocardial fibrosis.

[0322] In some embodiments, the disease or illness mediated by LPAR1 include pulmonary fibrosis. In some embodiments, pulmonary fibrosis includes idiopathic pulmonary fibrosis (IPF). In some embodiments, pulmonary fibrosis includes progressive fibrosing interstitial lung disease (PF-ILD). In some embodiments, pulmonary fibrosis includes pulmonary fibrosis secondary to systemic inflammatory diseases, such as rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrosing alveolitis, radiation fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, chronic asthma, silicosis, asbestos-induced pulmonary fibrosis or pleural fibrosis, acute lung injury and acute respiratory distress (including bacterial pneumonia-induced, trauma-induced, viral pneumonia-induced, ventilator-induced, non-pulmonary sepsis-induced and inhaled).

[0323] In some embodiments, the disease or disorder mediated by LPAR1 includes renal fibrosis. In some embodiments, renal fibrosis includes chronic kidney disease (renal fibrosis) associated with injury / fibrosis, such as secondary to systemic inflammatory diseases such as lupus and scleroderma, diabetes, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allografts and Alport's glomerulonephritis; intestinal fibrosis, such as scleroderma and radiation intestinal fibrosis.

[0324] In some embodiments, the LPAR1-mediated disease or disorder comprises liver fibrosis. In some embodiments, liver fibrosis comprises cirrhosis, alcoholic liver fibrosis, non-alcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis, infection or virus-induced liver fibrosis (e.g., chronic HCV infection) and autoimmune hepatitis.

[0325] In some embodiments, the LPAR1 -mediated disease or condition comprises head and neck fibrosis, such as radiation-induced head and neck fibrosis.

[0326] In some embodiments, LPAR1-mediated diseases or conditions include, for example, corneal scarring caused by LASIK (laser in situ keratomileusis), keratoplasty, or trabeculectomy. In some embodiments, the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or pharmaceutically acceptable salts thereof are used to improve decreased corneal sensation caused by corneal surgery (such as LASIK or cataract surgery), decreased corneal sensation caused by corneal degeneration, and dry eye caused thereby. In some embodiments, the compounds of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or pharmaceutically acceptable salts thereof are used to treat or prevent ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis, and papillary conjunctivitis. In some embodiments, the compound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or a pharmaceutically acceptable salt thereof is used to treat or prevent Sjögren's syndrome or an inflammatory disease associated with dry eye.

[0327] In some embodiments, the LPAR1-mediated disease or disorder comprises another fibrotic disorder, such as hypertrophic scars and keloids, e.g., burn-induced or surgical sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, mixed connective tissue disease, and Peyronie's disease.

[0328] In some embodiments, the LPAR1-mediated disease or condition comprises pain. In some embodiments, the pain comprises neuropathic pain. In some embodiments, the pain comprises acute pain. In some embodiments, the pain comprises chronic pain.

[0329] In some embodiments, the disease or condition mediated by LPAR1 includes cancer. In some embodiments, cancer includes ovarian cancer, colon cancer, prostate cancer, breast cancer, melanoma, head and neck cancer, intestinal cancer (colorectal cancer) and thyroid cancer. In some embodiments, cancer includes solid tumors, such as bladder tumors, intestinal tumors, brain tumors, breast tumors, endometrial tumors, heart tumors, kidney tumors, lung tumors, lymphoid tissue tumors (lymphomas), ovarian tumors, pancreatic or other endocrine organ (thyroid) tumors, prostate tumors, skin tumors (melanoma or basal cell carcinoma) or blood tumors (such as leukemia) at any stage of the disease with or without cancer cell metastasis.In some embodiments, cancers include acute lymphocytic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumor, brain and spinal cord tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumor, endometrial cancer, ependymoma, ependymoma, esophageal cancer, Ewing's tumor Tumor family, eye cancer, retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor (endocrine pancreas), Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt lymphoma, skin T Cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medullary epithelioma, melanoma, mesothelioma, oral cancer, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low-grade tumor, pancreatic cancer, papillomatous hyperplasia, parathyroid cancer, penile cancer, nasopharyngeal carcinoma, moderately differentiated pineal parenchymal tumor, pineoblastoma and supratentorial primitive neuroblastoma Transectodermal tumors, pituitary tumors, plasmacytoma / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma (kidney cancer), retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, Kaposi, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, supratentorial primitive neuroectodermal tumor, T-cell lymphoma, testicular cancer, laryngeal cancer, thymic cancer, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstmm macroglobulinemia, and Wilms tumor.

[0330] In some embodiments, LPAR1-mediated diseases or conditions include respiratory diseases or allergic diseases. In some embodiments, respiratory diseases or allergic diseases include asthma, peribronchial fibrosis, obliterative bronchiolitis and chronic obstructive pulmonary disease (COPD). In some embodiments, COPD includes chronic bronchiolitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and / or airway inflammation and cystic fibrosis. In some embodiments, respiratory diseases include adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (endogenous) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin asthma, exercise-induced asthma, carbon dioxide hyperventilation, childhood onset asthma, adult onset asthma, cough variant asthma, occupational asthma, hormone-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis and hypoxia.

[0331] In some embodiments, LPAR1 mediated diseases or conditions include nervous system diseases. In some embodiments, nervous system diseases include Alzheimer's disease, cerebral edema, cerebral ischemia, stroke, multiple sclerosis, neuropathy, Parkinson's disease, neurological disorders found after blunt trauma or surgical trauma (including postoperative cognitive dysfunction and spinal cord injury or brainstem injury), and neurological aspects of the disease (such as lumbar degenerative disc disease and sciatica).

[0332] In some embodiments, LPAR1-mediated diseases or conditions include cardiovascular diseases. In some embodiments, cardiovascular diseases include arrhythmias (atrial arrhythmias or ventricular arrhythmias or both); atherosclerosis and its complications; angina pectoris; heart rhythm disorders; myocardial ischemia; myocardial infarction; cardiac aneurysms or vascular aneurysms; vasculitis; stroke; peripheral occlusive arterial disease of limbs, organs or tissues; reperfusion injury after ischemia of the brain, heart or other organs or tissues; endotoxin shock, surgical shock or traumatic shock; hypertension; valvular heart disease; heart failure; abnormal blood pressure; shock; vasoconstriction (including vasoconstriction associated with migraine); vascular abnormalities; and cardiovascular insufficiency confined to a single organ or tissue.

[0333] In some embodiments, LPAR1-mediated diseases or conditions include pulmonary fibrosis, renal fibrosis, liver fibrosis, scarring, asthma, rhinitis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, interstitial lung fibrosis, arthritis, allergies, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, pain, proliferative diseases, and inflammatory disorders.

[0334] In some embodiments, the disease or condition mediated by LPAR1 is liver disease. In some embodiments, liver disease is hepatitis C, liver cancer, familial mixed hyperlipidemia, non-alcoholic fatty liver disease (NAFLD), progressive familial intrahepatic cholestasis, primary biliary cirrhosis (PBC) or (PSC). In some embodiments, liver disease is PSC. In some embodiments, liver disease includes portal hypertension. In some embodiments, liver cancer includes hepatocellular carcinoma (HCC), cholangiocarcinoma, angiosarcoma or hemangioendothelioma. In some embodiments, liver cancer includes HCC. In some embodiments, NAFLD includes fatty degeneration. In some embodiments, NAFLD includes NASH. In some embodiments, NAFLD or NASH include liver fibrosis. In some embodiments, NAFLD or NASH include liver cirrhosis. In some embodiments, NAFLD or NASH include compensated liver cirrhosis. In some embodiments, NAFLD or NASH include decompensated liver fibrosis. In some embodiments, NAFLD includes HCC. In some embodiments, the liver disease is NASH.

[0335] In some embodiments, provided herein is a method for treating and / or preventing NAFLD or NASH in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or a pharmaceutically acceptable salt thereof. In some embodiments, NAFLD or NASH comprises liver fibrosis. In some embodiments, NAFLD or NASH comprises cirrhosis. In some embodiments, cirrhosis is compensated cirrhosis. In some embodiments, cirrhosis is decompensated cirrhosis. In some embodiments, NAFLD or NASH comprises HCC.

[0336] In some embodiments, provided herein is a method for preventing a liver disease or condition in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or a pharmaceutically acceptable salt thereof. In some embodiments, the liver disease or condition is liver fibrosis. In some embodiments, the liver disease or condition is cirrhosis. In some embodiments, cirrhosis is compensated cirrhosis. In some embodiments, cirrhosis is decompensated cirrhosis. In some embodiments, the liver disease or condition is HCC.

[0337] In some embodiments, the present disclosure relates to the use of a compound according to Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating an LPAR1-mediated disease or condition disclosed herein.

[0338] dose

[0339] The effective dosage of active ingredient employed may vary depending on the specific compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosages can be readily determined by those skilled in the art.

[0340] When treating or preventing LPAR1-mediated diseases or conditions to which the compounds of the present invention are applicable, satisfactory results are generally obtained when the compounds of the present invention are administered at a daily dose of about 0.1 mg to about 300 mg per kg of animal body weight. In some embodiments, the compounds of the present invention are administered in a single daily dose or in divided doses twice to six times a day or in a sustained release form. For most large mammals, the total daily dose is about 1 mg to about 1000 mg, or about 1 mg to about 50 mg. In the case of a 70 kg adult, the total daily dose will generally be about 0.1 mg to about 200 mg. The dosage regimen can be adjusted to provide the best therapeutic response. In some embodiments, the total daily dose is from about 1 mg to about 900 mg, from about 1 mg to about 800 mg, from about 1 mg to about 700 mg, from about 1 mg to about 600 mg, from about 1 mg to about 400 mg, from about 1 mg to about 300 mg, from about 1 mg to about 200 mg, from about 1 mg to about 100 mg, from about 1 mg to about 50 mg, from about 1 mg to about 20 mg, or from about 1 mg to about 10 mg.

[0341] The compounds of the present application or compositions thereof can be administered once, twice, three times or four times a day using any suitable mode described above. Moreover, administration or treatment with the compound can continue for multiple days; for example, for a treatment cycle, treatment will generally continue for at least 7 days, 14 days or 28 days. Treatment cycles are generally alternating with rest periods of about 1 day to 28 days, generally about 7 days or about 14 days, between cycles. In other embodiments, treatment cycles can also be continuous.

[0342] In some embodiments, the methods provided herein include administering to a subject an initial daily dose of about 1 mg to 800 mg of a compound described herein, and gradually increasing the dose until clinical efficacy is achieved. Increments of about 5 mg, 10 mg, 25 mg, 50 mg, or 100 mg may be used to increase the dose. The dose may be increased daily, every other day, twice a week, or once a week.

[0343] combination

[0344] In some embodiments, a compound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) provided herein, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more additional therapeutic agents to treat or prevent a disease or condition disclosed herein. In some embodiments, the one or more additional therapeutic agents are one, two, three or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are two additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are three additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are four additional therapeutic agents.

[0345] In some embodiments, the pharmaceutical compositions provided herein have a compound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg), or (IVa)-(IVj) provided herein, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one, two, three, or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are two additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are three additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are four additional therapeutic agents.

[0346] In some embodiments, the one or more additional therapeutic agents are selected from angiotensin converting enzyme (ACE) inhibitors, adenosine A3 receptor agonists, adiponectin receptor agonists, AKT protein kinase inhibitors, AMP kinase activators, AMP activated protein kinase (AMPK) activators, amylin receptor agonists, angiotensin II AT-1 receptor antagonists, androgen receptor agonists, apoptosis signal regulating kinase 1 (ASK1) inhibitors, ATP citrate lyase inhibitors, apolipoprotein C3 (APOC3) antagonists, autophagy protein regulators, autotaxin inhibitors, Axl tyrosine kinase receptor inhibitors, Bax protein stimulators, bioactive lipids, calcitonin agonists, cannabinoid receptor modulators, cysteine ​​protease inhibitors, caspase-3 stimulators, cathepsin inhibitors (such as cathepsin B inhibitors), caveolin 1 inhibitors, CCR2 chemokine antagonists, CCR3 chemokine antagonists, CCR5 chemokine antagonists, CD3 antagonists, chloride channel stimulators, cholesterol solubilizers, CNR1 inhibitors, cyclin D1 inhibitors, cytochrome P450 7A1 inhibitors, cytochrome P450 2E1 (CYP2E1) inhibitors, diacylglycerol O acyltransferase 1 inhibitors (DGAT1 inhibitors), diacylglycerol O acyltransferase 1 inhibitors (DGAT2 inhibitors), CXCR4 chemokine antagonists, dipeptidyl peptidase IV inhibitors, endosialin modulators, endothelial nitric oxide synthase stimulators, eotaxin ligand inhibitors, extracellular matrix protein modulators, farnesoid X receptor agonists, fatty acid synthase inhibitors, FGF1 receptor agonists, fibroblast activation protein (FAP) inhibitors, fibroblast growth factor receptor ligands (such as FG F-15, FGF-19, FGF-21), fish oil, galectin-3 inhibitors, glucagon receptor agonists, glucagon-like peptide 1 receptor agonists, glucocorticoid receptor antagonists, glucose 6-phosphate 1-dehydrogenase inhibitors, glutaminase inhibitors, glutathione precursors, G-protein coupled bile acid receptor 1 agonists, G-protein coupled receptor 84 antagonists, hedgehog (Hh) modulators, hepatitis C virus NS3 protease inhibitors, hepatocyte nuclear factor 4 alpha regulator (HNF4A), hepatocyte growth factor regulators, histone deacetylase inhibitors, HMGCoA reductase inhibitors, 11β-hydroxysteroid dehydrogenase (11β-HSD1) inhibitors, hypoxia-inducible factor-2α inhibitors, IL-1β antagonists, IL-6 receptor agonists, IL-10 agonists, IL-11 antagonists, IL-17 antagonists, ileal sodium bile acid cotransporter inhibitors, insulin sensitizers, insulin ligand agonists, insulin receptor agonists, integrin modulators, integrin antagonists, interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, Jak2 tyrosine kinase inhibitors, ketohexokinase (KHK) inhibitors, Klothoβ stimulators, leptin, leptin analogs, 5-lipoxygenase inhibitors, lipoprotein lipase inhibitors, liver X receptor , LPL gene stimulators, lysophosphatidic acid-1 receptor (LPAR-1) antagonists, lysyl oxidase homolog 2 (LOXL2) inhibitors, LXR inverse agonists, macrophage mannose receptor 1 modulators, matrix metalloproteinase (MMP) inhibitors, MCH receptor-1 antagonists, MEKK-5 protein kinase inhibitors, membrane copper amine oxidase (VAP-1) inhibitors, methionine aminopeptidase-2 inhibitors, methyl CpG binding protein 2 regulators, MicroRNA-132 (miR-132) antagonists, MicroRNA-21 (miR-21) inhibitors, mitochondrial uncouplers, mixed lineage kinase-3 inhibitors, myelin basic protein stimulators, NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, NAD-dependent deacetylase sirtuin-1 stimulators, NADPH oxidase inhibitors (NOX), nicotinic acid receptor 1 agonists, P2X7 purinergic receptor modulators, P2Y13 purinergic receptor stimulators, PDE 3 inhibitors, PDE 4 inhibitors, PDE5 inhibitors, PDGF receptor β modulators, peptidyl-prolyl cis-trans isomerase A inhibitors, phenylalanine hydroxylase stimulators, phospholipase C inhibitors, PPARα agonists, PPARγ agonists, PPARδ agonists, PPARγ modulators, PPARα / δ agonists, PPARα / γ / δ agonists, protease-activated receptor-2 antagonists, protein kinase modulators, Rho-associated protein kinase 2 (ROCK2) inhibitors, nitrosoglutathione reductase (GSNOR) enzyme inhibitors, sodium glucose transporter-2 (SGLT2) inhibitors, SREBP transcription factor inhibitors, STAT-1 inhibitors, STAT-3 modulators, stearoyl-CoA desaturase-1 inhibitors, nitrosoglutathione reductase (GSNOR) enzyme inhibitors, cytokine signaling inhibitory factor-1 stimulators, inhibitory factor-3 stimulators of cytokine signaling, spleen tyrosine kinase (SYK) inhibitors, transforming growth factor β (TGF-β), TGF-β antagonists (e.g., TGF-β1 antagonists, TGF-β2 antagonists, TGF-β3 antagonists, potential TGFβ complex modulators), TGF-β receptor antagonists, transforming growth factor β activated kinase 1 (TAK1), thyroid hormone receptor β agonists, Toll-like receptor (TLR)-4 antagonists, transglutaminase inhibitors, tumor necrosis factor α (TNFα) ligand inhibitors, tumor progression locus 2 (Tpl2) kinase inhibitors, tyrosine kinase receptor modulators, GPCR modulators, nuclear hormone receptor modulators, WNT modulators, YAP / TAZ modulators and human zonulin inhibitors.

[0347] Non-limiting examples of the one or more additional therapeutic agents include:

[0348] ACE inhibitors, such as enalapril;

[0349] Acetyl-CoA carboxylase (ACC) inhibitors, such as NDI-010976 (firsocostat), DRM-01, gemcabene, PF-05175157, QLT-091382, or PF-05221304;

[0350] Acetyl-CoA carboxylase / diacylglycerol O-acyltransferase 2 inhibitors, such as PF-07055341;

[0351] Aldehyde dehydrogenase inhibitors, such as ADX-629;

[0352] Adenosine receptor agonists, such as CF-102 (namodenoson), CF-101, CF-502, or CGS21680;

[0353] Adiponectin receptor agonists, such as ADP-355 or ADP-399;

[0354] Amylin / calcitonin receptor agonists, such as KBP-042 or KBP-089;

[0355] AMP-activated protein kinase stimulators, such as PXL-770 or O-304;

[0356] AMP kinase activators / ATP citrate lyase inhibitors, such as bempedoic acid (ETC-1002, ESP-55016);

[0357] AMP-activated protein kinase / endothelial nitric oxide synthase / NAD-dependent deacetylase sirtuin-1 stimulators, such as NS-0200 (leucine + metformin + sildenafil);

[0358] Androgen receptor agonists, such as LPCN-1144;

[0359] Angiotensin II AT-1 receptor antagonists, such as irbesartan;

[0360] Angiopoietin-related protein-3 inhibitors, such as IONIS-ANGPTL3-LRx;

[0361] Autotaxin inhibitors, such as PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, AM-063, or BBT-877;

[0362] Axl tyrosine kinase receptor inhibitors, such as bemcentinib (BGB-324, R-428);

[0363] Bax protein stimulators, such as CBL-514;

[0364] Bioactive lipids, such as DS-102;

[0365] Cannabinoid receptor type 1 (CNR1) inhibitors such as namacizumab, GWP-42004, REV-200, or CRB-4001;

[0366] Cysteine ​​protease inhibitors, such as emricasan;

[0367] Pan cathepsin B inhibitors, such as VBY-376;

[0368] Pan cathepsin inhibitors, such as VBY-825;

[0369] CCR2 / CCR5 chemokine antagonists such as cenicriviroc, maraviroc, CCX-872 or WXSH-0213;

[0370] CCR2 chemokine antagonists, such as propagermanium;

[0371] CCR2 chemokine / angiotensin II AT-1 receptor antagonists, such as DMX-200 or DMX-250;

[0372] CCR2 / CCR5 chemokine antagonists and FXR agonists, such as LJC-242 (tropifexor + cenivriviroc); CCR3 chemokine antagonists, such as bertilimumab;

[0373] Chloride channel stimulators, such as cobiprostone or lubiprostone;

[0374] CD3 antagonists, such as NI-0401 (foralumab);

[0375] CXCR4 chemokine antagonists, such as AD-214;

[0376] Diacylglycerol acyltransferase 1 (DGAT1) inhibitors, such as GSK-3008356;

[0377] Diacylglycerol O-acyltransferase 1 (DGAT1) / cytochrome P450 2E1 inhibitors (CYP2E1), such as SNP-610;

[0378] Diacylglycerol acyltransferase 2 (DGAT2) inhibitors, such as IONIS-DGAT2Rx or PF-06865571;

[0379] Dipeptidyl peptidase IV inhibitors, such as linagliptin or evogliptin;

[0380] Eotaxin ligand inhibitors, such as cefixime or CM-101;

[0381] Extracellular matrix protein modulators, such as CNX-024;

[0382] Farnesoid X receptor (FXR) agonists, such as AGN-242266, AGN-242256, EP-024297, RDX-023, BWL-200, AKN-083, EDP-305, GNF-5120, GS-9674, LMB-763, obeticholic acid, Px-102, Px-103, M790, M780, M450, M-480, MET-409, PX20606, EYP-001, TERN-101, TC-100, INT-2228;

[0383] Farnesoid X receptor (FXR) / G protein-coupled bile acid receptor 1 (TGR5) agonists, such as INT-767;

[0384] Fatty acid synthase inhibitors, such as TVB-2640;

[0385] FGF receptor agonists / Klothoβ stimulators, such as BFKB-8488A (RG-7992);

[0386] Fibroblast growth factor 19 (rhFGF19) / cytochrome P450 (CYP) 7A1 inhibitors, such as NGM-282;

[0387] Fibroblast growth factor 21 (FGF-21) ligands, such as BMS-986171, BIO89-100, B-1344 or BMS-986036;

[0388] Fibroblast growth factor 21 (FGF-21) / glucagon-like peptide 1 (GLP-1) agonists, such as YH-25723 (YH-25724; YH-22241) or AKR-001;

[0389] Fish oil compositions, such as eicosapentaenoic acid ethyl

[0390] Galectin-3 inhibitors, such as GR-MD-02, GB-1107 (Gal-300) or GB1211 (Gal-400);

[0391] Glucagon-like peptide 1 receptor (GLP1R) agonists, such as AC-3174, liraglutide, cotadutide (MEDI-0382), exenatide, SAR-425899, LY-3305677, HM-15211, YH-25723, YH-GLP1, RPC-8844, PB-718, or semaglutide;

[0392] Glucocorticoid receptor antagonists, such as CORT-118335 (miricorilant);

[0393] Glucose 6-phosphate 1-dehydrogenase inhibitors, such as ST001;

[0394] G-protein-coupled bile acid receptor 1 (TGR5) agonists, such as RDX-009 or INT-777;

[0395] Heat shock protein 47 (HSP47) inhibitors, such as ND-L02-s0201;

[0396] HMG CoA reductase inhibitors such as atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin or simvastatin;

[0397] Hypoxia-inducible factor-2α inhibitors, such as PT-2567;

[0398] IL-10 agonists, such as peg-ilodecakin;

[0399] Ileal sodium bile acid co-transporter inhibitors such as odevixibat (A-4250), volixibat potassium ethanolate hydrate (SHP-262), GSK2330672, CJ-14199, or elobixibat (A-3309);

[0400] Insulin sensitizers, such as KBP-042, MSDC-0602K, MSDC-5514, Px-102, RG-125 (AZD4076), VVP-100X, CB-4211, or ETI-101;

[0401] Insulin ligands / ds-insulin receptor agonists, such as ORMD-0801;

[0402] Integrin antagonists, such as IDL-2965;

[0403] IL-6 receptor agonists, such as KM-2702;

[0404] Ketohexokinase (KHK) inhibitors, such as PF-06835919;

[0405] βKlotho (KLB)-FGF1c agonists, such as MK-3655 (NGM-313);

[0406] 5-lipoxygenase inhibitors, such as tipelukast (MN-001), DS-102 (AF-102);

[0407] Lipoprotein lipase inhibitors, such as CAT-2003;

[0408] LPL gene stimulators, such as alipogene tiparvovec;

[0409] Liver X receptor (LXR) modulators, such as PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, or SR-9238;

[0410] Lysophosphatidic acid-1 receptor antagonists, such as BMT-053011, UD-009 (CP-2090), AR-479, ITMN-10534, BMS-986020, or KI-16198;

[0411] Lysyl oxidase homolog 2 inhibitors, such as simtuzumab or PXS-5382A (PXS-5338);

[0412] Macrophage mannose receptor 1 modulators, such as temanoselt-Cy3 (technetium Tc 99m temanoselt);

[0413] Membrane copper amine oxidase (VAP-1) inhibitors, such as TERN-201;

[0414] MEKK-5 protein kinase (ASK-1) inhibitors, such as GS-4997, SRT-015 or GS-444217, GST-HG-151;

[0415] MCH receptor-1 antagonists, such as CSTI-100 (ALB-127158);

[0416] Methionine aminopeptidase-2 inhibitors, such as ZGN-839, ZGN-839 or ZN-1345;

[0417] Methyl CpG binding protein 2 modulators, such as cysteamine;

[0418] Mitochondrial uncouplers, such as 2,4-dinitrophenol or HU6;

[0419] Mixed lineage kinase-3 inhibitors, such as URMC-099-C;

[0420] Myelin basic protein stimulators, such as olesoxime;

[0421] NADPH oxidase 1 / 4 inhibitors, such as GKT-831 or APX-311;

[0422] Nicotinic acid receptor 1 agonists, such as ARI-3037MO;

[0423] Nitazoxinide;

[0424] NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, such as KDDF-201406-03, NBC-6, IFM-514, or JT-194 (JT-349);

[0425] Nuclear receptor modulators, such as DUR-928 (DV-928);

[0426] P2X7 purinergic receptor modulators, such as SGM-1019;

[0427] P2Y13 purinergic receptor stimulators, such as CER-209;

[0428] PDE 3 / 4 inhibitors, such as talukast (MN-001);

[0429] PDE 5 inhibitors, such as sildenafil or MSTM-102;

[0430] PDGF receptor β modulators, such as BOT-191 or BOT-509;

[0431] Peptidyl-prolyl cis-trans isomerase inhibitors, such as CRV-431 (CPI-432-32), NVP-018 or NV-556 (NVP-025);

[0432] Phenylalanine hydroxylase stimulators, such as HepaStem;

[0433] PPAR agonists (including PPAR alpha agonists, PPAR alpha / delta agonists, PPAR alpha / delta / gamma agonists, PPAR delta agonists), such as elafibranor (GFT-505), MBX-8025, deuterated pioglitazone R-enantiomer, pioglitazone, DRX-065, saroglitazar, or IVA-337; PPAR alpha agonists, such as aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clobemide, fenofibrate, gemfibrozil, pemafibrate, clonifibrate, bisfibrate, omega-3 fatty acids (fish oils, e.g., eicosapent ethyl) or docosahexaenoic acid), pironic acid, GW409544, AZ 242, LY518674, NS-220, AVE8134, BMS-711939, aleglitazar, muraglitzar, or saroglitazar;

[0434] PPARα / δ agonists, such as elabeno;

[0435] PPARα / δ / γ agonists, such as laifibranor;

[0436] PPARδ agonists, such as seladelpar;

[0437] PR2 antagonists, such as PZ-235;

[0438] Protein kinase modulators, such as CNX-014;

[0439] Rho-associated protein kinase (ROCK) inhibitors, such as REDX-10178 (REDX-10325) or KD-025;

[0440] Semicarbazide-sensitive amine oxidase / vascular adhesion protein-1 (SSAO / VAP-1) inhibitors, such as PXS-4728A;

[0441] S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, such as SL-891;

[0442] Sodium glucose transporter-2 (SGLT2) inhibitors such as ipragliflozin, remogliflozin etabonate, ertugliflozin, dapagliflozin, tofogliflozin, or sotagliflozin;

[0443] SREBP transcription factor inhibitors, such as CAT-2003 or MDV-4463;

[0444] Stearoyl-CoA desaturase-1 inhibitors, such as aramchol;

[0445] Thyroid hormone receptor (THR) beta agonists, such as resmetriom (MGL-3196), MGL-3745, or VK-2809;

[0446] TLR-2 / TLR-4 antagonists, such as VB-201 (CI-201);

[0447] TLR-4 antagonists, such as JKB-121;

[0448] Tyrosine kinase receptor modulators, such as CNX-025 or GFE-2137 (repurposed nitazoxanide);

[0449] GPCR modulators, such as CNX-023;

[0450] Nuclear hormone receptor modulators, such as Px-102;

[0451] Xanthine oxidase / urate anion exchanger 1 (URAT1) inhibitors, such as RLBN-1001, RLBN-1127; and

[0452] Zonulin inhibitors, such as lorazotide acetate (INN-202).

[0453] In some embodiments, the one or more additional therapeutic agents are selected from A-4250, AC-3174, acetylsalicylic acid, AK-20, alipokine, AMX-342, AN-3015, eicosanylaminocholanic acid, ARI-3037MO, ASP-8232, AZD-2693, bertilimumab, anhydrous betaine, BI-1467335, BMS-986036, BMS-986171, BMT-053011, BOT-191, BTT-1023, CAT-2003, Cinevir, CBW-511, CER-209, CF-102, CGS21680, CNX-014, CNX-023, CNX-024, CNX-030, CNX-040, CNX-0511, CNX-060, CNX-070, CNX-080, CNX-090, CNX-091, CNX-080, CNX-090, CNX-014, CNX-023, CNX-080, CNX-090, CNX-080, CNX-090, 4. CNX-025, cobiprostone, colesevelam, dapagliflozin, DCR-LIV1, deuterated pioglitazone R-enantiomer, 2,4-dinitrophenol, DRX-065, DS-102, DUR-928, EDP-305, elabeno (GFT-505), enlicasin, enalapril, erpagliflozin, emalagliflozin, F-351, fluasterone (ST-002), FT-4101, GKT-831, GNF-5120, GRI-0621, GR-MD-02, GS-300, GS-4997, GS-9674, HTD-1801, HST-202, HST-201, hydrochlorothiazide, Icosabutate (PRC-4016) eicosapentaenoic acid ethyl ester, IMM-124-E, INT-767, INV-240, IONIS-DGAT2Rx, empagliflozin, irbesartan, propagermanium, IVA-337, JKB-121, KB-GE-001, KBP-042, KD-025, M790, M780, M450, metformin, sildenafil, LC-280126, linagliptin, liraglutide, LJN-452 (zopifilox), LM-011, LM-002 (CVI-LM-002), LMB-763, LYN-100, MBX-8025, MDV-4463, Cysteine, MGL-3196, MGL-3745, MP-301, MSDC-0602K, namasizumab, NC-101, NDI-010976, ND-L02-s0201 (BMS-986263), NGM-282, NGM-313, NGM-386, NGM-395, NP-160, nordeoxycholic acid, NVP-022, O-304, obeticholic acid (OCA), 25HC3S, olesoxime, PAT-505, PAT-048, PBI-4547, pegylated ilobekinin, biglitazone, pirfenidone, PRI-724, PX20606, Px-102, PX-L603,PX-L493, PXS-4728A, PZ-235, RDX-009, repagliflozin etabonate, RG-125 (AZD4076), RPI-500, saroglitazar, semaglutide, cintuzumab, solithromycin, sogliflozin, statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), symbiotic, TCM-606F, TEV-45478, TQA-3526, tylosin MN-001, TLY-012, TRX-318, TVB-2640, UD-009, ursodeoxycholic acid, VBY-376, VBY-825, VK-2809, Vimodegib, Voxibater potassium ethanolate hydrate (SHP-626), VVP-100X, WAV-301, WNT-974, XRx-117, ZGN-839, ZG-5216, ZSYM-008 and ZYSM-007.

[0454] In some embodiments, the methods and pharmaceutical compositions provided herein comprise a therapeutically effective amount of an apoptosis signal-regulating kinase 1 (ASK1) inhibitor and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) provided herein, or a pharmaceutically acceptable salt thereof.

[0455] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the ASK1 inhibitor is GS-4997 (selonsertib, SEL).

[0456] ASK1 inhibitors can be synthesized and characterized using methods known to those skilled in the art, such as those described in US Pat. No. 2007 / 0276050, US Pat. No. 2011 / 0009410, and US Pat. No. 2013 / 0197037.

[0457] In some embodiments, the methods and pharmaceutical compositions provided herein comprise a therapeutically effective amount of an acetyl-CoA carboxylase (ACC) inhibitor and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) provided herein, or a pharmaceutically acceptable salt thereof.

[0458] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the ACC inhibitor is GS-0976 (firsocostat, FIR).

[0459] ACC inhibitors can be synthesized and characterized using methods known to those skilled in the art, such as those described in US Pat. No. 9,453,026 and US Pat. No. 10,183,951.

[0460] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of a PPAR agonist (e.g., a PPARα agonist, a PPARα / δ agonist, a PPARα / δ / γ agonist, a PPARδ agonist) or fish oil, a therapeutically effective amount of an acetyl-CoA carboxylase (ACC) inhibitor (such as GS-0976 (firsocostat, FIR)) and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the PPAR agonist is a PPARα agonist. In some embodiments, the PPARα agonist is selected from aluminum clofibrate, bezafibrate), ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clobemide, fenofibrate, gemfibrozil, permafibrate, ronifibrate, simfibrate, pironic acid, GW409544, AZ 242, LY518674, NS-220, AVE8134, BMS-711939, aleglitazar, moraglitazar and saroglitazar. In some embodiments, the PPAR agonist (e.g., PPARα agonist) is fibrate. In some embodiments, the PPAR agonist (e.g., PPARα agonist) is fenofibrate. In some embodiments, the PPAR agonist is a PPARα / δ agonist (e.g., elabenot). In some embodiments, the PPAR agonist is a PPARα / δ / γ agonist (e.g., lanfibenot). In some embodiments, the PPAR agonist is a PPAR delta agonist (e.g., Celadepa). In some embodiments, the fish oil is an omega-3 fatty acid or docosahexaenoic acid. In some embodiments, the fish oil is eicosapentaenoic acid ethyl ester (e.g., ).

[0461] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of a farnesoid X receptor (FXR) agonist and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of Formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg), or (IVa)-(IVj) provided herein, or a pharmaceutically acceptable salt thereof.

[0462] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the FXR agonist is GS-9674 (cilofexor, CILO).

[0463] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the FXR agonist is a compound having the structure:

[0464]

[0465] or a pharmaceutically acceptable salt thereof.

[0466] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of a GLP-1 receptor agonist and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of formula (I), (Ia), (II) or (IIa) provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is liraglutide or semaglutide. In some embodiments, the GLP-1 receptor agonist is semaglutide.

[0467] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of a TGFβ antagonist and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of formula (I), (Ia), (II), (IIa), (IIIa)-(IIIg) or (IVa)-(IVj) provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the TGFβ antagonist is a TGFβ1-specific antibody. TGFβ1-specific antibodies can be prepared and characterized using methods known to those skilled in the art (such as those described in PCT International Application Publication No. WO 2018 / 129329 and U.S. Patent No. 9,518,112). In some embodiments, the TGFβ antagonist binds to a TGFβ potential associated peptide (LAP), such as TGFβ1-LAP. TGFβ1-LAP-specific antibodies can be prepared and characterized using methods known to those skilled in the art (such as those described in U.S. Patent No. 8,198,412 or U.S. Patent No. 10,017,567). In some embodiments, the TGFβ antagonist binds to TGFβ (e.g., TGFβ1) in an environment-dependent manner (e.g., unrelated to the performance of TGFβ in a specific tissue or organ). In some embodiments, the TGFβ antagonist binds to TGFβ (e.g., TGFβ1) in an environment-dependent manner. In some embodiments, the TGFβ antagonist blocks the activation of potential TGFβ (e.g., potential TGFβ1) located in the extracellular matrix (e.g., connective tissue of the liver). In some embodiments, the TGFβ antagonist blocks the activation of potential TGFβ (e.g., potential TGFβ1) located in the thymus, lymph nodes, or tumor microenvironment (e.g., patients with liver cancer). In some embodiments, the TGFβ antagonist blocks the activation of potential TGFβδ (potential TGFβ1) by potential TGFβ binding protein (LTBP). In some embodiments, the TGFβ antagonist blocks the activation of potential TGFβδ (e.g., potential TGFβ1) by glycoprotein-A repeating major protein (GARP), as described, for example, in U.S. Patent No. 10,000,572. In some embodiments, the TGFβ antagonist is ARGX-115. In some embodiments, the TGFβ antagonist is an anti-potentially associated peptide (LAP) antibody that specifically binds to the LAP-TGFβ1 complex. In some embodiments, the anti-LAP antibody specifically binds to the LAP-TGFβ1 complex in the extracellular matrix (ECM) of connective tissue in the liver, for example. In some embodiments, the anti-LAP antibody specifically binds to the LAP-TGFβ1 complex on the surface of certain immunosuppressive cell types such as regulatory T cells (Treg), tumor-associated macrophages, or myeloid suppressor cells (e.g., in the tumor microenvironment). In some embodiments, the anti-LAP antibody is a TLS-01 antibody.In some embodiments, the anti-LAP antibody specifically binds to the LAP-TGFβ1 complex under any circumstances. In some embodiments, the anti-LAP antibody is a TLS-02 antibody. In some embodiments, the TGFβ antagonist includes a TGFβ receptor. In some embodiments, the TGFβ antagonist is a TGFβ receptor-Fc fusion protein. In some embodiments, the TGFβ antagonist is an antibody comprising a TGFβ receptor. For example, TGFβ antagonists comprising TGFβ receptors that can be used in combination with the compositions and methods provided herein have been described in PCT International Publication Nos. WO2019 / 113123 A1 and WO 2019 / 113464 A1.

[0468] Example

[0469] The following examples are included to demonstrate the specific embodiments of the present disclosure. It will be appreciated by those skilled in the art that the technology disclosed in the subsequent examples represents fully functional technology in the practice of the present disclosure, and therefore can be considered to constitute the specific mode of its practice. However, according to the present disclosure, it will be appreciated by those skilled in the art that these embodiments are exemplary rather than exhaustive. Without departing from the spirit and scope of the present disclosure, many changes can be made in the disclosed specific embodiments and still similar or similar results can be obtained.

[0470] Compounds disclosed herein can be prepared using appropriate materials according to the procedures of the following schemes and embodiments, and are further illustrated by the following specific examples. In addition, by utilizing the procedures described herein, in combination with ordinary techniques in the art, other compounds of the disclosure claimed herein can be easily prepared. The examples further illustrate the details for preparing the compounds disclosed herein. Those skilled in the art will readily appreciate that known variations of the conditions and methods of the following preparation procedures can be used to prepare these compounds. For compounds synthesizing the embodiments described in this disclosure, inspection of the structure of the compound to be synthesized will provide the identification of each of the substituent groups. In some cases, in view of the examples herein, by inspection processes, the identification of the final product can present an obvious identification of the starting material. The compound can be separated in the form of its pharmaceutically acceptable salt, such as those described above. The compounds described herein are generally stable and separable at room temperature and pressure.

[0471] The following is a description of the preparation of compounds disclosed herein. Unless otherwise indicated, variables have the same meanings as above. The examples presented below are intended to illustrate specific embodiments of the present disclosure. Suitable starting materials, building blocks and reagents used in the synthesis described below are commercially available, for example, from AbovChem, Acros Organics, Astatech, Combi Blocks, Oakwood Chemical or Sigma-Aldrich, or can be routinely prepared by procedures described in the literature, such as in "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 5th edition; John Wiley & Sons or T. Eicher, S. Hauptmann "The Chemistry of Heterocycles; Structures, Reactions, Synthesis and Application", 2nd edition, Wiley-VCH, 2003; Fieser et al., "Fiesers' Reagents for organic Synthesis" John Wiley & Sons 2000.

[0472] General approach

[0473] Plan A

[0474]

[0475] Scheme A provides the general synthesis of bicyclic triazole carbamate (IX). Bicyclic halide VII can be easily prepared by the electrophilic aromatic halogenation of the corresponding nitrogen-containing bicyclic. Step one describes the general synthesis of the triazole carboxylic acid (VIII) containing bicyclic carried out via cross-coupling reaction. Bicyclic halide (VII) can be first converted into corresponding boric acid esters such as pinacol borate via Miyaura boronization, and then subjected to Suzuki reaction conditions with bromotriazole carboxylic acid (III), to provide desired bicyclic triazole carboxylic acid (VIII). Alternatively, bromotriazole carboxylic acid (III) can be first converted into organozinc species via lithium-halogen exchange and captured with zinc chloride. Next, the root bank cross coupling with bicyclic halide (VII) provides desired bicyclic triazole carboxylic acid (VIII).

[0476] Step 2 describes the general synthesis of bicyclic triazoles (IX) containing carbamates. Bicyclic triazole carboxylic acids (VIII) undergo Curtius rearrangement when treated with diphenylphosphoryl azide (DPPA) or alternatively with 1-propylphosphoric anhydride solution (T3P) and trimethylsilyl azide. The intermediate isocyanate is then trapped with an alcohol (V) to provide the desired bicyclic triazole carbamate (IX).

[0477] Plan B

[0478]

[0479] Scheme B provides a general alternative synthesis of aryl, heteroaryl or bicyclic triazole carbamates (VI and IX). Step one describes the general synthesis of carbamate-containing bromotriazoles (X). Bromotriazole carboxylic acid (III) undergoes a Curtius rearrangement reaction when reacted with diphenylphosphoryl azide (DPPA) or alternatively with 1-propylphosphoric anhydride solution (T3P) and trimethylsilyl azide. The intermediate isocyanate is then trapped with an alcohol (V) to provide the desired bromotriazole carbamate (X).

[0480] Step 2 describes the general synthesis of bicyclic triazole carbamate (IX) carried out via cross-coupling reaction. Bromotriazole carbamate (X) can be first converted into an organozinc substance via lithium-halogen exchange and capture with zinc chloride. Next, the root bank cross coupling with bicyclic halide (VII) provides the desired bicyclic triazole carbamate (IX). Alternatively, bicyclic halide (VII) can be first converted into corresponding boric acid ester such as pinacol borate via Miyaura boronation, and then it is subjected to Suzuki reaction conditions with bromotriazole carbamate X to provide the desired bicyclic triazole carbamate (IX).

[0481] Example 1: Preparation of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1)

[0482]

[0483] Step 1: 4,5-Dibromo-2H-1,2,3-triazole

[0484] Bromine (2.8 mol) was added to a solution of 2H-1,2,3-triazole (1.4 mol) in water (600 mL) at 40 °C. The resulting mixture was stirred at 40 °C for 2 hours. After cooling to room temperature, the precipitate was collected by filtration. The solid was washed with water (2×300 mL) and dried under vacuum to give 4,5-dibromo-2H-1,2,3-triazole.

[0485] Step 2: 4,5-Dibromo-1-methyl-1H-1,2,3-triazole

[0486] 4,5-dibromo-2H-1,2,3-triazole (704 mmol) and K 2 CO 3 To a mixture of 4,5-dibromo-1-methyl-1H-1,2,3-triazole (1.4 mol) in THF (1000 mL) was added iodomethane (1.0 mol). The mixture was stirred at room temperature for 12 hours. The mixture was filtered and the filter cake was washed with ethyl acetate (2×500 mL), and the filtrate was concentrated at 40° C. to give a crude product, which was purified by column chromatography to give 4,5-dibromo-1-methyl-1H-1,2,3-triazole.

[0487] Step 3: 4-Bromo-1-methyl-1H-1,2,3-triazole-5-carboxaldehyde

[0488] To a solution of 4,5-dibromo-1-methyl-1H-1,2,3-triazole (168.0 mmol) in THF (600 mL) was added isopropylmagnesium chloride (252.0 mmol) at -10 °C. The mixture was stirred for 15 min and DMF (840 mmol) was added. After 1 hour, the mixture was treated with 250 mL of saturated ammonium chloride and extracted with DCM (2 x 350 mL). The combined organics were washed with 250 mL of brine and purified by Na 2 SO 4 Dry, filter and concentrate to give 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxaldehyde.

[0489] Step 4: 4-Bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid

[0490] Potassium persulfate (651 mmol) was added to a solution of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxaldehyde (536 mmol) in DMF (800 mL), and the resulting suspension was stirred at room temperature overnight. 2 O (1000 mL), adjusted to pH 3 with 1N HCl, and the aqueous phase was extracted with ethyl acetate (3×800 mL). The combined organics were washed with saturated Na 2 CO 3 (2 x 500 mL) and the aqueous phase was adjusted to pH 3 with 1 N HCl. The precipitate was isolated by filtration and dried under reduced pressure to provide 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1).

[0491] Example 2: (R)-1-(2-chlorophenyl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamic acid Preparation of ester (Intermediate 2A)

[0492]

[0493] DPPA (24.5mmol), triethylamine (24.5mmol) and (R)-1-(2-chlorophenyl)ethane-1-ol (36.5mmol) were added to a suspension of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (24.3mmol) in toluene (80mL). The mixture was heated at 80°C for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica chromatography to obtain (R)-1-(2-chlorophenyl)ethyl (4-bromo-1-methyl-1H-1,2,3-triazole-5-yl)carbamate (Intermediate 2A).

[0494] Example 3: (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)amino Preparation of formate (Intermediate 2B)

[0495]

[0496] Under argon atmosphere, 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (95mmol), 50% 1-propanephosphonic anhydride solution (143mmol) DMF solution and trimethylsilane azide (143mmol) were suspended in THF (350mL). Triethylamine (143mmol) was added, and the resulting solution was stirred for 30 minutes. (R)-1-(2-chloropyridine-3-yl) second-1-alcohol (143mmol) was added, and the mixture was heated under reflux for 12 hours, wherein an auxiliary bubbler was connected to allow exhaust. The reaction mixture was cooled to room temperature, and THF was removed under vacuum. The resulting crude material was dissolved in 500mL ethyl acetate and extracted three times with 300mL water. The crude mixture was then dried over sodium sulfate, filtered, and the filtrate was concentrated. The crude was purified by silica gel column chromatography to give (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B).

[0497] Example 4: (R)-1-(2-fluoropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)amino Preparation of formate (Intermediate 2C)

[0498]

[0499] Following the procedure described in Example 3 for the synthesis of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)aminocarboxylate (Intermediate 2B), using (R)-1-(2-fluoropyridin-3-yl)ethan-1-ol (143 mmol) instead of (R)-1-(2-chloropyridin-3-yl)ethan-1-ol, (R)-1-(2-fluoropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2C) was obtained.

[0500] Example 5: 1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H- Preparation of 1,2,3-triazole-5-carboxylic acid (Intermediate 4)

[0501]

[0502] 4-Bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (intermediate 1) (10.8mmol) was dissolved in 98mL tetrahydrofuran and immersed in a -78°C bath for 15 minutes. A 1M solution of bis(trimethylsilyl)lithium amide in tetrahydrofuran (11.7mmol) was added dropwise over 15 minutes. A hexane solution of 2.5M n-butyllithium (19.6mmol) was added dropwise over 20 minutes and stirred for another hour. A 2-methyltetrahydrofuran solution of 1.9M zinc chloride (24.5mmol) was added dropwise over 15 minutes. The reaction mixture was warmed to ambient temperature by immersion in a water bath and stirred for 30 minutes. The resulting mixture was bubbled with argon for 10 minutes, and then 6-iodo-1H-pyrido[2,3-b][1,4]oxazine-2-one (9.78 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1 mmol) complexed with dichloromethane were added. The reaction system was heated at 70 ° C for 1 hour and then cooled to ambient temperature. The reaction system was diluted with 100 mL of 2M aqueous sodium hydroxide solution and 100 mL of diethyl ether. The aqueous layer was separated and the organic layer was extracted with 2M aqueous sodium hydroxide solution (50 mL). The combined aqueous layer was washed with a 1:1 mixture of ethyl acetate and diethyl ether (100 mL×2). Under vigorous stirring, 25 mL of concentrated hydrochloric acid was added dropwise within 15 minutes to adjust the pH to 4. The mixture was filtered and the filter cake was washed with water (50 mL) and a 1:1 mixture of ethyl acetate and diethyl ether (50 mL×2). The precipitate was dried under reduced pressure to give 1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 4).

[0503] Example 6: 1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H- Alternative preparation of 1,2,3-triazole-5-carboxylic acid (Intermediate 4)

[0504] To a mixture of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (2.17 mmol) in tetrahydrofuran (14.5 mL) was added a 1 M solution of lithium bis(trimethylsilyl)amide (2.17 mmol) in tetrahydrofuran at -78°C. After 10 minutes, a 2.5 M solution of n-butyl lithium (4.35 mmol) in hexane was added. After 45 minutes, a 1.9 M solution of zinc chloride (6.52 mmol) in 2-methyltetrahydrofuran was added, and the reaction system was stirred at room temperature for 45 minutes. At this point, 6-iodo-1H-pyrido[2,3-b][1,4]oxazine-2-one (1.45 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.145 mmol) complexed with dichloromethane were added to the reaction system, and the reaction mixture was heated to 70°C for 1 hour. After the reaction was completed, the mixture was cooled and quenched with acetic acid. The mixture was concentrated under reduced pressure and purified by column chromatography to give 1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-6-yl)-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 4).

[0505] Example 7: Preparation of 1-(2-chloro-6-fluoropyridin-3-yl)ethan-1-ol

[0506]

[0507] 2-Chloro-6-fluoronicotinaldehyde (2.51mmol) dissolved in methyltetrahydrofuran (20mL) was cooled in an ice / acetonitrile bath, and then methylmagnesium bromide solution (3.0M, 7.20mmol) was added dropwise. The reaction mixture was quenched by adding ethanol, then diluted with ethyl acetate and washed with 10% citric acid. The organic layer was concentrated. The residue was purified by column chromatography to obtain 1-(2-chloro-6-fluoropyridin-3-yl)ethan-1-ol.

[0508] Example 8: Preparation of 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol

[0509]

[0510] A solution of 2-fluoro-4-iodo-5-methylpyridine (4.22 mmol) in 20 mL of THF was cooled to 0°C and treated with a 1.6 M solution of nBuLi in hexane (5.06 mmol). After 15 minutes, DMF (12.7 mmol) was added dropwise. The reaction was stirred for 30 minutes, then warmed to room temperature and heated with saturated NH 4 The mixture was extracted with EtOAc and MgSO 4Dry and concentrate to give 2-fluoro-5-methylisonicotinaldehyde. 2-Fluoro-5-methylisonicotinaldehyde (5.5 mmol) was dissolved in 25 mL THF and cooled to -15 °C in an ice-acetone bath. Treated with 3M MeMgBr in THF (11.2 mmol) and stirred for 20 minutes. 4 Cl was quenched and extracted with EtOAc, and MgSO 4 Dry, filter and concentrate to give 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol (MS (m / z) 155.9 [M+H]+).

[0511] Example 9: Preparation of 1-(2,5-difluoropyridin-4-yl)ethan-1-ol

[0512]

[0513] Following the procedure described in Example 8 for the synthesis of 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol, 2,5-difluoroisonicotinaldehyde (11.9 mmol) was used instead of 2-fluoro-5-methylisonicotinaldehyde to obtain 1-(2,5-difluoropyridin-4-yl)ethan-1-ol. (MS (m / z) 160.11 [M+H]+)

[0514] Example 10: Preparation of 1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol

[0515]

[0516] Following the procedure described in Example 8 for the synthesis of 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol, using 5-bromo-2-fluoronicotinaldehyde (7.35 mmol) instead of 2-fluoro-5-methylisonicotinaldehyde, 1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol was obtained. (MS (m / z) 220.01 [M+H]+)

[0517] Example 11: Preparation of 1-(5-bromo-2-chloropyridin-3-yl)ethan-1-ol

[0518]

[0519] Following the procedure described in Example 8 for the synthesis of 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol, using 5-bromo-2-chloronicotinaldehyde (10.6 mmol) instead of 2-fluoro-5-methylisonicotinaldehyde, 1-(5-bromo-2-chloropyridin-3-yl)ethan-1-ol was obtained. (MS (m / z) 235.99 [M+H]+)

[0520] Example 12: Preparation of 1-(2,5-difluoropyridin-4-yl)ethan-1-ol

[0521]

[0522] Following the procedure described in Example 8 for the synthesis of 1-(2-fluoro-5-methylpyridin-4-yl)ethan-1-ol, 5-bromo-2-fluoronicotinaldehyde (7.4 mmol) was used instead of 2-fluoro-5-methylisonicotinaldehyde to give 1-(5-bromo-2-fluoropyridin-3-yl)ethan-1-ol. (MS (m / z) 220.01 [M+H]+)

[0523] Example 13: Preparation of Compounds 1 to 5

[0524] Compounds 1 to 5 were generally synthesized according to Step 2 of Scheme A. For example, (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 1) was prepared as follows.

[0525]

[0526] To a mixture of 1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 4) (0.247 mmol), 1-propanephosphonic acid cyclic anhydride (50% in DMF, 0.371 mmol) and trimethylsilylazide (0.371 mmol) acid in THF (1.24 mL) was added triethylamine (0.494 mmol) dropwise. (1R)-1-(2-chloro-5-fluoro-3-pyridyl)ethanol (0.333 mmol) was added and the reaction system was heated at 70 °C for 1 hour. After the reaction was complete, the mixture was cooled and diluted with water. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 1). (MS (m / z) 448.1 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 )δ8.27(s,1H),7.95(dd,J=9.0,3.2Hz,1H),7.64(d,J=8.0Hz,1H),7.32(s,1H),6.05(q,J=6.5Hz,1H),4.82(s,2H),3.99(s,3H),1.64(s,3H).

[0527] Following the general procedure described for compound 1, compound 2-5 (Table 1) was similarly prepared according to Scheme A, Step 2 by reacting intermediate 4 (Example 5 or 6) with a reagent listed in Table 1 instead of (1R)-1-(2-chloro-5-fluoro-3-pyridinyl)ethanol.

[0528]

[0529]

[0530] Example 14: [(1R)-1-(2-chloro-3-pyridyl)ethyl]N-[5-(7-fluoro-2-oxo-3,4-dihydro-1H-quinoline Preparation of [[(4- ...

[0531]

[0532] Step 1: 7-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H- Quinolin-2-one

[0533] A mixture of 6-bromo-7-fluoro-3,4-dihydro-1H-quinolin-2-one (1.23 mmol), 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) complex with dichloromethane (0.123 mmol), bis(pinacol)diboron (1.84 mmol) and potassium acetate (1.84 mmol) in 1,4-dioxane (12 mL) was heated to 100 °C for 4 hours. After the reaction was completed, the mixture was cooled and diluted with water. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one.

[0534] Step 2: [[(1R)-1-(2-chloro-3-pyridyl)ethyl]N-[5-(7-fluoro-2-oxo-3,4-dihydro-1H-quinoline [(1-( ...

[0535] A mixture of 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (0.211 mmol), (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B) (0.222 mmol) and potassium carbonate (0.444 mmol) in 3:1 1,4-dioxane / water (3 mL) was heated to 80 °C for 30 minutes. After the reaction was complete, the mixture was cooled and diluted with water. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give [(1R)-1-(2-chloro-3-pyridinyl)ethyl]N-[5-(7-fluoro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-methyl-triazol-4-yl]carbamate (Compound 6). (MS (m / z) 445.1 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 )δ8.33(s,1H),8.00(s,1H),7.42(d,J=7.6Hz,2H),6.67(d,J=11.2Hz,1H),6.04(s ,1H),3.95(s,3H),2.95(t,J=7.6Hz,2H),2.60(dd,J=8.5,6.6Hz,2H),1.60(s,3H).

[0536] Example 15: (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-6- Preparation of 1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 7)

[0537]

[0538] Following the synthesis of [(1R)-1-(2-chloro-3-pyridinyl)ethyl]N-[5-(7-fluoro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-methyl-triazol-4-yl]carbamate described in Example 14, using 6-bromo-5-fluoro-3,4-dihydroquinolin-2(1H)-one (1.23 mmol) instead of 6-bromo-7-fluoro-3,4-dihydro-1H-quinolin-2-one in step 1, (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 7) was obtained. (MS (m / z) 445.1 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4)δ8.36(s,1H),8.03(s,1H),7.44(q,J=11.0,7.9Hz,2H),6.78(d,J=8.4Hz,1H),6. 09(s,1H),3.98(s,3H),2.99(q,J=7.3Hz,2H),2.63(t,J=7.8Hz,2H),1.63(s,3H).

[0539] Example 16: (R)-1-(2-chloropyridin-3-yl)ethyl (1-methyl-4-(3-oxo-3,4-dihydro-2H-pyridine Preparation of 2-(3,2-b][1,4]oxazin-7-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 8)

[0540]

[0541] Following the synthesis of [(1R)-1-(2-chloro-3-pyridinyl)ethyl]N-[5-(7-fluoro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-methyl-triazol-4-yl]carbamate described in Example 14, using 7-bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one (1.31 mmol) instead of 6-bromo-7-fluoro-3,4-dihydro-1H-quinolin-2-one in step 1, (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 8) was obtained. (MS (m / z) 430.1 [M+H] + ). 1 HNMR (400 MHz, methanol-d 4 )δ8.33(s,1H),8.25(d,J=1.9Hz,1H),8.04(s,1H),7.59(d,J=1.9Hz,1H), 7.49(s,1H),6.09(q,J=6.6Hz,1H),4.70(s,2H),3.94(s,3H),1.63(s,3H).

[0542] Example 17: (R)-1-(2-fluoropyridin-3-yl)ethyl (4-(4,4-dimethyl-2-oxo-1,4-dihydro-2H- Preparation of benzo[d][1,3]oxazin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 9)

[0543]

[0544] Following the synthesis of 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one as described in Example 14, 6-bromo-4,4-dimethyl-1H-3,1-benzoxazin-2-one (1.17 mmol) was used in step 1 instead of 6-bromo-7-fluoro-3,4-dihydro-1H-quinolin-2-one to obtain 4,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-3,1-benzoxazin-2-one.

[0545] Following the synthesis of [(1R)-1-(2-chloro-3-pyridinyl)ethyl]N-[5-(7-fluoro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-methyl-triazol-4-yl]carbamate described in Example 14, (R)-1-(2-fluoropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2C) was used in step 2 instead of ( R)-1-(2-fluoropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B) gave (R)-1-(2-fluoropyridin-3-yl)ethyl(4-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 9). (MS(m / z)441.1[M+H] + ). 1 H NMR (400 MHz, methanol-d 4 )δ8.18(s,1H),8.05(s,1H),7.59(d,J=15.0Hz,2H),7.37(s,1H),6.93(d,J=8.3Hz,1H),6.02(s,1H),3.94(s,3H),1.67(s,9H).

[0546] Example 18: (R)-1-(2-chloropyridin-3-yl)ethyl (1-methyl-4-(2-oxo-2,3,4,5-tetrahydro-1H- Preparation of benzo[b]azepin-7-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 10)

[0547]

[0548] Following the synthesis of 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one as described in Example 14, using 7-bromo-1,3,4,5-tetrahydro-1-benzazepin-2-one (0.833 mmol) instead of 6-bromo-7-fluoro-3,4-dihydro-1H-quinolin-2-one in step 1, 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-1-benzazepin-2-one was obtained.

[0549] Following the synthesis of [(1R)-1-(2-chloro-3-pyridinyl)ethyl]N-[5-(7-fluoro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-methyl-triazol-4-yl]carbamate described in Example 14, sodium carbonate (0.416 mmol) was used instead of potassium carbonate in step 2 to obtain (R)-1-(2-chloropyridin-3-yl)ethyl (1-methyl-4-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 10). (MS (m / z) 441.2 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 )δ8.36(s,1H),8.07(s,1H),7.67–7.58(m,2H),7.49(s,1H),7.09(d,J=8.3Hz,1H),6.13(s,1H) ,3.96(s,3H),2.82(t,J=7.0Hz,2H),2.32(d,J=6.7Hz,2H),2.27(q,J=7.0Hz,2H),1.67(s,3H).

[0550] Example 19: Preparation of Compounds 11 to 20

[0551] Compounds 11 to 20 were generally synthesized according to Step 2 of Scheme B. For example, (R)-1-(2-chlorophenyl)ethyl(1-methyl-4-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 11) was prepared as follows.

[0552]

[0553] A mixture of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (1.67 mmol), (R)-1-(2-chlorophenyl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2A) (0.556 mmol) and sodium carbonate (1.67 mmol) in 3:1 1,4-dioxane / water (7 mL) was heated to 100 °C for 1 hour. The mixture was cooled and diluted with water. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give (R)-1-(2-chlorophenyl)ethyl(1-methyl-4-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 11). (MS (m / z) 426.1 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 )δ7.61(s,1H),7.54(d,J=1.7Hz,1H),7.51(d,J=8.4Hz,1H),7.36(d,J=33.0Hz,3H),6.91(d,J= 8.2Hz, 1H), 6.19 (s, 1H), 3.92 (s, 3H), 2.95 (t, J = 7.6Hz, 2H), 2.58 (t, J = 7.6Hz, 2H), 1.61 (s, 3H).

[0554] Following the general procedure described for compound 11, compounds 12-15 (Table 2) were similarly prepared according to Scheme B, Step 2 by reacting (R)-1-(2-chlorophenyl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2A) (Example 2) with the reagents listed in Table 2 instead of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one.

[0555] Following the general procedure described for compound 11, compounds 16-18 (Table 2) were similarly prepared according to Scheme B, Step 2 by reacting (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B) (Example 3) with the reagents listed in Table 2 instead of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one.

[0556]

[0557]

[0558]

[0559]

[0560] Example 20: (R)-1-(2-chlorophenyl)ethyl (1-methyl-4-(4-methyl-2-oxo-1,2,3,4-tetrahydroquinoline Preparation of 6-oxalin-1H-1,2,3-triazol-5-yl)carbamate (Compound 19)

[0561]

[0562] A mixture of 6-bromo-4-methyl-1,3-dihydroquinoxaline-2-one (0.556 mmol), 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) complex with dichloromethane (0.0278 mmol), bis(pinacolato)diboron (0.834 mmol) and potassium acetate (0.834 mmol) in 1,4-dioxane (3 mL) was heated to 100°C for 1 hour. At this point, the reaction was cooled to room temperature, and (R)-1-(2-chlorophenyl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2A) (0.278 mmol), potassium carbonate (0.834 mmol) and water (1 mL) were added to the reaction system. The reaction system was purged with nitrogen and heated to 100°C for 1 hour. After the reaction was complete, the mixture was cooled and diluted with water. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give (R)-1-(2-chlorophenyl)ethyl(1-methyl-4-(4-methyl-2-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 19). (MS (m / z) 441.1 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 )δ7.61(s,1H),7.48–7.24(m,3H),7.12(s,2H),6.85(d,J=8.1Hz,1H),6.22(q,J =6.3,5.9Hz,1H),3.92(s,3H),3.73(s,2H),2.82(s,3H),1.59(d,J=6.6Hz,3H).

[0563] Example 21: (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl (1-methyl-4-(2-oxo-1,2,3,4-tetrahydro Preparation of quinolin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 20)

[0564]

[0565] Step 1: 3-Methyl-5-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)triazole-4-carboxylic acid

[0566] A mixture of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-quinoline-2-one (0.583mmol), 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (intermediate 1) (0.485mmol) and potassium carbonate (1.46mmol) in 3:1 1,4-dioxane / water (6mL) was heated to 100 °C for 6 hours. After the reaction was completed, the mixture was cooled and quenched with 1M HCl (5mL), resulting in the formation of a precipitate. The precipitated solid was filtered to obtain 3-methyl-5-(2-oxo-3,4-dihydro-1H-quinoline-6-yl)triazole-4-carboxylic acid.

[0567] Step 2: [(1R)-1-(2-chloro-5-fluoro-3-pyridinyl)ethyl]N-[3-methyl-5-(2-oxo-3,4-dihydro- 1H-quinolin-6-yl)triazol-4-yl]carbamate (Compound 20)

[0568] To a mixture of 3-methyl-5-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)triazole-4-carboxylic acid (0.294 mmol), 1-propanephosphonic acid cyclic anhydride (50% in DMF, 0.441 mmol) and trimethylsilyl azide (0.441 mmol) acid in THF (1.5 mL) was added triethylamine (0.588 mmol) dropwise. (1R)-1-(2-chloro-5-fluoro-3-pyridyl)ethanol (0.396 mmol) was added and the flask was heated at 70 °C for 1 hour. After the reaction was complete, the mixture was cooled and diluted with water. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 20) (MS (m / z) 445.1 [M+H] + ). 1 H NMR (400 MHz, DMSO-d 6 )δ10.18(s,1H),9.96(s,1H),8.49(s,1H),7.99(s,1H),7.59–7.36(m,2H),6.87(d,J=8.2H z, 1H), 5.91 (s, 1H), 3.84 (s, 3H), 2.87 (t, J = 7.6Hz, 2H), 2.45 (d, J = 7.7Hz, 2H), 1.61 (s, 3H).

[0569] Example 22: (R)-1-(2-chloropyridin-3-yl)ethyl (4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H- Pyrido[2,3-b][1,4]oxazin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 21) preparation

[0570]

[0571] Step 1: 6-Bromo-3,3-dimethyl-1H-pyrido[2,3-b][1,4]oxazin-2-one

[0572] To a suspension of 3,3-dimethyl-1H-pyrido[2,3-b][1,4]oxazine-2-one (5.61 mmol) in acetonitrile (56 mL) was added N-bromosuccinimide (6.17 mmol) and then trifluoroacetic acid (1.12 mmol). The reaction system was then heated at 70 ° C for 8 hours. After the reaction was completed, the mixture was diluted with water. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 6-bromo-3,3-dimethyl-1H-pyrido[2,3-b][1,4]oxazine-2-one.

[0573] Step 2: (R)-1-(2-chloropyridin-3-yl)ethyl (4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyridine (2,3-b][1,4]oxazin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 21)

[0574] To a mixture of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B) (0.42 mmol) in THF (4.2 mL) was added 1 M THF solution of lithium bis(trimethylsilyl)amide (0.46 mmol). After 10 minutes, a hexane solution of 2.5 M n-butyllithium (0.83 mmol) was added. After 45 minutes, a 2-MeTHF solution of 1.9 M zinc chloride (1.3 mmol) was added, and the reaction was stirred at room temperature for 45 minutes. At this time, 6-bromo-3,3-dimethyl-1H-pyrido[2,3-b][1,4]oxazine-2-one (0.39mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.042mmol) were added to the reaction system, and the reaction mixture was heated to 70°C for 1 hour. After the reaction was completed, the mixture was cooled and quenched with saturated aqueous ammonium chloride. The mixture was diluted with ethyl acetate and the organic matter was separated. The aqueous layer was extracted with ethyl acetate (3×10mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl(4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 21) (MS (m / z) 458.1 [M+H] + ). 1H NMR (400 MHz, methanol-d 4 )δ8.38–7.93(m,2H),7.62(d,J=8.0Hz,1H),7.52–7.35(m,1H),7.35–7.24(m,1H),6.08(q,J=6.4Hz,1H),3.95(s,3H),1.74–1.43(m,9H).

[0575] Example 23: (R)-1-(2-chloropyridin-3-yl)ethyl (1-methyl-4-(3-methyl-2-oxo-2,3-dihydro- Preparation of 1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 22)

[0576]

[0577] Following the synthesis of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 21) described in Example 19, 3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2-one (0.60 9mmol) was used instead of 3,3-dimethyl-1H-pyrido[2,3-b][1,4]oxazin-2-one to obtain (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 22) (MS (m / z) 444.1 [M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 8.42–7.92 (m, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.31 (s, 1H), 6.08 (q, J = 6.6 Hz, 1H), 4.94–4.90 (m, 1H), 4.58 (s, 3H), 3.95 (s, 3H), 1.58 (d, J = 6.9 Hz, 3H).

[0578] Example 24: (R)-1-(2-chlorophenyl)ethyl (1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2, Preparation of 3-b] [1,4]oxazine-6-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 23)

[0579]

[0580] A 2.5M hexane solution of n-butyl lithium (0.417mmol) was added to a mixture of (R)-1-(2-chlorophenyl)ethyl (4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (intermediate 2A) (0.139mmol) in THF (1.4mL) at -78°C. After 30 minutes, a 2-MeTHF solution of 1.9M zinc chloride (0.417mmol) was added, and the reaction system was stirred at room temperature for 45 minutes. At this time, 6-bromo-1H-pyrido[2,3-b][1,4]oxazine-2-one (0.139mmol) and a complex of [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) and dichloromethane (0.0139mmol) were added to the reaction system, and the reaction mixture was heated to 70°C for 1 hour. After the reaction was completed, the mixture was cooled and quenched with a saturated aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate and the organics were separated. The aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give (R)-1-(2-chlorophenyl)ethyl(1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 23) (MS (m / z) 429.0 [M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 7.64–7.50 (m, 2H), 7.37 (d, J = 7.9 Hz, 1H), 7.34–7.17 (m, 3H), 6.16 (q, J = 6.6 Hz, 1H), 4.82 (s, 2H), 3.94 (s, 3H), 1.56 (s, 3H).

[0581] Example 25: (R)-1-(2-chloropyridin-3-yl)ethyl (1-methyl-4-(2-oxo-2,3-dihydro-1H-pyridine Preparation of 2-(2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 24)

[0582]

[0583] To a mixture of (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B) (2.77 mmol) in THF (28 mL) was added 1 M THF solution of lithium bis(trimethylsilyl)amide (3.05 mmol). After 10 minutes, a 2.5 M hexane solution of n-butyllithium (6.93 mmol) was added. After 45 minutes, a 1.9 M 2-MeTHF solution of zinc chloride (9.71 mmol) was added, and the reaction was stirred at room temperature for 45 minutes. At this time, 6-iodo-1H-pyrido[2,3-b][1,4]oxazine-2-one (2.77 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.277 mmol) were added to the reaction system, and the reaction mixture was heated to 70°C for 1 hour. After the reaction was completed, the mixture was cooled and quenched with saturated aqueous ammonium chloride. The mixture was diluted with ethyl acetate and the organic matter was separated. The aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 24) (MS (m / z) 430.0 [M+H] + ). 1 H NMR (400 MHz, methanol-d 4 )δ8.30(s,1H),8.12(s,1H),7.60(d,J=8.4Hz,1H),7.45(s,1H),7.31(s,1H), 6.11(dd,J=22.0,6.6Hz,1H),4.90(s,2H),3.95(s,3H),1.63(d,J=6.6Hz,3H).

[0584] Example 26: [(1R)-1-(2-chloro-3-pyridinyl)ethyl]N-[3-methyl-5-(2-oxo-1,4-dihydropyridine Preparation of [3,2-d][1,3]oxazin-6-yl)triazol-4-yl]carbamate (Compound 25)

[0585]

[0586] The synthesis of (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate was followed as described in Example 25, using 6-bromo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazin-2-one (0.277 mmol) in place of 6-iodo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one and using (2-dihydro)-1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate. Cyclohexylphosphine-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]methanesulfonate palladium(II) (0.0277 mmol) was used to replace the complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane to obtain [(1R)-1-(2-chloro-3-pyridyl)ethyl]N-[3-methyl-5-(2-oxo-1,4-dihydropyrido[3,2-d][1,3]oxazin-6-yl)triazol-4-yl]carbamate (Compound 25). (MS(m / z)430.0[M+H] + ). 1 H NMR (400 MHz, methanol-d 4 )δ8.31(d,J=19.5Hz,1H),8.05(s,1H),7.87(d,J=8.4Hz,1H),7.43(s,1H), 7.30 (s, 1H), 6.11 (s, 1H), 5.33 (s, 2H), 3.99 (s, 3H), 1.63 (d, J = 17.1Hz, 3H).

[0587] Example 27: (R)-1-(2-chloropyridin-3-yl)ethyl (4-(3-ethyl-2-oxo-2,3-dihydro-1H-pyridine Preparation of 1-(2,3-b][1,4]oxazin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 26)

[0588]

[0589] Following the synthesis described in Example 25 for (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate, 6-bromo-3-ethyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (0. 555mmol) was used instead of 6-iodo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one to obtain (R)-1-(2-chloropyridin-3-yl)ethyl(4-(3-ethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 26). (MS(m / z)458.0[M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 8.30 (s, 1H), 8.11 (s, 1H), 7.60 (dd, J = 8.0, 3.2 Hz, 1H), 7.41 (s, 1H), 7.29 (d, J = 7.8 Hz, 1H), 6.08 (d, J = 6.5 Hz, 1H), 4.79–4.71 (m, 1H), 3.96 (s, 3H), 2.09–1.82 (m, 2H), 1.62 (s, 3H), 1.08 (q, J = 7.1 Hz, 3H).

[0590] Example 28: (R)-1-(2-chloropyridin-3-yl)ethyl (1-methyl-4-(2-oxo-3-phenyl-2,3-dihydro- Preparation of 1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 27)

[0591]

[0592] Following the synthesis described in Example 25 for (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate, 6-bromo-3-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (0. 555mmol) was used instead of 6-iodo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one to obtain (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-3-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 27). (MS(m / z)506.0[M+H] + ). 1H NMR (400MHz, DMSO-d6) δ11.19(d,J=4.6Hz,1H),9.82(s,1H),8.30(d,J=26.8Hz,1H),7.96(s,1H),7.64(t,J=7.5H z,1H),7.48–7.31(m,6H),7.27(s,1H),6.01(d,J=13.3Hz,1H),5.86(s,1H),3.86(s,3H),1.35(d,J=83.8Hz,3H).

[0593] Example 29: (R)-1-(2-chloropyridin-3-yl)ethyl (4-(7-fluoro-2-oxo-2,3-dihydro-1H-pyrido) Preparation of [2,3-b][1,4]oxazin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 28)

[0594]

[0595] The synthesis of (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate was followed as described in Example 25, using 6-bromo-7-fluoro-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (0.555 mmol) in place of 6-iodo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one and using (2-dicyclohexylphosphine-2 ',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II) (0.0555mmol) was used to replace the complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane to obtain (R)-1-(2-chloropyridin-3-yl)ethyl(4-(7-fluoro-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 28). (MS(m / z)448.0[M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 8.32 (s, 1H), 8.06 (s, 1H), 7.45 (d, J = 5.7 Hz, 1H), 7.12 (s, 1H), 6.09–6.00 (m, 1H), 4.82 (s, 2H), 3.97 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H).

[0596] Example 30: (R)-1-(2-chloropyridin-3-yl)ethyl (4-(8-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-6- Preparation of 1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 29)

[0597]

[0598] Following the synthesis of [(1R)-1-(2-chloro-3-pyridinyl)ethyl]N-[5-(7-fluoro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-methyl-triazol-4-yl]carbamate described in Example 14, using 6-bromo-8-fluoro-3,4-dihydroquinolin-2(1H)-one (0.82 mmol) instead of 6-bromo-7-fluoro-3,4-dihydro-1H-quinolin-2-one in step 1, (R)-1-(2-chloropyridin-3-yl)ethyl (4-(8-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 29) was obtained. (MS (m / z) 445.2 [M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 8.34 (s, 1H), 8.05 (s, 1H), 7.48 (s, 1H), 7.38 (d, J = 5.5 Hz, 1H), 7.35 (d, J = 1.7 Hz, 1H), 6.11 (s, 1H), 3.93 (s, 3H), 3.02 (t, J = 7.6 Hz, 2H), 2.69–2.51 (m, 2H), 1.75–1.22 (m, 3H).

[0599] Example 31: (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl (1-methyl-4-(2-oxo-3-(trifluoromethyl) 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate ( Preparation of Compound 30

[0600]

[0601] Step 1: 2-[(6-bromo-3-nitro-2-pyridinyl)oxy]-3,3,3-trifluoro-propionic acid methyl ester

[0602] To a suspension of 2,6-dibromo-3-nitro-pyridine (3.55 mmol) and 3,3,3-trifluoro-2-hydroxy-propionic acid methyl ester (3.90 mmol) in THF (6 mL) was added sodium hydride (4.26 mmol) at 0 ° C. The reaction system was stirred at room temperature. After the reaction was completed, the mixture was diluted with water. The reaction mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-[(6-bromo-3-nitro-2-pyridyl)oxy]-3,3,3-trifluoro-propionic acid methyl ester. The material was continued without further purification.

[0603] Step 2: 6-Bromo-3-(trifluoromethyl)-1H-pyrido[2,3-b][1,4]oxazin-2-one

[0604] Iron powder (24.8 mmol) was added to a suspension of 2-[(6-bromo-3-nitro-2-pyridyl)oxy]-3,3,3-trifluoro-propionic acid methyl ester (3.55 mmol) in acetic acid (10 mL) and heated to 80 ° C for 30 minutes. After the reaction was completed, the reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with ethyl acetate, and the combined filtrate was concentrated. The residue was purified by column chromatography to obtain 6-bromo-3-(trifluoromethyl)-1H-pyrido[2,3-b][1,4]oxazine-2-one.

[0605] Step 3: 1-methyl-4-(2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxadiazole Oxazine-6-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0606] 4-Bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (intermediate 1) (2.43mmol) was dissolved in 24mL tetrahydrofuran and immersed in a -78°C bath for 15 minutes. A 1M solution of bis(trimethylsilyl)lithium amide in tetrahydrofuran (2.67mmol) was added dropwise over 15 minutes. A hexane solution of 2.5M n-butyllithium (4.85mmol) was added dropwise over 20 minutes and stirred for another hour. A 2-methyltetrahydrofuran solution of 1.9M zinc chloride (7.52mmol) was added dropwise over 15 minutes. The reaction mixture was warmed to ambient temperature by immersion in a water bath and stirred for 30 minutes. The resulting mixture was bubbled with argon for 10 minutes, and then 6-bromo-3-(trifluoromethyl)-1H-pyrido[2,3-b][1,4]oxazine-2-one (1.70mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.24mmol) complexed with dichloromethane were added. The reaction system was heated at 70°C for 1 hour and then cooled to ambient temperature. The reaction system was diluted with 20mL of 2M aqueous sodium hydroxide solution and 20mL of diethyl ether. The aqueous layer was separated, and the organic layer was extracted with 2M aqueous sodium hydroxide solution (20mL). The combined aqueous layer was washed with a 1:1 mixture of ethyl acetate and diethyl ether (20mL×2). Under vigorous stirring, 5mL of concentrated hydrochloric acid was added dropwise within 15 minutes to adjust the pH to 4. The mixture was filtered, and the filter cake was washed with water (10mL) and a 1:1 mixture of ethyl acetate and diethyl ether (10mL×2). The precipitate was dried under reduced pressure to obtain 1-methyl-4-(2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylic acid.

[0607] Step 4: (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl (1-methyl-4-(2-oxo-3-(trifluoromethyl)-2, 3-Dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate

[0608] To a mixture of 1-methyl-4-(2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylic acid (0.208 mmol), 1-propanephosphonic acid cyclic anhydride (50% in DMF, 0.312 mmol) and trimethylsilylazide (0.312 mmol) acid in THF (1.05 mL) was added triethylamine (0.417 mmol) dropwise. (1R)-1-(2-chloro-5-fluoro-3-pyridyl)ethanol (0.309 mmol) was added and the reaction system was heated at 70° C. for 1 hour. After the reaction was complete, the mixture was cooled and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(1-methyl-4-(2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 30). (MS (m / z) 516.0 [M+H]+). 1H NMR (400MHz, methanol-d4) δ8.27(s,1H),7.92(s,1H),7.73(dd,J=8.0,3.1Hz,1H),7.39(d ,J=8.0Hz,1H),6.05(d,J=6.9Hz,1H),5.64–5.44(m,1H),3.99(s,3H),1.64(s,3H).

[0609] Example 32: (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl (1-methyl-4-(3-methyl-2-oxo-2,3- Dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 31) Preparation

[0610]

[0611] Step 1: 6-Bromo-3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

[0612] To a suspension of 3-methyl-1H-pyrido[2,3-b][1,4]oxazine-2(3H)-one (6.09mmol) in acetonitrile (60mL) was added N-bromosuccinimide (6.70mmol) and then trifluoroacetic acid (1.22mmol). The reaction system was then heated at 70°C for 8 hours. After the reaction was complete, the mixture was diluted with water. The mixture was extracted with ethyl acetate (3×50mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 6-bromo-3-methyl-1H-pyrido[2,3-b][1,4]oxazine-2(3H)-one.

[0613] Step 2: 1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-6-yl)- 1H-1,2,3-triazole-5-carboxylic acid

[0614] 4-Bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (intermediate 1) (2.43mmol) was dissolved in 24mL tetrahydrofuran and immersed in a -78°C bath for 15 minutes. A 1M solution of bis(trimethylsilyl)lithium amide in tetrahydrofuran (2.67mmol) was added dropwise over 15 minutes. A hexane solution of 2.5M n-butyllithium (4.85mmol) was added dropwise over 20 minutes and stirred for another hour. A 2-methyltetrahydrofuran solution of 1.9M zinc chloride (7.52mmol) was added dropwise over 15 minutes. The reaction mixture was warmed to ambient temperature by immersion in a water bath and stirred for 30 minutes. The resulting mixture was bubbled with argon for 10 minutes, and 6-bromo-3-methyl-1H-pyrido[2,3-b][1,4]oxazine-2(3H)-one (1.70mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.24mmol) complexed with dichloromethane were added. The reaction system was heated at 70°C for 1 hour and then cooled to ambient temperature. The reaction system was diluted with 20mL of 2M aqueous sodium hydroxide solution and 20mL of diethyl ether. The aqueous layer was separated, and the organic layer was extracted with 2M aqueous sodium hydroxide solution (20mL). The combined aqueous layer was washed with a 1:1 mixture of ethyl acetate and diethyl ether (20mL×2). Under vigorous stirring, 5mL of concentrated hydrochloric acid was added dropwise within 15 minutes to adjust the pH to 4. The mixture was filtered, and the filter cake was washed with water (10mL) and a 1:1 mixture of ethyl acetate and diethyl ether (10mL×2). The precipitate was dried under reduced pressure to obtain 1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylic acid.

[0615] Step 3: (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl (1-methyl-4-(3-methyl-2-oxo-2,3-dihydropyridin-3-yl)ethyl) Hydrogen-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate

[0616] To a mixture of 1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylic acid (0.211 mmol), 1-propanephosphonic acid cyclic anhydride (50% in DMF, 0.312 mmol) and trimethylsilylazide (0.316 mmol) acid in THF (1.05 mL) was added triethylamine (0.422 mmol) dropwise. (1R)-1-(2-chloro-5-fluoro-3-pyridyl)ethanol (0.313 mmol) was added and the reaction system was heated at 70° C. for 1 hour. After the reaction was completed, the mixture was cooled and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 31). (MS (m / z) 462.0 [M+H] + ). 1 H NMR (400MHz, methanol-d4) δ8.24(s,1H),7.90(s,1H),7.63(d,J=8.0Hz,1H),7.30(s,1H),6.0 4(q,J=6.6Hz,1H),4.95–4.87(m,1H),3.97(s,3H),1.61(s,3H),1.56(d,J=6.9Hz,3H).

[0617] Example 33: (R)-1-(2,5-difluoropyridin-3-yl)ethyl (1-methyl-4-(3-methyl-2-oxo-2,3-difluoropyridin-3-yl)ethyl Hydrogen-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 32) preparation

[0618]

[0619] Step 1: 6-Bromo-3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

[0620] To a suspension of 3-methyl-1H-pyrido[2,3-b][1,4]oxazine-2(3H)-one (6.09mmol) in acetonitrile (60mL) was added N-bromosuccinimide (6.70mmol) and then trifluoroacetic acid (1.22mmol). The reaction system was then heated at 70°C for 8 hours. After the reaction was complete, the mixture was diluted with water. The mixture was extracted with ethyl acetate (3×50mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 6-bromo-3-methyl-1H-pyrido[2,3-b][1,4]oxazine-2(3H)-one.

[0621] Step 2: 1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-6-yl)- tert-Butyl)-1H-1,2,3-triazole-5-carboxylate

[0622] 4-Bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid tert-butyl ester (1.53mmol) is dissolved in 5.5mL tetrahydrofuran and immersed in -78 ℃ of baths for 15 minutes.In 15 minutes, add dropwise 1M tetrahydrofuran solution (1.68mmol) of bis(trimethylsilyl) lithium amide.In 20 minutes, add dropwise 2.5M hexane solution of n-butyl lithium (3.05mmol), and stir it for another 1 hour.In 15 minutes, add dropwise 1.9M 2-methyltetrahydrofuran solution of zinc chloride (4.73mmol).By being immersed in a water bath, the reaction mixture is warmed to ambient temperature and stirred for 30 minutes. The resulting mixture was bubbled with argon for 10 minutes, and 6-bromo-3-methyl-1H-pyrido[2,3-b][1,4]oxazine-2(3H)-one (1.53 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.15 mmol) complexed with dichloromethane were added. The reaction system was heated at 70 °C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature and quenched with ammonium chloride. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain tert-butyl 1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-6-yl)-1H-1,2,3-triazole-5-carboxylate.

[0623] Step 3: 1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-6-yl)- 1H-1,2,3-triazole-5-carboxylic acid

[0624] To a solution of tert-butyl 1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylate (0.20 mmol) was added trifluoroacetic acid (0.98 mmol). The reaction was complete after 3 hours and concentrated under reduced pressure to give 1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylic acid. This material was carried forward without further purification.

[0625] Step 4: (R)-1-(2,5-difluoropyridin-3-yl)ethyl (1-methyl-4-(3-methyl-2-oxo-2,3-dihydro- 1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate

[0626] To a mixture of 1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazole-5-carboxylic acid (0.211 mmol), 1-propanephosphonic acid cyclic anhydride (50% in DMF, 0.313 mmol) and trimethylsilylazide (0.316 mmol) acid in THF (1.05 mL) was added triethylamine (0.422 mmol) dropwise. (1R)-1-(2,5-difluoro-3-pyridyl)ethanol (0.313 mmol) was added and the reaction system was heated at 70°C for 1 hour. After the reaction was completed, the mixture was cooled and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(1-methyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 32). (MS (m / z) 446.0 [M+H] + ). 1 HNMR (400 MHz, methanol-d4) δ7.96 (d, J = 44.1 Hz, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.05–5.86 (m, 1H), 4.94–4.89 (m, 1H), 3.96 (s, 3H), 1.73–1.42 (m, 6H).

[0627] Example 34: Calcium Assay

[0628] In vitro LPAR1 activity was measured in an intracellular calcium mobilization assay.

[0629] CHO-K1 EDG2 cells (DiscoverX, catalog number 93-0644C2) expressing human LPAR1 (NM_001401.3) were seeded at 15,000 cells / well into 384-well tissue culture plates (Grenier #781091) in a total volume of 25 μL of Dulbecco's modified Eagle's medium (DMEM) with 10% fetal bovine serum, 1x PenStrepGlutamine, 300ug / ml hygromycin and 800ug / ml G418 and incubated overnight at 37°C. Prior to the assay, 25 μL of calcium loading dye component A (FLIPR Calcium 6 Assay Kit, Molecular Device #R8190) and 2.5 mM probenecid (Invitrogen #P36400, freshly prepared) in Hank's balanced salt solution (Corning #21-023-CV), 20 mM HEPES (Corning #25-060-CI), and 0.1% bovine serum albumin (Sigma-Aldrich #A7906-500G) were added to the cells and kept at 37°C for 60 minutes.

[0630] Agonist dose curves of LPA 18:2 (Avanti Polar Lipids, Cat. No. 857138, 0.5 nM to 10 μM) were recorded to determine the LPA 18:2 EC 80 , for subsequent antagonist determination. For agonist dose curves, cells were removed from the incubator and transferred to a FLIPR Tetra instrument (Molecular Devices, San Jose, CA) 2 hours after dye loading. Calcium mobilization was monitored for 5 min, and 10 μL of 6X LPA in HBSS / 20 mM Hepes / 0.1% bovine serum albumin (BSA) was added to the cells 5 seconds before the start of the assay.

[0631] To determine the LPAR1 antagonist activity of the test compounds, cells were pre-incubated with the test compounds in a dose range of 0.5 nM to 10 μM, followed by EC 80 After dye loading, cells were removed from the incubator and 0.3 μL of 200X antagonist was added. Cells were incubated at 37°C for 60 minutes. Antagonist activity was measured on the FLIPR Tetra. Calcium mobilization was monitored for 5 minutes and 10 μL of 6X EC 80 A solution of LPA in HBSS, 20 mM HEPES, and 0.1% BSA was added to the cells. The signal amplitude (maximum minus minimum) was plotted against log 0.10 Antagonist concentrations were plotted to determine the EC 50 .

[0632] To evaluate the antagonistic potential of exemplary compounds, the EC values ​​of compounds 1 to 32 were determined in the LPAR1 calcium mobilization assay. 50 The results are shown in Table 3 (LPAR1 EC 50 ). The compound numbers correspond to the compound numbers in Examples 1 to 33.

[0633] Table 3

[0634] Compound <![CDATA[LPAR1(EC 50 ;[nM])]]> Compound 1 85 Compound 2 1,984 Compound 3 66 Compound 4 118 Compound 5 100 Compound 6 115 Compound 7 1,234 Compound 8 765 Compound 9 4,606 Compound 10 not applicable Compound 11 46 Compound 12 218 Compound 13 38 Compound 14 4,157 Compound 15 565 Compound 16 525 Compound 17 390 Compound 18 265 Compound 19 265 Compound 20 118 Compound 21 2,280 Compound 22 86 Compound 23 not applicable Compound 24 123 Compound 25 140 Compound 26 3,783 Compound 27 135 Compound 28 660 Compound 29 5 Compound 30 <5 Compound 31 <5 Compound 32 3,783

[0635] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0636] Therefore, it should be understood that although the present disclosure has been specifically disclosed by preferred embodiments and optional features, modifications, improvements and variations of the disclosure implemented therein disclosed herein may be adopted by those skilled in the art, and such modifications, improvements and variations are considered to be within the scope of the present disclosure. The materials, methods and examples provided herein represent preferred embodiments, are exemplary, and are not intended to limit the scope of the present disclosure.

[0637] The present disclosure has been described broadly and generically herein. Each narrower genus and subgeneric grouping falling within the generic disclosure also forms a part of the present disclosure. This includes the generic description of the present disclosure with a proviso or negative limitation removing any subject matter from the genus, regardless of whether the excised material is specifically recited herein.

[0638] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0639] It should be understood that although the present disclosure has been described in conjunction with the above embodiments, the foregoing description and examples are intended to illustrate rather than limit the scope of the present disclosure. Other aspects, advantages and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which the present disclosure belongs.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, in: R 1 is hydrogen; Can be the same or different for each R 2 are independently -CH3, -CF3, -C2H5 or phenyl; R 3 is a halogen; R 4 is -CH3; m is 0, 1 or 2; n is 1, 2 or 3; o is 0, 1, or 2; X 1 , X 2 and X 3 are each independently selected from CH and N; Each U is independently -CH=, -CH2-, -NH- or -O-; Y 1 is methyl optionally substituted by 1 to 3 substituents, which may be the same or different and are each independently selected from -F and -Cl; Y 2 is hydrogen or deuterium; and Z is phenyl optionally substituted by 1 to 3 halogens; or Z is pyridyl optionally substituted by 1 to 3 substituents, which may be the same or different and are independently selected from -F, -Cl or -Br.

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

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II): in: R 1 is hydrogen; Each R 2 are independently -CH3, -CF3 or -C2H5; W 1 is -CH2-; W 2 is -CH=, -CH2- or -O-; W 3 is -CH=, -CH2-, -O- or -NH-; and p and q are each independently 0 or 1. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein p is 0 and q is 0. 5 . The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein p is 0 and q is 1. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein p is 1 and q is 1.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIIa): in: m is 0, 1 or 2; and o is 0, 1, or 2.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIIb): in: m is 0, 1 or 2; and o is 0, 1, or 2.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIIc): in: m is 0, 1 or 2; and o is 0, 1, or 2.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIId): in: m is 0, 1 or 2; and o is 0, 1, or 2.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIIe): in: m is 0, 1 or 2; and o is 0, 1, or 2.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIIf): in: m is 0, 1 or 2; and o is 0, 1, or 2.

13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIIg): in: m is 0, 1 or 2; and o is 0, 1, or 2.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IVa): in m is 0, 1 or 2; and o is 0, 1, or 2.

15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IVb): in m is 0, 1 or 2; and o is 0, 1, or 2.

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IVc): in m is 0, 1 or 2; and o is 0, 1, or 2.

17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IVd): in m is 0, 1 or 2; and o is 0, 1, or 2.

18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IVe): in m is 0, 1 or 2; and o is 0, 1, or 2.

19. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IVf): in m is 0, 1 or 2; and o is 0, 1, or 2.

20. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IVg): in m is 0, 1 or 2; and o is 0, 1, or 2.

21. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IVh): in m is 0, 1 or 2; and o is 0, 1, or 2.

22. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IVi): in m is 0, 1 or 2; o is 0, 1, or 2.

23. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IVj): in m is 0, 1 or 2; and o is 0, 1, or 2.

24. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein o is 0 or 1.

25. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein m is 0 and o is 0.

26. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein m is 1 and o is 0.

27. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein m is 2 and o is 0.

28. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein m is 0 and o is 1.

29. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R, which may be the same or different, 2 are independently -CH3 or -C2H5.

30. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is -F.

31. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y 1 It is -CH3 or -CH2F.

32. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is phenyl optionally substituted by 1 to 3 substituents, which substituents may be the same or different and are each independently selected from -F and -Cl.

33. The compound according to claim 32 or a pharmaceutically acceptable salt thereof, wherein Z is 34. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is 35. A compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein Y 1 is -CH3, and Z is 36. A compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein Y 1 is -CH3, and Z is 37. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

38. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

39. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 40. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 41. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 42. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 43. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

44. The pharmaceutical composition of claim 43, further comprising an additional therapeutic agent, wherein the additional therapeutic agent is an acetyl-CoA carboxylase (ACC) inhibitor, an apoptosis signal regulating kinase (ASK-1) inhibitor, a farnesoid X receptor (FXR) agonist, fish oil, a glucagon-like peptide 1 (GLP-1) receptor agonist, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, or a TGFβ antagonist.

45. Use of a compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 43 or 44, in the preparation of a medicament for treating, stabilizing, or reducing the severity or progression of a LPAR1-mediated disease or condition.

46. ​​The use according to claim 45, wherein the LPARl mediated disease or condition is selected from the group consisting of wound healing, cancer, pain, respiratory diseases, allergic diseases, nervous system diseases, cardiovascular diseases and inflammatory diseases.

47. The use according to claim 45 or 46, wherein the LPAR1 mediated disease or disorder is fibrosis.

48. The use according to claim 47, wherein the fibrosis is pulmonary fibrosis, renal fibrosis, liver fibrosis, ocular fibrosis, myocardial fibrosis or systemic sclerosis.

49. The use according to claim 48, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF) or progressive fibrosing interstitial lung disease (PF-ILD).

50. The use according to claim 48, wherein the pulmonary fibrosis is secondary to a systemic inflammatory disease.

51. The use according to claim 48, wherein the systemic inflammatory disease is rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrosing alveolitis, radiation fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, chronic asthma, silicosis, asbestos-induced pulmonary fibrosis or pleural fibrosis, acute lung injury or acute respiratory distress.

52. The use according to claim 48, wherein the renal fibrosis is associated with diabetic nephropathy.

53. The use according to claim 48, wherein the LPAR1 mediated disease or disorder is liver disease.

54. The use according to claim 53, wherein the liver disease is liver fibrosis.

55. The use according to claim 53, wherein the liver disease is non-alcoholic fatty liver disease (NAFLD).

56. The use according to claim 53, wherein the liver disease is steatosis.

57. The use according to claim 53, wherein the liver disease is non-alcoholic steatohepatitis (NASH).

58. The use according to claim 53, wherein the liver disease is cirrhosis.

59. The use according to claim 58, wherein the liver cirrhosis is compensated liver cirrhosis.

60. The use according to claim 58, wherein the liver cirrhosis is decompensated liver cirrhosis.

61. The use according to claim 53, wherein the liver disease is hepatocellular carcinoma (HCC).

62. The use according to claim 53, wherein the liver disease is primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC).

63. The use according to claim 53, wherein the liver disease is portal hypertension.

64. The use according to any one of claims 53-63, wherein the compound or a pharmaceutically acceptable salt thereof is administered in combination with an additional therapeutic agent, wherein the additional therapeutic agent is an acetyl-CoA carboxylase (ACC) inhibitor, an apoptosis signal regulating kinase (ASK-1) inhibitor, a farnesoid X receptor (FXR) agonist, fish oil, a glucagon-like peptide 1 (GLP-1) receptor agonist, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, or a TGFβ antagonist.

65. The use of claim 64, wherein the additional therapeutic agent is one, two, three or four additional therapeutic agents.

66. The use according to claim 64, wherein the ACC inhibitor is firsocostat.

67. The use according to claim 64, wherein the ASK-1 inhibitor is selosertin.

68. The use according to claim 64, wherein the FXR agonist is cilofexor.

69. The use according to claim 64, wherein the PPARα agonist is fibrate.

70. The use according to claim 64, wherein the fish oil is eicosapentaenoic acid ethyl ester.

71. The use according to claim 64, wherein the GLP-1 receptor agonist is liraglutide or semaglutide.

72. The use according to claim 64, wherein the TGFβ antagonist is an anti-TGFβ1 specific antibody.

73. The use according to claim 64, wherein the TGFβ antagonist is a TGFβ receptor.

74. The use according to claim 64, wherein the additional therapeutic agents are firsocostat and cilofexor.

75. The use according to claim 64, wherein the additional therapeutic agent is firsocostat and liraglutide or semaglutide.

76. The use of claim 64, wherein the additional therapeutic agent is fibrate or icosapent ethyl.

77. The use according to claim 64, wherein the additional therapeutic agent is cilofexor and liraglutide or semaglutide.

78. Use of a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating an ACC-mediated disease or condition.

79. The pharmaceutical composition of claim 44, wherein the additional therapeutic agent is one, two, three or four additional therapeutic agents.

80. The pharmaceutical composition of claim 44, wherein the ACC inhibitor is firsocostat.

81. The pharmaceutical composition of claim 44, wherein the ASK-1 inhibitor is selosertin.

82. The pharmaceutical composition of claim 44, wherein the FXR agonist is cilofexor.

83. The pharmaceutical composition of claim 44, wherein the PPARα agonist is fibrate.

84. The pharmaceutical composition of claim 44, wherein the fish oil is eicosapentaenoic acid ethyl ester.

85. The pharmaceutical composition of claim 44, wherein the GLP-1 receptor agonist is liraglutide or semaglutide.

86. The pharmaceutical composition according to claim 44, wherein the TGFβ antagonist is an anti-TGFβ1 specific antibody.

87. The pharmaceutical composition of claim 44, wherein the TGFβ antagonist is a TGFβ receptor.

88. The pharmaceutical composition of claim 44, wherein the additional therapeutic agents are firsocostat and cilofexor.

89. The pharmaceutical composition of claim 44, wherein the additional therapeutic agent is firsocostat and liraglutide or semaglutide.

90. The pharmaceutical composition of claim 44, wherein the additional therapeutic agent is fibrate or icosapent ethyl.

91. The pharmaceutical composition of claim 44, wherein the additional therapeutic agent is cilofexor and liraglutide or semaglutide.

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