Lpa receptor antagonists and uses thereof

Abstract

The present application relates to triazole derivatives of general formula (I) that bind to lysophosphatidic acid receptor 1 (LPAR1) and act as antagonists of LPAR1. These compounds can be used to treat diseases and / or conditions, including fibrosis and liver diseases, such as nonalcoholic steatohepatitis (NASH), interstitial lung disease (ILD), or chronic kidney disease (CKD), by binding to LPAR1.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 188,281, filed May 13, 2021, pursuant to 35 USC §119(e), the entire contents of which are incorporated herein by reference. Technical Field

[0002] This disclosure relates to compounds that bind to lysophosphatidylcholine (LPA) receptors (such as LPAR1) and act as their antagonists. This disclosure also relates to the use of these compounds for the treatment and / or prevention of diseases and / or conditions associated with one or more LPA receptors (e.g., LPAR1-related diseases or conditions). Background Technology

[0003] Lysophosphatidic acid (monoacyl-glycerol-3-phosphate, LPA) is a class of bioactive phospholipids that can be synthesized, for example, from lysophosphatidylcholine (LPC) via enzymatic autocrine motor factor production. A typical LPA has glycerol, an ester-linked fatty acid 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 arachidonicyl 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 their tissue distribution and downstream signaling pathways have been found to differ. These six LPA receptors are generally referred to interchangeably as LPAR1-6 (gene) or LPA1-6 (protein). It has been shown that LPA receptor-mediated signaling affects many biological processes, such as wound healing, immunity, carcinogenesis, angiogenesis, and neurogenesis.

[0004] In vivo studies involving LPA receptor-deficient mice or certain tool compounds have demonstrated the potential of LPA receptors as a potential drug target in a variety of diseases, including cancer, fibrosis, inflammation, pain, and cardiovascular disease. Recently, LPAR1 antagonists have been investigated clinically in conjunction with fibrotic disease states such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis.

[0005] However, there is still a need for LPA antagonists that have the desired selectivity, potency, metabolic stability, or reduced harmful effects. Summary of the Invention

[0006] This disclosure provides compounds that can be used as inhibitors of lysophosphatidylcholine receptor 1 (LPAR1). This disclosure also relates to the use of the compounds for treating and / or preventing diseases and / or conditions by means of the compounds binding to LPAR1.

[0007] In one embodiment, compounds of formula (I) are provided herein.

[0008]

[0009] Or its pharmaceutically acceptable salt.

[0010] in:

[0011] R 1 For hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 10-membered heterocyclic group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R... 1A Replace these R 1A They can be the same or different, where each R 1A Independently selected from halogen, cyano, nitro, oxo, C 1-4 Alkyl, C 3-10 Cycloalkyl groups, consisting of 3- to 10-membered heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6- to 10-membered aryl groups, consisting of 5- to 10-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; -N(R 1B1 (R) 1B2 ), -OR 1B1 -SR 1B1 , -C(O)N(R 1B1 (R) 1B2 ), -N(R 1B1 )C(O)R 1B2 , -N(R 1B1 )C(O)N(R 1B2 (R) 1B3 ), -S(O) 0-2 R 1B1 , -S(O)2N(R 1B1 (R) 1B2 ) and -N(R 1B1 )S(O)2R 1B2 , where each R 1B1 R 1B2 and R 1B3 Independently hydrogen, C1-6 Alkyl or C 3-6 cycloalkyl,

[0012] Each R 1A Alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 1 to 4 R groups. 1C Replace these R 1C They can be the same or different, and each of R... 1C Independently for C 1-4 Alkyl, halogen, cyano, -OR 1D1 or -N(R) 1D1 (R) 1D2 ), where each R 1D1 and R 1D2 Independently hydrogen or C 1-6 Alkyl, and

[0013] Each R 1B1 R 1B2 and R 1B3 Alkyl groups and cycloalkyl groups may optionally be substituted with one to three halogens; or

[0014] R 2 C is hydrogen or optionally substituted with 1 to 3 substituents. 1-6 Alkyl groups, wherein the substituents may be the same or different, and are independently selected from halogens, cyano groups, and C6 groups. 1-4 Alkoxy and C 3-10 cycloalkyl; or

[0015] R 2 C is optionally substituted with 1 to 3 substituents 3-6 Cycloalkyl, wherein the substituents may be the same or different, and are independently selected from halogens, cyano groups, C... 1-4 Alkoxy and C 1-6 alkyl;

[0016] R 3 Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 3-6 cycloalkyl, -OR 3A1 and -N(R) 3A1 (R) 3A2 ), where C 1-6 The alkyl group is optionally substituted with 1 to 3 substituents, which may be the same or different, and are independently selected from C10. 1-4 Alkoxy and halogen, and each of the R... 3A1 and R 3A2 C is independently hydrogen or optionally substituted with 1 to 3 halogens. 1-3 Alkyl groups, these halogens may be the same or different;

[0017] Each R 4Independently selected from deuterium, halogens, and C 1-6 Alkyl, C 3-6 cycloalkyl, -OR 3A1 and -N(R) 4A1 (R) 4A2 ), where C 1-6 The alkyl group is optionally substituted with 1 to 3 substituents, which may be the same or different, and are independently selected from C10. 1-4 Alkoxy and halogen, and each of the R... 4A1 and R 4A2 C is independently hydrogen or optionally substituted with 1 to 3 halogens. 1-3 Alkyl groups, these halogens may be the same or different;

[0018] n is 0, 1, or 2;

[0019] R 5 C is optionally substituted with 1 to 3 substituents 1-6 Alkyl groups, these substituents may be the same or different, and are independently selected from halogens, cyano groups, C... 1-4 Alkoxy, -C(O)N(R) 5A1 ) and -N(R 5A1 (R) 5A2 ), where each R 5A1 and R 5A2 H and C independently 1-6 Alkyl or C 3-10 cycloalkyl; or

[0020] R 5 C 3-6 The cycloalkyl group or a 3- to 6-membered heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cycloalkyl group or heterocyclic group is optionally substituted by one to three substituents, which may be the same or different, and are independently selected from halogens, cyano groups, C... 1-4 Alkyl and C 1-4 Alkoxy;

[0021] Each Y 1 and Y 2 C is independently hydrogen, deuterium, or optionally substituted with 1 to 3 substituents. 1-6 Alkyl groups, wherein the substituents may be the same or different, and are independently selected from deuterium, halogen, cyano, C 2-3 alkynyl group, C 1-4 Alkoxy groups and -C(O)NH-(C 1-4 H 3-9 );as well as

[0022] Z is C 1-8 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 6-12The aryl group is a 3- to 12-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 12-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the alkyl, alkoxy, cycloalkyl, aryl, heterocyclic, or heteroaryl group 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, 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 selected from C10. 1-4 Alkoxy and halogen; or

[0023] Y 1 Z and the carbon atoms they are attached to form C. 3-6 cycloalkyl, C 6-12 The aryl group is a 3- to 12-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 12-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally substituted by 1 to 3 substituents, which may be the same or different, and are 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 with 1 to 3 substituents, which may be the same or different, and are independently selected from C10. 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 independently selected from C10. 1-4 Alkyl, C 1-4 Alkoxy and halogen, and Y 2 It is either hydrogen or deuterium.

[0024] In some embodiments, pharmaceutical compositions are provided herein 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.

[0025] 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.

[0026] In some embodiments, this disclosure provides methods for inhibiting LPAR1 activity in a subject in need of it, methods comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of formula (I), (Ia), (II), or (IIa)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0027] In some embodiments, this disclosure provides methods for treating patients with LPAR1-mediated conditions, including administering to the patient a therapeutically effective amount of a compound provided herein (e.g., a compound of formula (I), (Ia), (II), or (IIa)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein. Detailed Implementation

[0028] This disclosure relates to LPA receptor antagonists, such as LPAR1 antagonists. This disclosure also relates to compositions and methods relating to LPAR1 antagonists, and the use of such compounds for the treatment and / or prevention of LPAR1-mediated diseases and conditions. This disclosure further relates to compositions and methods for the treatment and / or prevention of liver diseases, including combinations of LPAR1 antagonists with one or more additional therapeutic agents.

[0029] 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)) are generally considered to benefit from treatment with LPAR1 antagonists and optionally one or more additional therapeutic agents.

[0030] Definitions and general parameters

[0031] It should be understood in the following description that this disclosure is considered illustrative of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience and should not be construed as limiting the claims in any way. Embodiments exemplified under any heading may be combined with embodiments exemplified under any other heading.

[0032] Unless otherwise defined, 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 “an,” “a,” and “the” include plural references unless the context clearly specifies otherwise. Thus, for example, reference to “compound” includes a plurality of such compounds, and reference to “determination” includes reference to one or more determinations known to those skilled in the art and their equivalents, and so on.

[0033] As used in this specification, the following terms and phrases are generally intended to have the meanings described below, unless the context in which they are used indicates otherwise.

[0034] A dash ("-") not between two letters or symbols is used to indicate the attachment point of a substituent. For example, -CONH2 is attached via a carbon atom. A dash at the beginning or end of a chemical group is for convenience; a chemical group can be depicted without one or more dashes without losing its general meaning. A wavy line drawn through a line in the structure indicates the attachment point of a group. The order in which chemical groups are written or named does not indicate or imply directionality unless required by chemistry or structure. A solid line extending from the center of the ring indicates that the attachment point of a substituent on the ring can be at any ring atom. For example, R in the following structure... a It can be attached to any one of the five carbon ring atoms, or R a Hydrogen atoms that can be replaced by those attached to nitrogen ring atoms:

[0035]

[0036] prefix "C" u-v "Indicates that the following groups have u to v carbon atoms. For example, "C 1-6 "Alkyl" indicates that the alkyl group has 1 to 6 carbon atoms. Similarly, the term "xy-membered" ring (where x and y are numerical ranges, such as "3- to 12-membered heterocyclic group") refers to a ring containing xy atoms (e.g., 3-12), of which up to 80% can be heteroatoms such as N, O, S, P, and the remaining atoms are carbon.

[0037] Furthermore, certain 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" group or "alkylenyl" group or "alkylyl group") and "arylene" groups ("arylene" group or "arylenyl" group or "arylyl group"), respectively.

[0038] The terms “compounds disclosed herein”, “compounds disclosed herein”, “compounds provided herein”, or “compounds described herein” refer to compounds of formula (I), (Ia), (II), or (IIa). Also included are specific compounds 1 to 66 provided herein (e.g., Examples 1 to 18).

[0039] The term "about" as used herein includes (and describes) embodiments relating to that value or parameter itself. In some embodiments, the term "about" includes an indicated amount ±10%. In other embodiments, the term "about" includes an indicated amount ±5%. In some other embodiments, the term "about" includes an indicated amount ±1%. Furthermore, the term "about X" includes a description of "X". Moreover, unless the context clearly specifies otherwise, the singular forms "a" and "the" include plural references. Thus, for example, reference to "compound" includes a variety of such compounds, and reference to "assay" includes reference to one or more assays and their equivalents known to those skilled in the art.

[0040] "Alkyl" refers to a saturated hydrocarbon chain that is unbranched or branched. As used herein, alkyl groups have 1 to 20 carbon atoms (i.e., C64-C ... 1-20 Alkyl groups, 1 to 8 carbon atoms (i.e., C64) 1-8 Alkyl groups, 1 to 6 carbon atoms (i.e., C64) 1-6 Alkyl groups, 1 to 4 carbon atoms (i.e., C46) 1-4 Alkyl group or 1 to 3 carbon atoms (i.e., C14) 1-3 Alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue with a specific number of carbons is named by a chemical name or identified by a molecular formula, it can encompass all positional isomers having that number of carbons; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0041] "Alkenyl" refers to a group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C24-C24-C24). 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 Alkenyl groups are aliphatic groups. Examples of alkenyl groups include vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0042] "Alkyne" refers to a group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C64-C ... 2-20 acetylsyl group), 2 to 8 carbon atoms (i.e., C64) 2-8 alkynyl group), 2 to 6 carbon atoms (i.e., C64) 2-6 (alkynyl group) 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.

[0043] "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.

[0044] "Acyl" refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of these can be optionally substituted, as defined herein. Examples of acyl groups include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0045] "Amino" refers to the -NR group. y R z , where R y and R z Independently selected from the group consisting of: hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic; each of which may optionally be substituted.

[0046] "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, aryl groups have 6 to 20 ring carbon atoms (i.e., C24 carbon atoms). 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl group or 6 to 10 carbon ring atoms (i.e., C46) 6-10 Aryl groups. Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthracene. However, aryl does not encompass heteroaryl groups as defined below or overlap with them in any way. If one or more aryl groups are fused with a heteroaryl ring, the resulting ring system is a heteroaryl ring.

[0047] "Cyano" or "formonitrile" refers to the -CN group.

[0048] "Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having a single ring or comprising multiple rings in fused, bridged, and spirocyclic systems. The term "cycloalkyl" includes a cycloalkenyl group (i.e., a cyclic group having at least one double bond). As used herein, cycloalkyl groups have 3 to 20 cyclic carbon atoms (i.e., C64 carbon atoms). 3-20 cycloalkyl groups), 3 to 12 cyclic carbon atoms (i.e., C12)3-12 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C1456) 3-10 cycloalkyl groups), 3 to 8 cyclic carbon atoms (i.e., C14 and C24) 3-8 cycloalkyl groups or 3 to 6 cyclic carbon atoms (i.e., C164-C ... 3-6 (Cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0049] "Fusing" refers to the bonding of one ring with an adjacent ring. In some embodiments, the fused ring system is a heterocyclic group. In some embodiments, the fused ring system is an oxabiscyclohexyl group. In some embodiments, the fused ring system is...

[0050] "Bridged" refers to ring fusion in which non-adjacent atoms on the ring are linked by a divalent substituent (such as an alkylene group, an alkylene group containing one or two heteroatoms) or a single heteroatom. Quinine cycloyl and adamantyl are examples of bridged ring systems. In some embodiments, the bridged ring is a bicyclopentyl (bicyclo[1.1.1]pentyl) or a bicyclooctyl (bicyclo[2.2.2]octyl). In some embodiments, the bridged ring is...

[0051] "Spiro" refers to a cyclic substituent linked by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, wherein cyclopentane and piperidine are spiro-substituents. In some embodiments, the spiro-substituent is spiropentyl (spiropentyl), spirohexyl, spiropentyl, or spiropentyl. In some embodiments, the spiro-substituent is...

[0052] "Halogen" or "halogen group" includes fluorine, chlorine, bromine and iodine.

[0053] "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, heteroaryl groups comprise 1 to 20 carbon ring atoms (i.e., C14-C2 ... 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 (Heteroaryl); and 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purine, pyridinyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass or overlap with aryl as defined above.

[0054] The term "heterocyclic group" or "heterocycle" refers to a non-aromatic cyclic alkyl group in which one or more cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, unless otherwise indicated, "heterocyclic group" or "heterocycle" refers to a saturated or partially saturated ring; for example, in some embodiments, "heterocyclic group" or "heterocycle" refers to a partially saturated ring under specified conditions. The term "heterocyclic group" or "heterocycle" includes a heterocyclic alkenyl group (i.e., a heterocyclic group having at least one double bond). A heterocyclic group can be a single ring or multiple rings, wherein the multiple rings can be fused, bridged, or spirocyclic. As used herein, a heterocyclic group has 2 to 20 carbon ring atoms (i.e., C64 carbon atoms). 2-20 Heterocyclic groups), 2 to 12 carbon ring atoms (i.e., C 2-12 Heterocyclic group), 2 to 10 carbon ring atoms (i.e., C 2-10 Heterocyclic group), 2 to 8 carbon ring atoms (i.e., C 2-8 Heterocyclic groups), 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 Heterocyclic group; having 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 cyclic heteroatoms independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, oxobutyl, dioxopentyl, azirrobutyl, and morpholinyl. As used herein, the terms “heterocyclic,” “heterocyclic group,” and “heterocyclic” are used interchangeably.

[0055] A hydroxyl group ("Hydroxy" or "hydroxyl") refers to the -OH group.

[0056] "Oxide group" refers to a group (=O) or (O).

[0057] "Sulfonyl" refers to the group -S(O)2R c , where R c It can be alkyl, heterocyclic, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl groups are methanesulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0058] Unless otherwise stated, whenever the graphical representation of a group terminates at a single-bonded nitrogen atom, the group represents an -NH2 group. Similarly, unless otherwise expressed, hydrogen atoms are implied and assumed to be present where necessary, based on knowledge of valence or to provide stability by those skilled in the art.

[0059] The terms “optional” or “optionally” mean that the event or situation described below may or may not occur, and the description includes instances where said event or situation occurs and instances where said event or situation does not occur. Furthermore, the term “optionally substituted” means that any one or more hydrogen atoms on the specified atom or group may be substituted with portions other than hydrogen, or may not be substituted with portions other than hydrogen.

[0060] 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 substitution does not exceed the normal valence of the specified atom. Such one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidyl, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidinyl, haloyl, haloalkyl, heteroalkyl, heteroaryl, heterocyclic, hydroxyl, hydrazyl, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof. Polymers or similar indeterminate structures obtained by defining substituents with an unlimited number of further substituents (e.g., substituted aryl groups with substituted alkyl groups, which themselves are substituted by substituted aryl groups, which are further substituted by substituted heteroalkyl groups, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of successive substitutions in the compounds described herein is three. For example, the successive substitution of a substituted aryl group having two other substituted aryl groups is limited to ((substituted aryl)-substituted aryl)-substituted aryl. Similarly, the above definition is not intended to include unacceptable substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify chemical groups, the term "substituted" may describe other chemical groups as defined herein. For example, the term "substituted aryl" includes, but is not limited to, "alkylaryl". Unless otherwise stated, groups are described as optionally substituted, and any substituted elements of these groups are themselves unsubstituted.

[0061] In some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, halogen, amino, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups. In other embodiments, "substituted cycloalkyl" refers to a cycloalkyl group having one or more substituents, including alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, amino, alkoxy, halogen, oxo, and hydroxyl groups; "substituted heterocyclic" refers to a heterocyclic group having one or more substituents, including alkyl, amino, haloalkyl, heterocyclic, cycloalkyl, aryl, heteroaryl, alkoxy, halogen, oxo, and hydroxyl groups; "substituted aryl" refers to an aryl group having one or more substituents. The substituent group includes halogen, alkyl, amino, haloalkyl, cycloalkyl, heterocyclic, heteroaryl, alkoxy, and cyano; "substituted heteroaryl" refers to a heteroaryl group having one or more substituents, including halogen, amino, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkoxy, and cyano; and "substituted sulfonyl" refers to the group -S(O)2R, wherein R is substituted by one or more substituents, including alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituent may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclic, aryl, or heteroaryl, each of which is unsubstituted.

[0062] In some embodiments, the substituted cycloalkyl, substituted heterocyclic, substituted aryl, and / or substituted heteroaryl groups comprise cycloalkyl, heterocyclic, aryl, and / or heteroaryl groups having substituents on the ring atom, which are linked to the remainder of the compound. For example, in the following moiety, the cyclopropyl group is substituted with a methyl group:

[0063]

[0064] The disclosure described illustratively herein may be practiced appropriately in the absence of any one or more elements or limitations not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be understood broadly and without limitation. Furthermore, the terminology and expressions used herein have been used as descriptive rather than restrictive, and are not intended to exclude any equivalents or portions thereof of the features shown and described, but it should be recognized that various modifications are possible within the scope of this claimed disclosure.

[0065] The compounds of this 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 alkali or acid (including inorganic bases or inorganic acids and organic bases or organic acids). Where the compounds of this disclosure contain one or more acidic or basic groups, this disclosure also includes their corresponding pharmaceutically or toxicologically acceptable salts, particularly their pharmaceutically usable salts. Thus, compounds of this disclosure containing acidic groups may be present on these groups and may be used according to this disclosure as, for example, alkali metal salts, alkaline earth metal salts, or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts containing ammonia or organic amines (e.g., ethylamine, ethanolamine, triethanolamine), amino acids, or other bases known to those skilled in the art. Compounds of this disclosure containing one or more basic groups (i.e., protonable groups) may exist in the form of addition salts of inorganic or organic acids and may be used according to this disclosure. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, tertralic acid, diethylacetic acid, malonic acid, succinic acid, pimecrolic 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.

[0066] If the compounds of this disclosure contain both acidic and basic groups in their molecules, then in addition to the salt forms mentioned, this disclosure also includes internal salts or betaines (zwitterions). The corresponding salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting them with organic or inorganic acids or bases in a solvent or dispersant, or by anion or cation exchange with other salts.

[0067] This disclosure also includes all salts of the compounds disclosed herein, which are not directly applicable to pharmaceuticals due to low physiological compatibility, but may be used, for example, as intermediates in chemical reactions or for the preparation of pharmaceutically acceptable salts. Acids and bases that can be used to react with the compounds below 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 compounds below (after disclosure) are known to those skilled in the art and disclosed, for example, in Berge et al., Journal of Pharmaceutical Science, January 1977, Vol. 66, No. 1, and other sources.

[0068] Furthermore, the compounds disclosed herein can undergo tautomerism. Where tautomerism (e.g., keto-enol tautomerism) is possible in the compound or its prodrug, individual forms (e.g., keto and enol forms) and mixtures thereof in any ratio are within the scope of this disclosure. This also applies to stereoisomers, such as enantiomers, cis / trans isomers, diastereomers, conformational isomers, etc.

[0069] The term "protecting group" refers to a part of a compound that masks or alters the properties of a functional group or the compound as a whole. Chemical protecting groups and strategies used 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 contribute to the efficiency of desired chemical reactions, such as the orderly and planned formation and breaking of chemical bonds. The term "deprotection" refers to the removal of the protecting group.

[0070] Those skilled in the art will understand that when a list of alternative substituents includes members that cannot be used to substitute for a particular group due to their valence requirements or other reasons, the list is intended to be interpreted by those skilled in the art as including only those members suitable for substituting for a particular group.

[0071] Furthermore, the compounds disclosed herein may exist in the form of solvates, such as those including water as a solvate, or pharmaceutically acceptable solvates, such as alcohols, particularly ethanol. A “solvate” is formed through the interaction of a solvent and a compound.

[0072] In some embodiments, optical isomers, racemates, or other mixtures thereof of the compounds described herein, or pharmaceutically acceptable salts thereof, or mixtures thereof, are provided. If desired, the isomers can be separated by methods well known in the art, such as liquid chromatography. In these cases, the single enantiomer or diastereomer, i.e., the optically active form, can be obtained by asymmetric synthesis or by resolution. For example, resolution can be achieved by conventional methods, such as crystallization in the presence of a resolving agent, or chromatography using, for example, a chiral high-performance liquid chromatography (HPLC) column.

[0073] "Stereoisomers" are compounds composed of identical atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. This invention covers various stereoisomers and mixtures thereof, and includes "enantiomers," which are two stereoisomers whose molecules are mirror images of each other that cannot be superimposed. "Diabeta-isomeric" are stereoisomers having at least two asymmetric atoms but not being mirror images of each other.

[0074] In some embodiments, the compounds disclosed herein and their pharmaceutically acceptable salts may include asymmetric centers, and thus may produce enantiomers, diastereomers, and other stereoisomers that can be defined by absolute stereochemistry as (R)- or (S)- or for amino acids as (D)- or (L)-. Some embodiments include all such possible isomers as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers can 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-performance liquid chromatography (HPLC). When the compounds described herein contain an alkene double bond or other geometrically asymmetric centers, and unless otherwise stated, the compounds are intended to include both E and Z geometric isomers.

[0075] The compositions provided herein, including the compounds described herein or their pharmaceutically acceptable salts, isomers, or mixtures, may comprise racemic mixtures or mixtures containing an enantiomer in excess of one enantiomer or a single diastereomer or a mixture of diastereomers. All such isomers of these compounds are expressly included herein as if each and every isomer were specifically and individually listed.

[0076] Any formula or structure given herein is intended to represent both the unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures described by the formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, isotopes of these elements. 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 isotope-labeled compounds disclosed herein, such as those containing radioactive isotopes such as 3 H, 13 C and 14C is incorporated. Such isotopically labeled compounds can be used 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 for radiation therapy of patients. The isotopically labeled compounds and their prodrugs of this disclosure can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents in the formulations or procedures disclosed in the examples and formulations described below.

[0077] This disclosure also includes “deuterated analogues” of the compounds disclosed herein, wherein one to n hydrogen atoms bonded to a carbon atom are replaced with deuterium, where n is the number of hydrogen atoms in the molecule. Such compounds may exhibit increased resistance to metabolism and are therefore used to extend the half-life of any compound of formula (I) when administered to mammals (e.g., humans). See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci. Vol. 5 (No. 12): pp. 524-527 (1984). Such compounds are synthesized by methods well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0078] The deuterium-labeled or substituted therapeutic compounds disclosed herein may possess beneficial DMPK (drug metabolism and pharmacokinetics) properties, which involve distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope (such as deuterium) can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dose requirements, and / or improved therapeutic index. 18 F-labeled compounds can be used in PET or SPECT studies.

[0079] The concentration of such heavier isotopes (particularly deuterium) can be defined by the isotope enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope means that atom represents any stable isotope. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," that position is understood to be hydrogen having its naturally occurring isotopic composition. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) means that deuterium is represented.

[0080] In addition, this disclosure provides pharmaceutical compositions comprising a compound of the present disclosure, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof, as an active ingredient, and a pharmaceutically acceptable carrier.

[0081] "Pharmaceutical composition" means one or more active ingredients, one or more inert ingredients constituting a carrier, and 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 compositions disclosed herein may cover any composition prepared by mixing at least one compound of this disclosure with a pharmaceutically acceptable carrier.

[0082] As used herein, “pharmaceutically acceptable carriers” include excipients or reagents that are harmless to the disclosed compound or its intended use, such as solvents, diluents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic and absorption-delaying agents, etc. Compositions for preparing pharmaceutically active substances using such carriers and reagents are 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 (edited by GS Banker and CTRhodes).

[0083] IC 50 "or "EC" 50 "The maximum expected effect" refers to the inhibitory concentration required to achieve 50% of the maximum expected effect. In many cases, the maximum expected effect in this paper is the inhibition of LPA-induced LPAR1 activation. This term is obtained using in vitro assays (such as calcium mobilization assays) that assess concentration-dependent inhibition of LPA-induced LPAR1 activity.

[0084] "Treatment" (or "treating") is a method used to achieve a beneficial or desired outcome, including clinical outcomes. Beneficial or desired clinical outcomes include one or more of the following: a) suppressing a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the severity of the disease or condition); b) slowing or halting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying its spread (e.g., metastasis of the disease or condition); and / or c) alleviating the disease, i.e., leading to the resolution of clinical symptoms (e.g., improving the disease state, providing partial or overall relief from the disease or condition, enhancing the effect of another medication, delaying the progression of the disease, increasing quality of life, and / or prolonging survival). In some implementations, the term "treatment" (or "treating") means administering a compound or pharmaceutically acceptable salt of formula (I), (Ia), (II), or (II) for the purpose of: (i) delaying the onset of a disease, i.e., preventing or delaying the development of clinical symptoms of the disease; (ii) suppressing the disease, i.e. preventing the development of clinical symptoms; and / or (iii) alleviating the disease, i.e. causing the reduction of clinical symptoms or their severity.

[0085] "Prevention" or "preventing" means any treatment of a disease or condition that prevents the development of clinical symptoms. In some implementations, the compound may be administered to subjects (including humans) who are at risk or have a family history of the disease or condition.

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

[0087] The term "therapeutic effective amount" or "effective amount" refers to an amount sufficient to achieve a therapeutic effect when administered to a subject, providing a therapeutic benefit such as improvement of symptoms or slowing disease progression. For example, a therapeutic effective amount may be an amount sufficient to alleviate symptoms of a disease or condition in response to an LPAR1 antagonist. Therapeutic effective amounts 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 route of administration, which can be readily determined by those skilled in the art.

[0088] List of abbreviations and acronyms

[0089] Abbreviation meaning

[0090] ACN or MeCN acetonitrile

[0091] aq. aqueous solution

[0092] Bn benzyl

[0093] COPD (Chronic Obstructive Pulmonary Disease)

[0094] DCM dichloromethane

[0095] DIEA N,N-Diisopropylethylamine

[0096] DMF N,N-dimethylformamide

[0097] DMSO (dimethyl sulfoxide)

[0098] DPPA (diphenyl azidophosphate)

[0099] EA (ethyl acetate)

[0100] EDTA (ethylenediaminetetraacetic acid)

[0101] ESI Electrospray Ionization

[0102] Et Ethyl

[0103] Et2O Diethyl ether

[0104] EtOAc (ethyl acetate)

[0105] h or hr hours

[0106] HBSS Hank balanced salt solution

[0107] HCC (hepatocellular carcinoma)

[0108] HPLC (High Performance Liquid Chromatography)

[0109] LCMS or liquid chromatography-mass spectrometry

[0110] LC / MS

[0111] LPA (lysophosphatidylcholine)

[0112] LPC lysophosphatidylcholine

[0113] Me methyl

[0114] MeOH (methanol)

[0115] MS mass spectrometry

[0116] m / z mass-to-charge ratio

[0117] NADPH (Nicotinamide-Adenine Dinucleotide Phosphate)

[0118] NAFLD (Non-alcoholic fatty liver disease)

[0119] NASH (Non-Alcoholic Steatohepatitis)

[0120] NMR (Nuclear Magnetic Resonance) spectroscopy

[0121] PBC (Primary Biliary Cirrhosis)

[0122] PE oil ether

[0123] PSC (Primary Sclerosing Cholangitis)

[0124] RPM (revolutions per minute)

[0125] RT or rt room temperature

[0126] sat. saturated

[0127] TEMPO 2,2,6,6-Tetramethylpiperidine-1-oxy

[0128] TFA (trifluoroacetic acid)

[0129] THF Tetrahydrofuran

[0130] T3P propanephosphonic anhydride

[0131] As used herein, “LPAR1 antagonist” refers to any agent capable of binding to and inhibiting LPAR1. LPAR1, also known as LPA1, is a GPCR that binds to the lipid signaling molecule lysophosphatidic acid (LPA). Exemplary reference sequences for 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 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., May 2011, Vol. 63, No. 5: pp. 1405-1415 or Swaney et al., J Pharmacol Exp Ther., March 2011, 336(3): 693-700.

[0132] As used herein, “ACC inhibitor” means any agent capable of binding to and inhibiting acetyl-CoA carboxylase (ACC). ACC inhibitors may act as inhibitors or partial inhibitors of ACC. Agents may 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 Nos. 8,969,557 and / or 10,208,063, both of which are incorporated herein by reference in their entirety.

[0133] As mentioned herein, an "ASK1 inhibitor" can be any agent capable of inactivating the apoptosis signal-regulated kinase 1 (ASK1) protein. The agent can be a chemical compound or a biomolecule (e.g., a protein or antibody). ASK1 protein activity can be measured using several different methods. For example, ASK1 protein activity can be determined based on the ability of the ASK1 protein to phosphorylate substrate proteins. Methods for identifying ASK1 inhibitors are known (see, for example, 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 threonine residues in the ASK1 protein corresponding to threonine 838 (T838) of the full-length human ASK1 protein or threonine 845 (T845) of the full-length mouse ASK1 protein). For example, when the ASK1 protein contains the full-length human ASK1 protein sequence, ASK1 inhibitors can attenuate phosphorylation at 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 phosphorylation levels.

[0134] 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 a bile acid receptor (BAR) or NR1H4 (nuclear receptor subfamily 1, H group, member 4) receptor. FXR agonists can act as agonists or partial agonists of FXR. The agent can be a chemical compound or a biomolecule (e.g., a protein or antibody). The activity of FXR agonists can be measured by several different methods, for example, in in vitro assays using a cell-free fluorescence resonance energy transfer (FRET) assay as described in Pellicciari et al., Journal of Medicinal Chemistry, 2002, Vol. 15, No. 45: pp. 3569-3572.

[0135] compound

[0136] In one embodiment, compounds of formula (I) are provided herein.

[0137]

[0138] Or its pharmaceutically acceptable salt.

[0139] in:

[0140] R 1 For hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 10-membered heterocyclic group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R... 1A Replace these R 1A They can be the same or different, where each R 1A Independently selected from halogen, cyano, nitro, oxo, C 1-4 Alkyl, C 3-10 Cycloalkyl groups, consisting of 3- to 10-membered heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6- to 10-membered aryl groups, consisting of 5- to 10-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; -N(R 1B1 (R) 1B2 ), -OR 1B1 -SR 1B1 , -C(O)N(R 1B1 (R) 1B2 ), -N(R 1B1 )C(O)R 1B2 , -N(R 1B1 )C(O)N(R 1B2 (R) 1B3 ), -S(O) 0-2 R 1B1 , -S(O)2N(R 1B1 (R) 1B2 ) and -N(R 1B1 )S(O)2R 1B2 , where each R 1B1 R 1B2 and R 1B3 Independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl,

[0141] Each R 1A Alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 1 to 4 R groups. 1C Replace these R1C They can be the same or different, and each of R... 1C Independently for C 1-4 Alkyl, halogen, cyano, -OR 1D1 or -N(R) 1D1 (R) 1D2 ), where each R 1D1 and R 1D2 Independently hydrogen or C 1-6 Alkyl, and

[0142] Each R 1B1 R 1B2 and R 1B3 Alkyl groups and cycloalkyl groups may optionally be substituted with one to three halogens; or

[0143] R 2 C is hydrogen or optionally substituted with 1 to 3 substituents. 1-6 Alkyl groups, these substituents may be the same or different, and are independently selected from halogens, cyano groups, C... 1-4 Alkoxy and C 3-10 cycloalkyl; or

[0144] R 2 C is optionally substituted with 1 to 3 substituents 3-6 Cycloalkyl, wherein the substituents may be the same or different, and are independently selected from halogens, cyano groups, C... 1-4 Alkoxy and C 1-6 alkyl;

[0145] R 3 Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 3-6 cycloalkyl, -OR 3A1 and -N(R) 3A1 (R) 3A2 ), where C 1-6 The alkyl group is optionally substituted with 1 to 3 substituents, which may be the same or different, and are independently selected from C10. 1-4 Alkoxy and halogen, and each of the R... 3A1 and R 3A2 C is independently hydrogen or optionally substituted with 1 to 3 halogens. 1-3 Alkyl groups, these halogens may be the same or different;

[0146] Each R 4 Independently selected from deuterium, halogens, and C 1-6 Alkyl, C 3-6 cycloalkyl, -OR 4A1 and -N(R) 4A1 (R) 4A2 ), where C 1-6The alkyl group is optionally substituted with 1 to 3 substituents, which may be the same or different, and are independently selected from C10. 1-4 Alkoxy and halogen, and each of the R... 4A1 and R 4A2 C is independently hydrogen or optionally substituted with 1 to 3 halogens. 1-3 Alkyl groups, these halogens may be the same or different;

[0147] n is 0, 1, or 2;

[0148] R 5 C is optionally substituted with 1 to 3 substituents 1-6 Alkyl groups, these substituents may be the same or different, and are independently selected from halogens, cyano groups, C... 1-4 Alkoxy, -C(O)N(R) 5A1 ) and -N(R 5A1 (R) 5A2 ), where each R 5A1 and R 5A2 H and C independently 1-6 Alkyl or C 3-10 cycloalkyl; or

[0149] R 5 C 3-6 The cycloalkyl group or a 3- to 6-membered heterocyclic group having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cycloalkyl group or heterocyclic group is optionally substituted by one to three substituents, which may be the same or different, and are independently selected from halogens, cyano groups, C... 1-4 Alkyl and C 1-4 Alkoxy;

[0150] Each Y 1 and Y 2 C is independently hydrogen, deuterium, or optionally substituted with 1 to 3 substituents. 1-6 Alkyl groups, wherein the substituents may be the same or different, and are independently selected from deuterium, halogen, cyano, C 2-3 alkynyl group, C 1-4 Alkoxy groups and -C(O)NH-(C 1-4 H 3-9 );as well as

[0151] Z is C 1-8 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 6-12The aryl group is a 3- to 12-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 12-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the alkyl, alkoxy, cycloalkyl, aryl, heterocyclic, or heteroaryl group 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, 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 selected from C10. 1-4 Alkoxy and halogen; or

[0152] Y 1 Z and the carbon atoms they are attached to form C. 3-6 cycloalkyl, C 6-12 The aryl group is a 3- to 12-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 12-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally substituted by 1 to 3 substituents, which may be the same or different, and are 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 with 1 to 3 substituents, which may be the same or different, and are independently selected from C10. 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 independently selected from C10. 1-4 Alkyl, C 1-4 Alkoxy and halogen, and Y 2 It is either hydrogen or deuterium.

[0153] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ia):

[0154]

[0155] Or its pharmaceutically acceptable salt.

[0156] In some embodiments of compounds of formula (I) or (Ia) or their pharmaceutically acceptable salts, R 2 It is hydrogen.

[0157] In some embodiments of compounds of formula (I) or (Ia) or their pharmaceutically acceptable salts, each Y 1 and Y 2C is independently hydrogen, deuterium, or optionally substituted with 1 to 3 substituents. 1-6 Alkyl groups, these substituents may be the same or different, and each is independently selected from halogens, cyano groups, C... 2-3 alkynyl group, C 1-4 Alkoxy groups and -C(O)NH-(C 1-4 H 3-9 ).

[0158] In some embodiments of compounds of formula (I) or (Ia) or their pharmaceutically acceptable salts, Y 1 C is optionally substituted with 1 to 3 substituents 1-4 Alkyl groups, these substituents may be the same or different, and each is independently selected from halogens, cyano groups, and C. 1-4 alkoxy groups, and Y 2 It is hydrogen.

[0159] In some embodiments of compounds of formula (I) or (Ia) or their pharmaceutically acceptable salts, Y 1 The methyl group is optionally substituted with 1 to 3 substituents, which may be the same or different and are each independently selected from -F, -Cl, -CN and -O-CH3.

[0160] In some embodiments of compounds of formula (I) or (Ia) or their pharmaceutically acceptable salts, Y 1 It is -CH3.

[0161] In some embodiments of compounds of formula (I) or (Ia) or their pharmaceutically acceptable salts, Y 2 It is hydrogen.

[0162] In some embodiments of compounds of formula (I) or (Ia) or their pharmaceutically acceptable salts, Z is a 5- or 6-membered heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl group is optionally substituted by 1 to 3 substituents, which may be the same or different, and are each independently selected from halogens and C. 1-4 alkyl.

[0163] In some embodiments of the compound of formula (I) or (Ia) or its pharmaceutically acceptable salt, Z is a pyridyl group optionally substituted with one or two substituents, each independently selected from -F and -Cl.

[0164] In some embodiments of compounds of formula (I) or (Ia) or their pharmaceutically acceptable salts, Z is...

[0165]

[0166] In some embodiments of compounds of formula (I) or (Ia) or their pharmaceutically acceptable salts, Y1 It is -CH3, and Z is

[0167]

[0168] In some embodiments of compounds of formula (I) or (Ia) or their pharmaceutically acceptable salts, R 5 C is optionally substituted with 1 to 3 substituents 1-6 Alkyl groups, these substituents may be the same or different, and are independently selected from halogens, cyano groups, C... 1-4 Alkoxy, -C(O)N(R) 5A1 ) and -N(R 5A1 (R) 5A2 ), where each R 5A1 and R 5A2 H and C independently 1-6 Alkyl or C 3-10 Cycloalkyl.

[0169] In some embodiments of compounds of formula (I) or (Ia) or their pharmaceutically acceptable salts, R 5 It is -CH3.

[0170] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II):

[0171]

[0172] Or its pharmaceutically acceptable salt.

[0173] In some embodiments, the compound of formula (I), (Ia), or (II), or a pharmaceutically acceptable salt thereof, is a compound of formula (IIa):

[0174]

[0175] Or a pharmaceutically acceptable salt thereof, wherein each R 4 They can be the same or different.

[0176] In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, R 1 To be arbitrarily assigned to 1 to 4 R 1A Replacement C 3-10 cycloalkyl groups, these R 1A They can be the same or different, where each R 1A Independently selected from halogen, cyano, oxo, nitro, C 1-4 Alkyl, C 3-10Cycloalkyl groups, consisting of 3- to 10-membered heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6- to 10-membered aryl groups, consisting of 5- to 10-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; -N(R 1B1 (R) 1B2 ), -OR 1B1 -SR 1B1 , -C(O)N(R 1B1 (R) 1B2 ), -N(R 1B1 )C(O)R 1B2 -NR 1B1 C(O)N(R 1B2 (R) 1B3 ), -S(O) 0-2 R 1B1 , -S(O)2N(R 1B1 (R) 1B2 ) and -N(R 1B1 )S(O)2R 1B2 , where each R 1B1 R 1B2 and R 1B3 Independently hydrogen, C 1-6 Alkyl or -C 3-6 cycloalkyl, wherein each R 1A Alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 1 to 4 R groups. 1C Replace these R 1C They can be the same or different, and each of R... 1C Independently for C 1-4 Alkyl, halogen, cyano, -OR 1D1 or -N(R) 1D1 (R) 1D2 ), where each R 1D1 and R 1D2 Independently hydrogen or C 1-6 Alkyl groups, and each R 1B1 and R 1B2 Alkyl and cycloalkyl groups may optionally be substituted with 1 to 3 halogens.

[0177] In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, R 1 It is cyclopropyl or cyclobutyl, each optionally surrounded by one or two R groups. 1A Replace these R 1A Independently selected from -F and phenyl, wherein each phenyl group is optionally surrounded by 1 to 4 R groups. 1C Replace these R 1C They can be the same or different, and each of R... 1CIndependently for C 1-4 Alkyl, halogen. In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, R 1 for

[0178] In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, R 1 C 3-10 Cycloalkyl group is C 5-10 Bicyclic cycloalkyl. In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, C 5-10 The bicyclic cycloalkyl group is C 5-8 Bridged bicyclic cycloalkyl groups.

[0179] In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, C 5-8 The bridged bicyclic cycloalkyl group is a bicyclopentyl group, each optionally substituted with 1 to 3 substituents, which may be the same or different, and are each independently selected from -F, -Cl, -CN, -CH3, -CH2-OH, -CHF2, -CF3, -O-CH3, -CO2-CH3, -SO2-CH3, and phenyl. In some embodiments of the compounds of formulas (I), (Ia), (II), and (IIa) or their pharmaceutically acceptable salts, C 5-8 Bridged bicyclic cycloalkyl groups are

[0180] In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, R 1 To be arbitrarily assigned to 1 to 4 R 1A Substituted 3- to 10-membered heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; these R 1A They can be the same or different, where each R 1A Independently selected from halogen, cyano, oxo, nitro, C 1-4 Alkyl, C 3-10 Cycloalkyl groups, consisting of 3- to 10-membered heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6- to 10-membered aryl groups, consisting of 5- to 10-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; -N(R 1B1 (R) 1B2 ), -OR 1B1 -SR 1B1 , -C(O)N(R 1B1 (R)1B2 ), -N(R 1B1 )C(O)R 1B2 , -N(R 1B1 )C(O)N(R 1B2 (R) 1B3 ), -S(O) 0-2 R 1B1 , -S(O)2N(R 1B1 (R) 1B2 ) and -N(R 1B1 )S(O)2R 1B2 , where each R 1B1 R 1B2 and R 1B3 Independently hydrogen, C 1-6 Alkyl or -C 3-6 cycloalkyl, wherein each R 1A Alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 1 to 4 R groups. 1C Replace these R 1C They can be the same or different, and each of R... 1C Independently for C 1-4 Alkyl, halogen, cyano, -OR 1D1 or -N(R) 1D1 (R) 1D2 ), where each R 1D1 and R 1D2 Independently hydrogen or C 1-6 Alkyl, wherein each R 1B1 and R 1B2 The alkyl and cycloalkyl groups are optionally substituted with one to three halogens. In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, R 1 To be arbitrarily assigned to 1 to 4 R 1A Substituted tetrahydropyranyl groups, these R 1A They may be the same or different, and are each independently selected from -F, -Cl, -OH, -CN, -CH3, -CH2F, -CHF2, -CF3, and -O-CH3. In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or their pharmaceutically acceptable salts, R 1 for

[0181] In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, R 1 To be arbitrarily assigned to 1 to 4 R 1A These R-terminal compounds replace 6- to 10-membered aryl groups. 1A They can be the same or different, where each R 1AIndependently selected from halogen, cyano, oxo, nitro, C 1-4 Alkyl, C 3-10 Cycloalkyl groups, consisting of 3- to 10-membered heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6- to 10-membered aryl groups, consisting of 5- to 10-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; -N(R 1B1 (R) 1B2 ), -OR 1B1 -SR 1B1 , -C(O)N(R 1B1 (R) 1B2 ), -N(R 1B1 )C(O)R 1B2 , -N(R 1B1 )C(O)N(R 1B2 (R) 1B3 ), -S(O) 0-2 R 1B1 , -S(O)2N(R 1B1 (R) 1B2 ) and -NR 1B1 S(O)2R 1B2 , where each R 1B1 R 1B2 and R 1B3 Independently hydrogen, C 1-6 Alkyl or -C 3-6 cycloalkyl, wherein each R 1A Alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 1 to 4 R groups. 1C Replace these R 1C They can be the same or different, and each of R... 1C Independently for C 1-4 Alkyl, halogen, cyano, -OR 1D1 or -N(R) 1D1 (R) 1D2 ), where each R 1D1 and R 1D2 Independently hydrogen or C 1-6 Alkyl, wherein each R 1B1 and R 1B2 The alkyl and cycloalkyl groups are optionally substituted with one to three halogens. In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, R 1 To be arbitrarily assigned to 1 to 4 R 1A Substituted phenyl groups, these R 1A They can be the same or different, where each R 1A Independently selected from halogen, cyano, C 1-3 Alkyl, C 1-4An alkoxy group, a 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each alkyl, heterocyclic, and heteroaryl group is optionally surrounded by 1 to 4 R... 1C Replace these R 1C They can be the same or different, and each of R... 1C Independently cyano, halogen or C 1-4 Alkyl group. In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, R 1 To be arbitrarily assigned to 1 to 4 R 1A Substituted phenyl groups, these R 1A They can be the same or different, where each R 1A Independently selected from cyano, -CF3, -F, -Cl, morpholino, phenyl, pyridyl, and oxadiazolyl, wherein each morpholino, phenyl, pyridyl, and oxadiazolyl is optionally surrounded by 1 to 4 R groups. 1C Replace these R 1C They can be the same or different, and each of R... 1C Independently cyano, halogen or C 1-4 Alkyl group. In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, R 1 for

[0182]

[0183] In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, R 1 To be arbitrarily assigned to 1 to 4 R 1A Substituted 5- to 10-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, these R 1A They can be the same or different, where each R 1A Independently selected from halogen, cyano, oxo, nitro, C 1-4 Alkyl, C 3-10 Cycloalkyl groups, consisting of 3- to 10-membered heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6- to 10-membered aryl groups, consisting of 5- to 10-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; -N(R 1B1 (R) 1B2 ), -OR 1B1 -SR 1B1 , -C(O)N(R 1B1 (R) 1B2 ), -N(R 1B1 )C(O)R1B2 , -N(R 1B1 )C(O)N(R 1B2 (R) 1B3 ), -S(O) 0-2 R 1B1 , -S(O)2N(R 1B1 (R) 1B2 ) and -NR 1B1 S(O)2R 1B2 , where each R 1B1 R 1B2 and R 1B3 Independently hydrogen, C 1-6 Alkyl or -C 3-6 cycloalkyl, wherein each R 1A Alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 1 to 4 R groups. 1C Replace these R 1C They can be the same or different, and each of R... 1C Independently for C 1-4 Alkyl, halogen, cyano, -OR 1D1 or -N(R) 1D1 (R) 1D2 ), where each R 1D1 and R 1D2 Independently hydrogen or C 1-6 Alkyl, wherein each R 1B1 and R 1B2 The alkyl and cycloalkyl groups are optionally substituted with one to three halogens. In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, R 1 Each can be arbitrarily assigned to 1 to 4 Rs 1A Substituted thiazolyl, oxazolyl, pyridyl, pyrimidinyl, or pyridazinyl groups, these R 1A They can be the same or different, where each R 1A Independently selected from halogen, cyano, oxo, C 1-4 Alkyl, C 3-10 Cycloalkyl groups, having 1 to 4 heterocyclic groups of 3 to 10 members independently selected from nitrogen and oxygen, -N(R 1B1 (R) 1B2 ), -0-R 1B1 and -S(O) 0-2 R 1B1 , where each R 1B1 and R 1B2 Independently hydrogen or C 1-6 Alkyl, wherein each R 1A Alkyl, cycloalkyl, and heterocyclic groups are optionally surrounded by 1 to 4 R groups. 1C Replace these R 1CThey can be the same or different, and each of R... 1C Independently for C 1-4 Alkyl, halogen, or cyano, wherein each R 1B1 and R 1B2 The alkyl and cycloalkyl groups are optionally substituted with one to three halogens. In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, R 1 for

[0184] In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, R 3 It is hydrogen.

[0185] In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, R 3 Selected from deuterium, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, -OR 3A1 and -N(R) 3A1 (R) 3A2 ), where C 1-6 The alkyl group is optionally substituted with 1 to 3 substituents, which may be the same or different, and are independently selected from C10. 1-4 Alkoxy and halogen, and each of the R... 3A1 and R 3A2 C is independently hydrogen or optionally substituted with 1 to 3 halogens. 1-4 Alkyl groups, these halogens may be the same or different. In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or their pharmaceutically acceptable salts, R 3 C is selected from halogens or optionally substituted with 1 to 3 halogens. 1-3 Alkyl group. In some embodiments, the halogen is -F. In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, R 3 Selected from -F, -Cl, -CH3 or -CF3.

[0186] In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, each R 4 Independently selected from deuterium, halogens, and C 1-6 Alkyl, C 3-6 cycloalkyl, -OR 4A1 and -N(R) 4A1 (R) 4A2 ), where C 1-6The alkyl group is optionally substituted with 1 to 3 substituents, which may be the same or different, and are independently selected from C10. 1-4 Alkoxy and halogen, and each of the R... 4A1 and R 4A2 C is independently hydrogen or optionally substituted with 1 to 3 halogens. 1-4 Alkyl groups, these halogens may be the same or different. In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or their pharmaceutically acceptable salts, each R 4 For halogens. In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, each R 4 -F. In some embodiments of the compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, n is 0, 1, or 2. In some embodiments of the compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, n is 0. In some embodiments of the compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, n is 1. In some embodiments of the compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, n is 2.

[0187] In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, R 6 It is hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 cycloalkyl, wherein C 1-4 The alkyl group is optionally substituted with 1 to 3 substituents, which may be the same or different, selected from C10. 1-4 Alkyl groups and halogens. In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or their pharmaceutically acceptable salts, R 6 It is a halogen. In some embodiments of compounds of formulas (I), (Ia), (II) and (IIa) or their pharmaceutically acceptable salts, -F or -Cl.

[0188] In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or pharmaceutically acceptable salts thereof, R 7 It is hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 cycloalkyl, wherein C 1-4 The alkyl group is optionally substituted with 1 to 3 substituents, which may be the same or different, selected from C10. 1-4Alkyl groups and halogens. In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or their pharmaceutically acceptable salts, R 7 It is hydrogen or halogen. In some embodiments of compounds of formulas (I), (Ia), (II), and (IIa) or their pharmaceutically acceptable salts, R 7 It can be hydrogen or -F.

[0189] In some embodiments, the compounds of formula (I), (Ia), (II), or (IIa), or their pharmaceutically acceptable salts, are selected from the group consisting of:

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196] Or its pharmaceutically acceptable salt.

[0197] In some embodiments, the compound of formula (I), (Ia), (II), or (IIa), or a pharmaceutically acceptable salt thereof, is:

[0198]

[0199] Or its pharmaceutically acceptable salt.

[0200] In some embodiments, the compound of formula (I), (Ia), (II), or (IIa), or a pharmaceutically acceptable salt thereof, is:

[0201]

[0202] Or its pharmaceutically acceptable salt.

[0203] In some embodiments, the compound of formula (I), (Ia), (II), or (IIa), or a pharmaceutically acceptable salt thereof, is:

[0204]

[0205] Or its pharmaceutically acceptable salt.

[0206] In some embodiments, the compound of formula (I), (Ia), (II), or (IIa), or a pharmaceutically acceptable salt thereof, is:

[0207]

[0208] Or its pharmaceutically acceptable salt.

[0209] In some embodiments, the compound of formula (I), (Ia), (II), or (IIa), or a pharmaceutically acceptable salt thereof, is:

[0210]

[0211] Or its pharmaceutically acceptable salt.

[0212] Pharmaceutical Compositions and Administration Methods

[0213] In addition, this disclosure provides pharmaceutical compositions comprising at least one compound of this disclosure as an active ingredient, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0214] The pharmaceutical compositions disclosed herein may additionally comprise one or more other compounds as active ingredients, such as prodrug compounds or other enzyme inhibitors.

[0215] 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 appropriate route in any given case will depend on the nature and severity of the condition being treated and the nature of the active ingredient. They are readily available in unit dosage forms and can be prepared by any of the methods well known in the pharmaceutical field.

[0216] In practical use, the compounds of this disclosure can be tightly blended with drug carriers as active ingredients using conventional drug formulation techniques. Depending on the desired formulation, such as oral or parenteral (including intravenous) administration, the carrier can take various forms. When preparing compositions for oral dosage forms, any commonly used drug medium can be used. In the case of oral liquid formulations (e.g., suspensions, elixirs, and solutions), carriers such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., can be used; or in the case of oral solid formulations (e.g., powders, hard capsules, soft capsules, and tablets), carriers such as starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc., are preferred, with solid oral formulations being generally preferred over liquid formulations.

[0217] Because of their ease of application, tablets and capsules represent the most advantageous form of oral dosage unit, in which case a solid drug carrier is used. If desired, tablets can be coated using standard aqueous or non-aqueous techniques. Such compositions and formulations 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% by weight. The amount of the active compound in the composition useful for such treatment ensures an effective dose. The active compound can also be administered, for example, as drops or sprays into the nose.

[0218] Tablets, pills, capsules, etc., may also contain binders such as gum arabic, gum arabic, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, or alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose, or saccharin. When the dosage unit is in capsule form, in addition to the above-mentioned materials, it may also contain a liquid carrier such as fatty oil.

[0219] Various other materials may exist as coatings or alter the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. In addition to the active ingredient, syrups or elixirs may also contain sucrose as a sweetener, methylparaben and propylparaben as preservatives, dyes, and flavorings (such as cherry or orange flavorings).

[0220] In some embodiments, the compounds disclosed herein can also be used as salts having various countercations to produce orally available formulations.

[0221] The compounds disclosed herein can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water appropriately mixed with a surfactant, such as hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. Under normal storage and use conditions, these formulations contain preservatives to prevent microbial growth.

[0222] Suitable drug forms for injectable applications include sterile aqueous solutions or dispersions and sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be a fluid sufficient for easy injection. It must be stable under manufacturing and storage conditions and must be protected against contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0223] Any suitable route of administration may be used to deliver an effective dose of the disclosed compound to mammals, particularly humans. For example, it may be administered orally, rectally, topically, parenterally, ocularly, pulmonaryly, or nasally. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc. In some embodiments, the disclosed compound is administered orally.

[0224] Reagent test kit

[0225] This document also provides kits comprising the compounds of this disclosure or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs thereof, and suitable packaging. In one embodiment, the kit further includes instructions for use. In one aspect, the kit comprises the compounds of this disclosure, or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs thereof, and a label and / or instructions for use of the compound in a therapeutic indication, including the diseases or conditions described herein.

[0226] This document also provides articles comprising the compounds described herein or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs thereof in suitable containers. Containers may be vials, wide-mouth bottles, ampoules, pre-loaded syringes, and intravenous bags.

[0227] Treatment methods and uses

[0228] This disclosure also relates to the use of the disclosed compounds for treating and / or preventing diseases and / or conditions by means of said compounds binding to LPAR1. This disclosure further relates to the use of said compounds in the preparation of medicaments for treating and / or preventing diseases and / or conditions by means of said compounds binding to LPAR1.

[0229] The drugs mentioned herein can be prepared by conventional methods, including combinations of compounds according to this disclosure and pharmaceutically acceptable carriers.

[0230] In some embodiments, this document provides a method for treating and / or preventing LPAR1-mediated diseases or conditions in patients in need, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (II), or (IIa) or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula (I), (Ia), (II), or (IIa) or a pharmaceutically acceptable salt thereof.

[0231] In some implementations, LPAR1-mediated diseases or conditions include those in which an absolute or relative excess of LPA is present and / or observed.

[0232] In some implementations, LPAR1-mediated diseases or conditions include fibrosis, wound healing, cancer, pain, respiratory diseases, allergic diseases, neurological diseases, cardiovascular diseases, or inflammatory diseases.

[0233] In some implementations, the LPAR1-mediated disease or condition is interstitial lung disease (ILD). In some implementations, interstitial lung disease (ILD) includes nonspecific interstitial pneumonia (NSIP), sarcoidosis, asbestosis, occupational exposure-related ILD, progressive fibrotic ILD, idiopathic interstitial pneumonia (IIP), connective tissue disease-related interstitial lung disease (CTD-ILD), rheumatoid arthritis-related ILD, scleroderma-related ILD, or extrinsic alveolitis.

[0234] In some implementations, the LPAR1-mediated disease or condition is chronic kidney disease (CKD). In some implementations, chronic kidney disease is complement glomerulonephropathy, membranous glomerulonephropathy, polycystic kidney disease, IgA nephropathy, focal segmental glomerulosclerosis (FSGS), or Alport syndrome.

[0235] In some implementations, LPAR1-mediated diseases or conditions include fibrosis. In some implementations, fibrosis includes pulmonary fibrosis, renal fibrosis, liver fibrosis, ocular fibrosis, or myocardial fibrosis.

[0236] In some implementations, LPAR1-mediated diseases or conditions include pulmonary fibrosis. In some implementations, pulmonary fibrosis includes idiopathic pulmonary fibrosis (IPF). In some implementations, pulmonary fibrosis includes progressive fibrotic interstitial lung disease (PF-ILD). In some implementations, pulmonary fibrosis includes pulmonary fibrosis secondary to systemic inflammatory diseases such as rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrotic 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 inhalation-induced).

[0237] In some implementations, LPAR1-mediated diseases or conditions include renal fibrosis. In some implementations, 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, allogeneic grafts, and Alport's glomerulonephritis; intestinal fibrosis, such as scleroderma and radiation-induced intestinal fibrosis.

[0238] In some implementations, LPAR1-mediated diseases or conditions include liver fibrosis. In some implementations, liver fibrosis includes cirrhosis, alcoholic liver fibrosis, nonalcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis, infection- or virus-induced liver fibrosis (e.g., chronic HCV infection), and autoimmune hepatitis.

[0239] In some implementations, LPAR1-mediated diseases or conditions include head and neck fibrosis, such as radiation-induced head and neck fibrosis.

[0240] In some embodiments, LPAR1-mediated diseases or conditions include, for example, corneal scarring resulting from LASIK (laser-assisted in situ keratomileusis), corneal transplantation, or trabeculectomy. In some embodiments, compounds of formula (I), (Ia), (II), or (IIa), or pharmaceutically acceptable salts thereof, are used to improve decreased corneal sensation due to corneal surgery (such as LASIK or cataract surgery), decreased corneal sensation due to corneal degeneration, and dry eye syndrome resulting therefrom. In some embodiments, compounds of formula (I), (Ia), (II), or (IIa), or pharmaceutically acceptable salts thereof, are used to treat or prevent ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis, and papillary conjunctivitis. In some embodiments, compounds of formula (I), (Ia), (II), or (IIa), or pharmaceutically acceptable salts thereof, are used to treat or prevent Sjögren's syndrome or inflammatory diseases accompanied by dry eye syndrome.

[0241] In some implementations, LPAR1-mediated diseases or conditions include another fibrotic condition, such as hypertrophic scars and keloids, such as burn-induced or surgical sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, mixed connective tissue disease, and Peroni's disease.

[0242] In some embodiments, LPAR1-mediated diseases or conditions include pain. In some embodiments, pain includes neuropathic pain. In some embodiments, pain includes acute pain. In some embodiments, pain includes chronic pain.

[0243] In some implementations, LPAR1-mediated diseases or conditions include cancer. In some implementations, cancers include ovarian cancer, colon cancer, prostate cancer, breast cancer, melanoma, head and neck cancer, colorectal cancer, and thyroid cancer. In some implementations, cancers include solid tumors, such as bladder tumors, intestinal tumors, brain tumors, breast tumors, endometrial tumors, heart tumors, kidney tumors, lung tumors, lymphoid tissue tumors (lymphoma), ovarian tumors, pancreatic or other endocrine organ (thyroid) tumors, prostate tumors, skin tumors (melanoma or basal cell carcinoma), or hematologic malignancies (such as leukemia) at any stage of the disease with or without metastasis.In some implementation schemes, cancers include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendiceal cancer, astrocytoma, atypical teratoma-like / rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brainstem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumor, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, and Ewing's sarcoma. Tumor family, ocular 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 carcinoma, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor (endocrine pancreas), Kaposi's sarcoma, renal cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphoblastic 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, cutaneous T-cell lymphoma. Neuroblastoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoma, Waldenstrom's macroglobulinemia, medulloblastoma, medullary epithelioma, melanoma, mesothelioma, oral cancer, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal carcinoma, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial carcinoma, ovarian germ cell tumors, low-grade ovarian tumors, pancreatic cancer, papillomatosis, parathyroid carcinoma, penile cancer, nasopharyngeal carcinoma, moderately differentiated pineal parenchymal tumors, pineal blastoma, and supratentorial primordial tumors. Ectodermal tumors, pituitary adenomas, plasmacytomas / multiple myeloma, pleural pulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma (renal carcinoma), retinoblastoma, rhabdomyosarcoma, salivary gland carcinoma, sarcoma, Ewing sarcoma family of tumors, sarcoma, Kaposi's, Cezari syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, supratentorial primitive neuroectodermal tumors, T-cell lymphoma, testicular cancer, laryngeal cancer, thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstmm macroglobulinemia, and nephroblastoma.

[0244] In some implementations, LPAR1-mediated diseases or conditions include respiratory diseases or allergic diseases. In some implementations, respiratory diseases or allergic diseases include asthma, peribronchial fibrosis, bronchiolitis obliterans, and chronic obstructive pulmonary disease (COPD). In some implementations, COPD includes chronic bronchiolitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or airway inflammation and cystic fibrosis. In some implementations, respiratory diseases include adult respiratory distress syndrome and allergic (exogenous) asthma, non-allergic (endogenous) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-induced asthma, exercise-induced asthma, carbon dioxide hyperventilation, childhood asthma attacks, adult asthma attacks, cough-variant asthma, occupational asthma, hormone-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, and hypoxia.

[0245] In some implementations, LPAR1-mediated diseases or conditions include neurological disorders. In some implementations, neurological disorders include Alzheimer's disease, cerebral edema, cerebral ischemia, stroke, multiple sclerosis, neuropathy, Parkinson's disease, neurological conditions discovered following blunt force trauma or surgical trauma (including postoperative cognitive impairment and spinal cord or brainstem injury), and neurological aspects of diseases (such as lumbar disc degeneration and sciatica).

[0246] In some implementations, LPAR1-mediated diseases or conditions include cardiovascular diseases. In some implementations, cardiovascular diseases include arrhythmias (atrial or ventricular arrhythmias, or both); atherosclerosis and its complications; angina pectoris; arrhythmias; myocardial ischemia; myocardial infarction; aortic aneurysm or vascular aneurysm; vasculitis; stroke; peripheral obstructive artery disease of a limb, organ, or tissue; ischemia-reperfusion injury to the brain, heart, or other organs or tissues; endotoxic shock, surgical shock, or traumatic shock; hypertension; valvular heart disease; heart failure; blood pressure abnormalities; shock; vasoconstriction (including migraine-related vasoconstriction); vascular abnormalities; and cardiovascular insufficiency limited to a single organ or tissue.

[0247] In some implementations, LPAR1-mediated diseases or conditions include pulmonary fibrosis, renal fibrosis, liver fibrosis, scarring, asthma, rhinitis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, interstitial pulmonary fibrosis, arthritis, allergies, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, pain, proliferative diseases, and inflammatory conditions.

[0248] In some embodiments, the LPAR1-mediated disease or condition is liver disease. In some embodiments, the liver disease is hepatitis C, hepatocellular carcinoma, familial mixed hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), progressive familial intrahepatic cholestasis, primary biliary cirrhosis (PBC), or primary biliary cirrhosis (PSC). In some embodiments, the liver disease is PSC. In some embodiments, the liver disease includes portal hypertension. In some embodiments, hepatocellular carcinoma includes hepatocellular carcinoma (HCC), cholangiocarcinoma, angiosarcoma, or hemangioendothelioma. In some embodiments, hepatocellular carcinoma includes HCC. In some embodiments, NAFLD includes steatosis. In some embodiments, NAFLD includes NASH. In some embodiments, NAFLD or NASH includes liver fibrosis. In some embodiments, NAFLD or NASH includes cirrhosis. In some embodiments, NAFLD or NASH includes compensated cirrhosis. In some embodiments, NAFLD or NASH includes decompensated liver fibrosis. In some embodiments, NAFLD includes HCC. In some implementations, liver disease is NASH.

[0249] In some embodiments, this document provides a method for treating and / or preventing NAFLD or NASH in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (II), or (IIa) or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula (I), (Ia), (II), or (IIa) or a pharmaceutically acceptable salt thereof. In some embodiments, NAFLD or NASH includes liver fibrosis. In some embodiments, NAFLD or NASH includes cirrhosis. In some embodiments, the cirrhosis is compensated cirrhosis. In some embodiments, the cirrhosis is decompensated cirrhosis. In some embodiments, NAFLD or NASH includes HCC.

[0250] In some embodiments, this document provides a method for preventing liver disease or condition in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (II), or (IIa) or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula (I), (Ia), (II), or (IIa) 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, the cirrhosis is compensated cirrhosis. In some embodiments, the cirrhosis is decompensated cirrhosis. In some embodiments, the liver disease or condition is HCC.

[0251] In some embodiments, this disclosure relates to the use of compounds of formula (I), (Ia), (II) or (IIa) or pharmaceutically acceptable salts thereof in the preparation of medicaments for the prevention and / or treatment of LPAR1-mediated diseases or conditions disclosed herein.

[0252] dose

[0253] The effective dosage of the active ingredient used can vary depending on the specific compound used, the administration method, the condition being treated, and the severity of the condition. Such dosages can be readily determined by those skilled in the art.

[0254] When treating or preventing LPAR1-mediated diseases or conditions to which the compounds of this disclosure are applicable, satisfactory results are generally obtained when the compounds of this disclosure are administered at a daily dose of about 0.1 mg to about 300 mg per kilogram of animal body weight. In some embodiments, the compounds of this disclosure are administered in a single daily dose or in divided doses two to six times daily 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 typically be about 0.1 mg to about 200 mg. This dosing regimen may be adjusted to provide the best therapeutic response. In some embodiments, the total daily dose is about 1 mg to about 900 mg, about 1 mg to about 800 mg, about 1 mg to about 700 mg, about 1 mg to about 600 mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 1 mg to about 20 mg, or about 1 mg to about 10 mg.

[0255] The compounds or compositions thereof of this application may be administered once, twice, three times, or four times daily using any of the suitable modes described above. Furthermore, administration or treatment with the compound may continue for multiple days; for example, for a treatment cycle, treatment typically continues for at least 7, 14, or 28 days. Treatment cycles typically alternate with rest periods of approximately 1 to 28 days, typically approximately 7 or 14 days, between cycles. In other embodiments, treatment cycles may also be continuous.

[0256] In some implementations, the method provided herein includes administering an initial daily dose of about 1 mg to 800 mg of the compound described herein to a subject, 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.

[0257] combination

[0258] In some embodiments, compounds of formula (I), (Ia), (II), or (IIa) provided herein, or pharmaceutically acceptable salts thereof, are administered in combination with one or more adjunctive therapeutic agents to treat or prevent the diseases or conditions disclosed herein. In some embodiments, the one or more adjunctive therapeutic agents are one, two, three, or four adjunctive therapeutic agents. In some embodiments, the one or more adjunctive therapeutic agents are one adjunctive therapeutic agent. In some embodiments, the one or more adjunctive therapeutic agents are two adjunctive therapeutic agents. In some embodiments, the one or more adjunctive therapeutic agents are three adjunctive therapeutic agents. In some embodiments, the one or more adjunctive therapeutic agents are four adjunctive therapeutic agents.

[0259] In some embodiments, the pharmaceutical compositions provided herein have a compound of formula (I), (Ia), (II), or (IIa) 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.

[0260] In some embodiments, the one or more adjunctive 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, and angiotensin II receptor agonists. AT-1 receptor antagonists, androgen receptor agonists, apoptosis signal-regulated kinase 1 (ASK1) inhibitors, ATP citrate lyase inhibitors, apolipoprotein C3 (APOC3) antagonists, autophagy protein regulators, autocrine motor factor inhibitors, Axl tyrosine kinase receptor inhibitors, Bax protein stimulants, bioactive lipids, calcitonin agonists, cannabinoid receptor regulators, cysteine ​​protease inhibitors, cysteine ​​protease-3 stimulants, cathepsin inhibitors (e.g., cathepsin B inhibitors), caveolin 1 inhibitors, CCR2 chemokine antagonists, CCR3 chemokine antagonists, CCR5 chemokine antagonists, CD3 antagonists, chloride channel stimulants, cholesterol solubilizers, CNR1 inhibitors, cyclin D1 inhibitors, cytochrome P450 7A1 inhibitors, cytochrome P450 CYP2E1 (CYP2E1) inhibitors, diacylglycerol O-acyltransferase 1 inhibitors (DGAT1) inhibitors, diacylglycerol O-acyltransferase 1 inhibitors (DGAT2) inhibitors, CXCR4 chemokine antagonists, dipeptidyl peptidase IV inhibitors, endothelial sialic acid protein modulators, endothelial nitric oxide synthase stimulators, eosinophil chemokine ligand inhibitors, extracellular matrix protein modulators, farnesoid X receptor agonists, fatty acid synthase inhibitors, FGF1 receptor agonists, fibroblast activating protein (FAP) inhibitors, and fibroblast growth factor receptor ligands (e.g., FG) inhibitors. F-15, FGF-19, FGF-21), fish oil, galactoglobulin-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) regulators, hepatitis C virus NS3 protease inhibitors, hepatocyte nuclear factor 4α regulators (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 receptors 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 modulators, microRNA-132 (miR-132) antagonists, microRNA-21 (miR-21) inhibitors, mitochondrial uncoupling agents, 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), niacin receptor 1 agonists, P2X7 purine receptor modulators, P2Y13 purine 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) 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) inhibitors, cytokine signaling. Inhibitor-1 stimulators, cytokine signaling inhibitor-3 stimulators, 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 (Tp12) kinase inhibitors, tyrosine kinase receptor modulators, GPCR modulators, nuclear hormone receptor modulators, WNT modulators, YAP / TAZ modulators, and human plasmin inhibitors.

[0261] Non-limiting examples of one or more additional therapeutic agents include:

[0262] ACE inhibitors, such as enalapril;

[0263] Acetyl-CoA carboxylase (ACC) inhibitors, such as NDI-010976 (firsocostat), DRM-01, gemcabene, PF-05175157, QLT-091382 or PF-05221304.

[0264] Acetyl-CoA carboxylase / diacylglycerol O acyltransferase 2 inhibitors, such as PF-07055341;

[0265] Acetaldehyde dehydrogenase inhibitors, such as ADX-629;

[0266] Adenosine receptor agonists, such as CF-102 (namodenoson), CF-101, CF-502 or CGS21680;

[0267] Adiponectin receptor agonists, such as ADP-355 or ADP-399;

[0268] Amyloidin / calcitonin receptor agonists, such as KBP-042 or KBP-089;

[0269] AMP-activated protein kinase stimulators, such as PXL-770 or O-304;

[0270] AMP kinase activators / ATP citrate lyase inhibitors, such as bempedoic acid (ETC-1002, ESP-55016);

[0271] AMP-activated protein kinase / endothelial nitric oxide synthase / NAD-dependent deacetylase sirtuin-1 stimulators, such as NS-0200 (leucine + metformin + sildenafil);

[0272] androgen receptor agonists, such as LPCN-1144;

[0273] Angiotensin II AT-1 receptor antagonists, such as irbesartan;

[0274] Angiopoietin-associated protein-3 inhibitors, such as IONIS-ANGPTL3-LRx;

[0275] Autocrine motor factor inhibitors, such as PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, AM-063, or BBT-877.

[0276] Axl tyrosine kinase receptor inhibitors, such as bemcentinib (BGB-324, R-428);

[0277] Bax protein stimulants, such as CBL-514;

[0278] Bioactive lipids, such as DS-102;

[0279] Cannabinoid receptor type 1 (CNR1) inhibitors, such as namacizumab, GWP-42004, REV-200, or CRB-4001;

[0280] Cysteine ​​protease inhibitors, such as emricasan;

[0281] Pan cathepsin B inhibitors, such as VBY-376;

[0282] Pan cathepsin inhibitors, such as VBY-825;

[0283] CCR2 / CCR5 chemokine antagonists, such as cenicriviroc, maraviroc, CCX-872, or WXSH-0213;

[0284] CCR2 chemokine antagonists, such as propargyl germanium;

[0285] CCR2 chemokine / angiotensin II AT-1 receptor antagonists, such as DMX-200 or DMX-250;

[0286] CCR2 / CCR5 chemokine antagonists and FXR agonists, such as LJC-242 (tropifexor + cenivriviroc); CCR3 chemokine antagonists, such as bertilimumab.

[0287] Chloride channel stimulants, such as cobiprostone or lubiprostone;

[0288] CD3 antagonists, such as NI-0401 (foralumab);

[0289] CXCR4 chemokine antagonists, such as AD-214;

[0290] Diacylacyltransferase 1 (DGAT1) inhibitors, such as GSK-3008356;

[0291] Diacylglycerol O-acyltransferase 1 (DGAT1) / cytochrome P450 2E1 inhibitor (CYP2E1), such as SNP-610;

[0292] Diacylacyltransferase 2 (DGAT2) inhibitors, such as IONIS-DGAT2Rx or PF-06865571;

[0293] Dipeptidyl peptidase IV inhibitors, such as linagliptin or evogliptin;

[0294] Eosinophil chemokine ligand inhibitors, such as bertilimab or CM-101;

[0295] Extracellular matrix protein regulators, such as CNX-024;

[0296] Farnesol 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;

[0297] Farnesol X receptor (FXR) / G protein-coupled bile acid receptor 1 (TGR5) agonists, such as INT-767;

[0298] Fatty acid synthase inhibitors, such as TVB-2640;

[0299] FGF receptor agonists / Klothoβ stimulators, such as BFKB-8488A (RG-7992);

[0300] Inhibitors of fibroblast growth factor 19 (rhFGF19) / cytochrome P450 (CYP) 7A1, such as NGM-282;

[0301] Fibroblast growth factor 21 (FGF-21) ligands, such as BMS-986171, BIO89-100, B-1344 or BMS-986036;

[0302] Fibroblast growth factor 21 (FGF-21) / glucagon-like peptide 1 (GLP-1) agonists, such as YH-25723 (YH-25724; YH-22241) or AKR-001;

[0303] Fish oil compositions, such as ethyl eicosapentaenoate.

[0304] Galactoglobulin-3 inhibitors, such as GR-MD-02, GB-1107 (Gal-300), or GB1211 (Ga1-400);

[0305] 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;

[0306] Glucocorticoid receptor antagonists, such as CORT-118335 (miricorilant);

[0307] Glucose 6-phosphate 1-dehydrogenase inhibitors, such as ST001;

[0308] G protein-coupled bile acid receptor 1 (TGR5) agonists, such as RDX-009 or INT-777;

[0309] Heat shock protein 47 (HSP47) inhibitors, such as ND-L02-s0201;

[0310] HMG CoA reductase inhibitors, such as atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin;

[0311] Hypoxia-inducible factor-2α inhibitors, such as PT-2567;

[0312] IL-10 agonists, such as pegylated ilo-10 interleukin (peg-ilodecakin);

[0313] Inhibitors of ileal sodium bile acid cotransporters, such as odevixibat (A-4250), volixibat potassium ethanolate hydrate (SHP-262), GSK2330672, CJ-14199, or elobixibat (A-3309).

[0314] Insulin sensitizers, such as KBP-042, MSDC-0602K, MSDC-5514, Px-102, RG-125 (AZD4076), VVP-100X, CB-4211 or ETI-101;

[0315] Insulin ligand / double-chain insulin receptor agonists, such as ORMD-0801;

[0316] Integrin antagonists, such as IDL-2965;

[0317] IL-6 receptor agonists, such as KM-2702;

[0318] Ketohexokinase (KHK) inhibitors, such as PF-06835919;

[0319] βKlotho(KLB)-FGF1c agonists, such as MK-3655 (NGM-313);

[0320] 5-Lipoxygenase inhibitors, such as tipelukast (MN-001) and DS-102 (AF-102);

[0321] Lipoprotein lipase inhibitors, such as CAT-2003;

[0322] LPL gene stimulators, such as alipogene tiparvovec;

[0323] Hepatic receptor X (LXR) modulators, such as PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965 or SR-9238;

[0324] Lysophosphatidylcholine-1 receptor antagonists, such as BMT-053011, UD-009 (CP-2090), AR-479, ITMN-10534, BMS-986020 or KI-16198;

[0325] Inhibitors of lysyl oxidase homology 2, such as simtuzumab or PXS-5382A (PXS-5338).

[0326] Macrophage mannose receptor 1 modulators, such as temannoxetine-Cy3 (Tc 99m temannoxetine);

[0327] Inhibitors of membrane copper amine oxidase (VAP-1), such as TERN-201;

[0328] MEKK-5 protein kinase (ASK-1) inhibitors, such as GS-4997, SRT-015 or GS-444217, GST-HG-151;

[0329] MCH receptor-1 antagonists, such as CSTI-100 (ALB-127158);

[0330] Methionine aminopeptidase-2 inhibitors, such as ZGN-839, ZGN-839 or ZN-1345;

[0331] Methyl CpG-binding protein 2 regulators, such as mercaptoethylamine;

[0332] Mitochondrial uncoupling agents, such as 2,4-dinitrophenol or HU6;

[0333] Mixed lineage kinase-3 inhibitors, such as URMC-099-C;

[0334] Myelin basic protein stimulants, such as olesoxime;

[0335] NADPH oxidase 1 / 4 inhibitors, such as GKT-831 or APX-311;

[0336] Nicotinic acid receptor 1 agonists, such as ARI-3037MO;

[0337] Nitazoxinide;

[0338] NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, such as KDDF-201406-03, NBC-6, IFM-514 or JT-194 (JT-349);

[0339] Nuclear receptor modulators, such as DUR-928 (DV-928);

[0340] P2X7 purine receptor modulators, such as SGM-1019;

[0341] P2Y13 purine receptor stimulators, such as CER-209;

[0342] PDE 3 / 4 inhibitors, such as tylucast (MN-001);

[0343] PDE 5 inhibitors, such as sildenafil or MSTM-102;

[0344] PDGF receptor β modulators, such as BOT-191 or BOT-509;

[0345] Peptidyl-prolyl cis-trans isomerase inhibitors, such as CRV-431 (CPI-432-32), NVP-018, or NV-556 (NVP-025);

[0346] Phenylalanine hydroxylase stimulants, such as HepaStem;

[0347] PPAR agonists (including PPARα agonists, PPARα / δ agonists, PPARα / δ / γ agonists, and PPARδ agonists), such as elafibranor (GFT-505), MBX-8025, deuterated pioglitazone R-enantiomer, pioglitazone, DRX-065, saroglitazar, or IVA-337; PPARα agonists, such as aluminum clofibrate, bezafibrate, ciprofibrate, fenofibrate, crifibrate, clofibrate, clobemide, fenofibrate, gemfibrozil, pemafibrate, ronifibrate, difibrate, and omega-3 fatty acids (fish oil, such as ethyl eicosapentaenoate). Or docosahexaenoic acid), pirinic acid, GW409544, AZ242, LY518674, NS-220, AVE8134, BMS-711939, alglitazar, muraglitzar or saroglitazar;

[0348] PPARα / δ agonists, such as erabenol;

[0349] PPARα / δ / γ agonists, such as lanifibranor;

[0350] PPARδ agonists, such as seladelpar;

[0351] Protease-activated receptor-2 antagonists, such as PZ-235;

[0352] Protein kinase modulators, such as CNX-014;

[0353] Rho-associated protein kinase (ROCK) inhibitors, such as REDX-10178 (REDX-10325) or KD-025;

[0354] Inhibitors of aminourea-sensitive amine oxidase / vascular adhesion protein-1 (SSAO / VAP-1), such as PXS-4728A;

[0355] S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, such as SL-891;

[0356] Sodium glucose transporter-2 (SGLT2) inhibitors, such as iprigliflozin, remogliflozin etabonate, ertugliflozin, dapagliflozin, tofogliflozin, or sotagliflozin;

[0357] SREBP transcription factor inhibitors, such as CAT-2003 or MDV-4463;

[0358] Stearoyl-CoA desaturase-1 inhibitors, such as eicosanoylaminocholanoic acid (aramchol);

[0359] Thyroid hormone receptor (THR) beta agonists, such as remetriom (MGL-3196), MGL-3745, or VK-2809;

[0360] TLR-2 / TLR-4 antagonists, such as VB-201 (CI-201);

[0361] TLR-4 antagonists, such as JKB-121;

[0362] Tyrosine kinase receptor modulators, such as CNX-025 or GFE-2137 (recycled nitrozonide);

[0363] GPCR modulators, such as CNX-023;

[0364] Nuclear hormone receptor modulators, such as Px-102;

[0365] Xanthine oxidase / uric acid anion exchanger 1 (URAT1) inhibitors, such as RLBN-1001 and RLBN-1127; and

[0366] Human plasmin inhibitors, such as lorazotide acetate (INN-202).

[0367] Additional non-limiting examples of the one or more additional therapeutic agents include:

[0368] ACE inhibitors, such as benazepril and imidapril;

[0369] Adenosine A3 receptor antagonists, such as FM-101;

[0370] Adropin stimulants, such as RBT-2;

[0371] Albumin modulators, such as SYNT-002;

[0372] Aldosterone / mineralocorticoid receptor antagonists, such as MT-3995;

[0373] Allogeneic bone marrow-derived mesenchymal stem cell therapy, such as ORBCEL-M;

[0374] Allogeneic adipose-derived stem cell therapies, such as Elixcyte TM ;

[0375] AMP-activated protein kinase stimulators / proprotein convertase PC9 inhibitors, such as O-304;

[0376] AMP-activated protein kinase stimulators, such as DZCY-01, MK-8722, and PXL-770;

[0377] Angiotensin II AT-1 receptor / CCR2 chemokine antagonists, such as DMX-200;

[0378] Angiotensin II AT-2 receptor agonists, such as MOR-107 and irbesartan;

[0379] Angiotensin II receptor antagonists, such as losartan;

[0380] Angiotensinogen ligand inhibitors, such as ALN-AGT;

[0381] Anti-C1 antibodies, such as BIVV-009 (sutimlimab);

[0382] Anti-CB1 antibodies, such as GFB-024;

[0383] Anti-CX3CR1 nanobodies, such as BI-655088;

[0384] Anti-IL-6 antibodies, such as COR-001;

[0385] Anti-VEGF-B antibodies, such as CSL-346;

[0386] APOA1 gene stimulators / protein 2 inhibitors containing bromine domains / protein 4 inhibitors containing bromine domains, such as apatalone.

[0387] Bone morphogenetic protein-7 ligand modulators, such as BMP-7;

[0388] Calcium channel inhibitors, such as TBN (xiaotongqin);

[0389] Cannabinoid CB1 receptor antagonists, such as JNJ-2463;

[0390] CB1 inverse agonists, such as CRB-4001;

[0391] Chymotrypsin inhibitors, such as flurfastat (BAY-1142524);

[0392] Cyclooxygenase 1 inhibitors, such as GLY-230;

[0393] Cyclooxygenase 2 / epoxide hydrolase inhibitors, such as COX-2 / soluble epoxide hydrolase;

[0394] Cytochrome P450 11B2 inhibitors, such as aldosterone synthase inhibitors;

[0395] Inhibitors of exonucleotide pyrophosphatase PDE-2, such as BLD-0409;

[0396] Endothelin ET-A / Endothelin ET-B receptor antagonists, such as aprocitentan;

[0397] Intestinal peptidase inhibitors, such as SCO-792;

[0398] Erythropoietin receptor antagonists, such as EPO-018B;

[0399] Farnesol X receptor agonists, such as LMB-763;

[0400] FGF / PDGF / β receptor antagonists / p38 MAP kinase inhibitors, such as pirfenidone;

[0401] GHR / IGF1 gene inhibitors, such as atesidorsen sodium;

[0402] GPR40 agonists / GPR84 antagonists, such as PBI-4050;

[0403] G protein β subunit inhibitors, such as galleon;

[0404] G protein-coupled receptor 84 regulators, such as PBI-4425;

[0405] Growth hormone ligands / growth hormone receptor agonists, such as Jintropin AQ TM ;

[0406] Growth hormone receptor agonists, such as LAT-8881;

[0407] Guanylate cyclase receptor agonists / guanylate cyclase stimulators, such as praliciguat;

[0408] Guanylate cyclase stimulants, such as MRL-001 and runcaciguat;

[0409] Heme oxygenase 1 regulators, such as RBT-1;

[0410] HIF prolyl hydroxylase inhibitors, such as TRGX-154;

[0411] Insulin sensitizers / kallikrein 1 modulators, such as DM-199;

[0412] Integrin α-V / β-3 antagonists, such as VPI-2690B;

[0413] Interleukin-33 ligand inhibitors, such as MEDI-3506;

[0414] Kelch-like ECH-related protein 1 regulators / nuclear factor erythroid 2-related factor 2 stimulators, such as SFX-01;

[0415] LDHA gene inhibitors, such as nedosiran;

[0416] 5-Lipooxygenase-activating protein inhibitors, such as AZD-5718;

[0417] Lysophosphatidylcholine-1 receptor antagonists, such as BMS-002 and EPGN-696;

[0418] Extracellular matrix phosphorylated glycoprotein regulators / phosphoprotein receptor agonists, such as TPX-200;

[0419] MEKK-5 protein kinase inhibitors, such as selosenoside;

[0420] Inhibitors of membrane copper amine oxidase, such as UD-014;

[0421] Intermediate factor ligand inhibitors, such as CAB-101;

[0422] Mineralocorticoid receptor antagonists, such as AZD-9977, esaxilone, feneperone, and KBP-5074;

[0423] Myosin 2 inhibitors, such as DeciMab TM ;

[0424] NADPH oxidase 1 inhibitors / NADPH oxidase 4 inhibitors, such as setanaxib;

[0425] NADPH oxidase inhibitors, such as APX-115;

[0426] NK1 receptor antagonists / κ opioid receptor agonists / μ opioid receptor antagonists, such as AV-104;

[0427] Nuclear factor erythroid 2-related factor 2 stimulators / TGFβ ligand inhibitors, such as CU01-1001;

[0428] Nuclear factor κB inhibitors, such as meflunidone and methylbardoxolone (NSC-713200);

[0429] PDE 4 inhibitors, such as ART-648 and PCS-499;

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

[0431] PDGF / VEGF receptor antagonists, such as ANG-3070;

[0432] PR84 antagonists / GPR40 (FFAR1) / GPR120 (FFAR4) agonists and partial activators of peroxisome proliferator-activated receptor (PPAR), such as PBI-4547;

[0433] PRKAA2 gene stimulators / AMPK activators, such as PF-06679142 and PF-06685249;

[0434] Cyclic prostaglandin (PGI2) agonists, such as YS-1402;

[0435] Protein C activators / glycoprotein Ib (GPIb) antagonists, such as AB-002;

[0436] Protein NOV homology regulators, such as BLR-200;

[0437] Inhibitors of protein tyrosine phosphatase-1B, such as MSI-1436;

[0438] Reactive oxygen species regulators and inhibitors, such as SUL-121;

[0439] Renin inhibitors, such as imarikiren hydrochloride;

[0440] Rho-associated protein kinase 2 inhibitors, such as ANG-4201 and RXC-007;

[0441] Sodium glucose transporter-2 inhibitors, such as canagliflozin, dapagliflozin propylene glycol, and empagliflozin;

[0442] Thromboxane A2 receptor antagonists / thromboxane synthesis inhibitors, such as SER-150;

[0443] Tissue transglutaminase inhibitors, such as ZED-1227;

[0444] TRP cation channel C5 inhibitors, such as GFB-887;

[0445] TRP cation channel C6 inhibitors, such as ALGX-2224;

[0446] Cell adhesion molecule inhibitors, such as glycoside bacterial adhesion antagonists;

[0447] Uric acid anion exchanger 1 (URAT1) / SLC22A12 inhibitors, such as velinoride (RDEA3170);

[0448] VIP 1 / VIP 2 receptor agonists, such as LBT-3627; and

[0449] Xanthine oxidase inhibitors, such as TMX-049 and TMX-049DN.

[0450] In some implementations, one or more adjunctive therapeutic agents are selected from A-4250, AC-3174, acetylsalicylic acid, AK-20, aripiprazole, AMX-342, AN-3015, eicosanoylaminocholanic acid, ARI-3037MO, ASP-8232, AZD-2693, bertilimab, anhydrous betaine, BI-1467335, BMS-986036, BMS-986171, BMT-053011, BOT-191, BTT-1023, CAT-2003, sinivirol, CBW-511, CER-209, CF-102, CGS21680, CNX-014, CNX-023, and CNX-02. 4. CNX-025, Cobiprostone, Colesvelam, Dapagliflozin, DCR-LIV1, Deuterated Pioglitazone R-enantiomer, 2,4-Dinitrophenol, DRX-065, DS-102, DUR-928, EDP-305, Erabenox (GFT-505), Enricafenone, Enalapril, Egliflozin, Igglitin, 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 Icosbutate (PRC-4016), Ethyl eicosapentaenoic acid, IMM-124-E, INT-767, INV-240, IONIS-DGAT2Rx, Epagliflozin, Irbesartan, Propargon, IVA-337, JKB-121, KB-GE-001, KBP-042, KD-025, M790, M780, M450, Metformin, Sildenafil, LC-280126, Linagliptin, Liraglutide, LJN-452 (Zopifexox), LM-011, LM-002 (CVI-LM-002), LMB-763, LYN-100, MBX-8025, MDV-4463. Mercaptoethylamine, MGL-3196, MGL-3745, MP-301, MSDC-0602K, Namasizozomab, NC-101, NDI-010976, ND-L02-s0201(BMS-986263), NGM-282, NGM-313, NGM-386, NGM-395, NP-160, Norursodeoxycholic acid, NVP-022, O-304, Obeticholic acid (OCA), 25HC3S, Olisoxoxicam, PAT-505, PAT-048, PBI-4547, Pegylated interleukin, Pioglitazone, Pirfenidone, PRI-724, PX20606, Px-102, PX-L603.PX-L493, PXS-4728A, PZ-235, RDX-009, Repaggliflozin Etoposide, RG-125 (AZD4076), RPI-500, Sarogligaza, Smegglutide, Simtuzumab, Sophormycin, Sopaggliflozin, Statins (Avastatin, Fluvastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin), Symbiotics, TCM-606F, TEV-45478, TQA-3526, Tylus The following are listed: MN-001, TLY-012, TRX-318, TVB-2640, UD-009, Ursodeoxycholic acid, VBY-376, VBY-825, VK-2809, Vimodil, Vocibart potassium ethoxide hydrate (SHP-626), VVP-100X, WAV-301, WNT-974, XRx-117, ZGN-839, ZG-5216, ZSYM-008, and ZYSM-007.

[0451] In some embodiments, the methods and pharmaceutical compositions provided herein comprise a therapeutically effective amount of an apoptosis signal-regulated 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), or (IIa) provided herein, or a pharmaceutically acceptable salt thereof.

[0452] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the ASK1 inhibitor is GS-4997 (selonsertib, SEL).

[0453] ASK1 inhibitors can be synthesized and characterized using methods known to those skilled in the art, such as those described in U.S. Patent Nos. 2007 / 0276050, 2011 / 0009410, and 2013 / 0197037.

[0454] 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), or (IIa) provided herein, or a pharmaceutically acceptable salt thereof.

[0455] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the ACC inhibitor is GS-0976 (filosocistat, FIR).

[0456] ACC inhibitors can be synthesized and characterized using methods known to those skilled in the art, such as those described in U.S. Patent Nos. 9,453,026 and 10,183,951.

[0457] 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 (filosoxat, FIR)), 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 PPAR agonist is a PPARα agonist. In some embodiments, the PPARα agonist is selected from aluminum clofibrate, bezafibrate, ciprofibrate, fenofibrate, crifibrate, clofibrate, clobemide, fenofibrate, gemfibrozil, pemafibrate, ronifibrate, difibrate, pirinic acid, GW409544, AZ 242, LY518674, NS-220, AVE8134, BMS-711939, agliflozil, mogliflozil, and salrogleeza. In some embodiments, the PPAR agonist (e.g., the PPARα agonist) is fibrate. In some embodiments, the PPAR agonist (e.g., the PPARα agonist) is fenofibrate. In some embodiments, the PPAR agonist is a PPARα / δ agonist (e.g., erabenol). In some embodiments, the PPAR agonist is a PPARα / δ / γ agonist (e.g., lanfebenol). In some embodiments, the PPAR agonist is a PPARδ agonist (e.g., celadepar). In some embodiments, the fish oil is an omega-3 fatty acid or docosahexaenoic acid. In some embodiments, the fish oil is ethyl eicosapentaenoate (e.g., ethyl eicosapentaenoate). ).

[0458] 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), or (IIa) provided herein, or a pharmaceutically acceptable salt thereof.

[0459] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the FXR agonist is GS-9674 (cilofexor, CILO).

[0460] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the FXR agonist is a compound having the following structure:

[0461]

[0462] Or its pharmaceutically acceptable salt.

[0463] 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 smegglutide. In some embodiments, the GLP-1 receptor agonist is smegglutide.

[0464] 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), or (IIa) provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the TGFβ antagonist is a TGFβ-specific antibody. TGFβ-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 is bound to a TGFβ potential related peptide (LAP) (e.g., 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 (i.e., independent of the expression of TGFδβ in a particular 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., a patient with hepatocellular carcinoma). In some embodiments, the TGFδβ antagonist blocks the activation of potential TGFβ (e.g., potential TGFβ1) via potential TGFβ-binding protein (LTBP). In some embodiments, the TGFβ antagonist blocks the activation of latent TGFβ (e.g., latent TGFβ1) via the glycoprotein-A repeat major protein (GARP), as described in, for example, 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-latent related peptide (LAP) antibody that specifically binds to the LAP-TGFβ complex. In some embodiments, the anti-LAP antibody specifically binds to the LAP-TGFβ complex in, for example, the extracellular matrix (ECM) of connective tissue in the liver. In some embodiments, the anti-LAP antibody specifically binds to the LAP-TGFβ complex on the surface of certain immunosuppressive cell types such as regulatory T cells (Tregs), tumor-associated macrophages, or myeloid-derived 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-TGFβ complex in any environment.In some embodiments, the anti-LAP antibody is a TLS-02 antibody. In some embodiments, the TGFβ antagonist comprises 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 containing a TGFβ receptor. For example, TGFβ antagonists containing a TGFβ receptor that can be used in conjunction with the compositions and methods provided herein have been described in PCT International Publications WO 2019 / 113123 A1 and WO 2019 / 113464A1.

[0465] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of an LPAR1 antagonist and an adjunct therapeutic agent selected from ACE inhibitors, adenosine A3 receptor antagonists, adropin stimulants, albumin modulators, aldosterone antagonists, AMP-activated protein kinase stimulants, angiotensin II AT-2 receptor agonists, angiotensin II receptor antagonists, angiotensinogen ligand inhibitors, APOA1 gene stimulants, apolipoprotein L1 modulators, bone morphogenetic protein-7 ligand modulators, protein 2 inhibitors containing brominated domains, protein 4 inhibitors containing brominated domains, calcium channel inhibitors, cannabinoid CB1 receptor antagonists, CB1 inverse agonists, CCR2 chemokine antagonists, chymotrypsin inhibitors, complement C1s component inhibitors, CX3CR1 chemokine antagonists, cyclooxygenase 1 inhibitors, cyclooxygenase 2 inhibitors, and cytochrome P450.11B2 inhibitors, exonucleotide pyrophosphatase PDE-2 inhibitors, endothelin ET-A receptor antagonists, endothelin ET-B receptor antagonists, intestinal peptidase inhibitors, epoxide hydrolase inhibitors, erythropoietin receptor antagonists, farnesol X receptor agonists, FGF receptor antagonists, free fatty acid receptor 1 agonists, GHR gene inhibitors, glycoprotein Ib (GPIb) antagonists, GPR40 agonists, GPR84 antagonists, G protein β subunit inhibitors, G protein-coupled receptor 120 agonists, G protein-coupled receptor 84 modulators, growth hormone ligands, growth hormone receptor agonists, guanylic acid. Cycloyl cyclase receptor agonists, guanylate cyclase stimulators, heme oxygenase 1 modulators, HIF prolyl hydroxylase inhibitors, IGF1 gene inhibitors, IgG receptor FcRn large subunit p51 modulators, IL-6 receptor antagonists, integrin α-V / β-3 antagonists, interleukin-33 ligand inhibitors, Kelch-like ECH-associated protein 1 modulators, LDHA gene inhibitors, 5-lipoxygenase activator protein inhibitors, lysophosphatidic acid-1 receptor antagonists, extracellular matrix phosphorylated glycoprotein modulators, membrane copper amine oxidase inhibitors, metaphase factor ligand inhibitors, mineralocorticoid receptor antagonists, myosin 2 inhibitors, NADPH oxidase 1 inhibitors, NADPH oxidase 4 inhibitors, NADPH oxidase inhibitors, NK1 receptor antagonists, nuclear factor erythroid 2-related factor 2 stimulators, nuclear factor κB inhibitors, κ opioid receptor agonists, μ opioid receptor antagonists, p38MAP kinase inhibitors, PDE4 inhibitors, PDGF receptor antagonists, PDGF receptor β modulators, phosphatidylcholine receptor agonists, PRKAA2 gene stimulators, proprotein convertase PC9 inhibitors, cyclic prostaglandin (PGI2) agonists, protein C activators, protein NOV homology modulators, protein tyrosine phosphatase-1B Inhibitors, reactive oxygen species regulator inhibitors, renin inhibitors, Rho-associated protein kinase 2 inhibitors, SLC22A12 inhibitors, sodium-glucose transporter-2 inhibitors, solute carrier family inhibitors, TGFβ ligand inhibitors, TGFβ receptor antagonists, thromboxane A2 receptor antagonists, thromboxane synthesis inhibitors, tissue transglutaminase inhibitors, TRP cation channel C5 inhibitors, TRP cation channel C6 inhibitors, tryptophanase inhibitors, nonspecific cell adhesion molecule inhibitors, uric acid anion exchanger 1 inhibitors, vasopressin V1a receptor antagonists, VEGF receptor antagonists, VIP 1 receptor agonists, VIP 2 receptor agonists, and xanthine oxidase inhibitors.

[0466] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of an LPAR1 antagonist and an adjunct therapeutic agent selected from VEGFR inhibitors, FGFR inhibitors, PDGFR inhibitors, autotoxin inhibitors, GPR84 agonists, PASK inhibitors, CFTR agonists, JAK1 inhibitors, ADAMTS5 inhibitors, TOL2 / 3 inhibitors, CTGF inhibitors, soluble PTX2, anti-galactoglobulin 3 antibodies, integrin α, etc. V -β6 / α V -β1 antagonists, JNK1 inhibitors, mineralocorticoid receptor antagonists, Nrf2 activators, chymotrypsin inhibitors, PDE inhibitors, NOX1 / 4 inhibitors, leukotriene / thromboxane receptor antagonists, SLC22A12 inhibitors, sGC inhibitors, and xanthine oxidase inhibitors.

[0467] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of an LPAR1 antagonist and an adjunct therapy selected from nintedanib, pirfenidone, perriluzumab, PRM-151, GB-0139, PLN-74809, CC-90001, fenelindone, BAY1142524, PCS-499, sitanaxib, SER150, RDEA3170, plascigut, TMX-049, GLPG1690, GLPG1205, GLPG1972, GLPG4059, GLPG2737, GLPG3970, and finortinib.

[0468] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of an LPAR1 antagonist and an adjunct therapy selected from A-717, ACF-TEI, alanyl-glutamine, ALLN-346, anti-SCF248 antibody, anti-TAGE monoclonal antibody, anti-TGFβ antibody, AST-120, BAY-2327949, BI-685509, DP-001, DZ-4001, GDT-01, LNP-1892, MEDI-8367, antisense oligonucleotide therapy targeting microRNA, MK-2060, MPC-300-IV, NAV-003, Neo-Kidney Augment TM (NKA), NP-135, NP-160, NP-251, NRF-803, PBI-4610, PHN-033, R-HSC-010, Tanshinone, SGF-3, SPD-01, Sugaheal variant, SZ-005, TCF-12, UMC119-06, VAR-400, Veverimer, VS-105, and XRx-221.

[0469] Example

[0470] The following embodiments are included to demonstrate specific implementations of this disclosure. Those skilled in the art will understand that the techniques disclosed in the following embodiments represent techniques that function adequately in the practice of this disclosure and can therefore be considered as specific patterns constituting its practice. However, those skilled in the art should understand that these embodiments are exemplary and not exhaustive. Many changes may be made to the specific implementations of the disclosure without departing from the spirit and scope of this disclosure and still obtaining similar or analogous results.

[0471] The compounds disclosed herein can be prepared using suitable materials according to the procedures and examples described below, and are further illustrated by the following specific examples. Furthermore, other compounds of this disclosure claimed herein can be readily prepared using the procedures described herein in conjunction with techniques common in the art. The examples further illustrate details for the preparation of the compounds of this disclosure. Those skilled in the art will readily understand that known variations of the conditions and methods of the following preparation procedures can be used to prepare these compounds. For the synthesis of compounds according to the embodiments described in this disclosure, examination of the structure of the compound to be synthesized will provide identification of each of the substituent groups. In some cases, given the examples herein, the identification of the final product through examination of the process may reveal the obvious identification of the starting material. The compounds can be isolated in the form of their pharmaceutically acceptable salts, such as those described above. The compounds described herein are generally stable and separable at room temperature and pressure.

[0472] The following describes the preparation of the compounds disclosed herein. Unless otherwise stated, variables have the same meaning as above. The examples presented below are intended to illustrate specific embodiments of this disclosure. Suitable starting materials, structural units, and reagents used in the synthesis described below are commercially available, for example, from AbovChem, Acros Organics, Astressch, Combi Blocks, Oakwood Chemical, or Sigma-Aldrich, or can be conventionally 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.

[0473] General Plan

[0474] Option A

[0475]

[0476] Scheme A provides a general synthesis of triazole carbamate heteroarylamides (VII). In the schemes disclosed herein, “A” can be a halogen, such as Cl, Br, or I. “W” can be a small alkyl group, such as methyl or ethyl. Step one describes the general synthesis of heteroaryl triazole carboxylic acids (III) via a cross-coupling reaction. The heteroaryl ester halide (I) can first be converted to the corresponding borate ester, such as pinacol borate, via Miyaura boronization, and then subjected to Suzuki reaction conditions with bromotriazole carboxylic acid (II) to provide the desired heteroaryl triazole carboxylic acid (III). Alternatively, bromotriazole carboxylic acid (II) can first be converted to an organozinc substance via lithium-halogen exchange and capture with zinc chloride. Next, Negishi cross coupling with the heteroaryl halide (I) provides the desired heteroaryl triazole carboxylic acid (III).

[0477] Step two describes the general synthesis of heteroaryltriazole carbamate (V). Heteroaryltriazole carboxylic acid (II) undergoes a Curtius rearrangement reaction upon treatment with diphenyl azidophosphate (DPPA) or alternatively with a solution of 1-propanephosphonic anhydride (T3P) and trimethyl azidosilane. The intermediate isocyanate is then captured with an alcohol (IV) to provide the desired heteroaryltriazole carbamate (V).

[0478] Step 3 describes the general synthesis of heteroaryltriazole carbamate (VI). Heteroaryltriazole carbamate (V) can be hydrolyzed by treatment with a base (such as sodium hydroxide or lithium hydroxide) to provide the corresponding heteroaryltriazole carbamate formic acid (VI).

[0479] Step four describes the general synthesis of triazole carbamate aryl and heteroaryl-amides (VII). Heteroaryl triazole carbamate formic acid (VI) can be treated with a combination of a standard peptide coupling agent (such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) or (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxyhexafluorophosphate (HATU)) and an amine to provide the corresponding triazole carbamate heteroaryl amide (VII). Alternatively, heteroaryl triazole carbamate formic acid (VI) can first be converted to an acyl chloride, for example, by treatment with a phosphoryl chloride, and then coupled with the desired amine to provide the corresponding triazole carbamate heteroaryl amide (VII).

[0480] Option B

[0481]

[0482] Scheme B provides a general alternative synthesis of heteroaryltriazole carbamate (VII). Step one describes the general synthesis of carbamate-containing bromotriazole (VIII). Bromotriazole carboxylic acid (II) undergoes a Curtius rearrangement reaction with diphenyl azidophosphate (DPPA) or alternatively with a solution of 1-propylphosphonic anhydride (T3P) and trimethyl azidosilane. The intermediate isocyanate is then captured with an alcohol (V) to provide the desired bromotriazole carbamate (VIII).

[0483] Step two describes the general synthesis of triazole carbamate aryl and heteroaryl esters or acids (V) via cross-coupling reactions. Bromotriazole carbamate (VIII) can first be converted to an organozinc compound via lithium-halogen exchange and capture with zinc chloride. Next, root-nose cross-coupling with a heteroaryl halide (I) provides the desired heteroaryl triazole carbamate (V). Alternatively, heteroaryl halide (I) can first be converted to a corresponding borate ester such as pinacol borate via Miyaura borylation, and then subjected to Suzuki reaction conditions with bromotriazole carbamate VIII to provide the desired heteroaryl triazole carbamate (V). In the case of Y = H, step three can be skipped.

[0484] Step 3 describes the general synthesis of heteroaryltriazole carbamate (VI). Heteroaryltriazole carbamate (V) can be hydrolyzed by treatment with a base (such as sodium hydroxide or lithium hydroxide) to provide the corresponding heteroaryltriazole carbamate formic acid (VI).

[0485] Step four describes the general synthesis of triazole carbamate aryl and heteroaryl-amides (VII). Heteroaryl triazole carbamate formic acid (VI) is treated with a combination of a peptide coupling agent (such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) or (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide (HATU)) and an amine to provide the corresponding triazole carbamate heteroaryl amide (VII). Alternatively, heteroaryl triazole carbamate formic acid (VI) can first be converted to an acyl chloride, for example, by treatment with a phosphoryl chloride, and then coupled with the desired amine to provide the corresponding triazole carbamate heteroaryl amide (VII).

[0486] Example 1: Preparation of 4-bromo-1-methyl-1H-1,2,3-triazol-5-carboxylic acid (intermediate 1) :

[0487]

[0488] Step 1: 4,5-Dibromo-2H-1,2,3-triazole

[0489] Bromine (2.8 mol) was added to an aqueous (600 mL) solution of 2H-1,2,3-triazole (1.4 mol) at 40 °C. The resulting mixture was stirred at 40 °C for 2 h. 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.

[0490] Step 2: 4,5-Dibromo-1-methyl-1H-1,2,3-triazole

[0491] Iodomethane (1.0 mol) was added to a mixture of 704 mmol of 4,5-dibromo-2H-1,2,3-triazole and 1.4 mol of K₂CO₃ in 1000 mL of THF. The mixture was stirred at room temperature for 12 h. The mixture was filtered and the filter cake was washed with ethyl acetate (2 × 500 mL). 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.

[0492] Step 3: 4-Bromo-1-methyl-1H-1,2,3-triazole-5-carboxaldehyde

[0493] Isopropyl magnesium chloride (252.0 mmol) was added to a THF (600 mL) solution of 168.0 mmol of 4,5-dibromo-1-methyl-1H-1,2,3-triazole at -10 °C. The mixture was stirred for 15 min, and DMF (840 mmol) was added. After 1 h, the mixture was treated with 250 mL of saturated ammonium chloride and extracted with DCM (2 × 350 mL). The combined organic matter was washed with 250 mL of brine, dried over Na2SO4, filtered, and concentrated to give 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxaldehyde.

[0494] Step 4: 4-Bromo-1-methyl-1H-1,2,3-triazol-5-carboxylic acid

[0495] Potassium persulfate (651 mmol) was added to a DMF (800 mL) solution of 4-bromo-1-methyl-1H-1,2,3-triazol-5-carboxaldehyde (536 mmol), and the resulting suspension was stirred overnight at room temperature. The mixture was diluted with H₂O (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 Na₂CO₃ (2 × 500 mL), and the aqueous phase was adjusted to pH 3 with 1N HCl. The precipitate was separated by filtration and dried under reduced pressure to give 4-bromo-1-methyl-1H-1,2,3-triazol-5-carboxylic acid (intermediate 1).

[0496] Example 2: (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)amino Preparation of formate ester (intermediate 2B) :

[0497]

[0498] Under an argon atmosphere, a solution of 4-bromo-1-methyl-1H-1,2,3-triazol-5-carboxylic acid (95 mmol), 50% 1-propanephosphonic anhydride solution (143 mmol) in DMF, and trimethylsilane azide (143 mmol) were suspended in THF (350 mL). Triethylamine (143 mmol) was added, and the resulting solution was stirred for 30 min. (R)-1-(2-chloropyridin-3-yl)ethanol-1-ol (143 mmol) was added, and the mixture was heated under reflux for 12 h, with an auxiliary bubbler connected to allow venting. The reaction mixture was cooled to room temperature, and THF was removed under vacuum. The resulting crude material was dissolved in 500 mL of ethyl acetate and extracted three times with 300 mL of water. The crude mixture was then dried over sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to obtain (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (intermediate 2B).

[0499] Example 3: (R)-1-(2-fluoropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)amino Preparation of formate (intermediate 2C) :

[0500]

[0501] 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)carbamate (intermediate 2B), (R)-1-(2-fluoropyridin-3-yl)ethanol-1-ol (143 mmol) was used instead of (R)-1-(2-chloropyridin-3-yl)ethanol-1-ol to obtain (R)-1-(2-fluoropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (intermediate 2C).

[0502]

[0503] Example 4: (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(5-(pyridin-4-ylcarbamoyl)pyridine) Synthesis of pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (compound 1)

[0504] Step 1: (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3- Preparation of triazol-4-yl)nicotinic acid methyl ester

[0505] (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (1.11 mmol) dissolved in tetrahydrofuran (8 mL) was cooled to -78 °C and treated with 1 M bis(trimethylsilyl)aminolithium solution (1.30 mmol). The reaction mixture was stirred at -78 °C for 15 min, and then 1.6 M n-butyllithium solution (2.40 mmol) was added. After stirring at -78 °C for another 30 min, 1.9 M zinc chloride solution (3.23 mmol) was added. The reaction mixture was warmed to room temperature after 5 min. Then methyl 6-bromonicotinic acid (1.11 mmol) was added to the reaction mixture, followed by XPhosPd G3 (0.118 mmol). The reaction mixture was heated at 70 °C for 2 h. After cooling to room temperature, the reaction mixture was quenched with 1 N HCl solution and extracted with ethyl acetate. The organic layer was then washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography to give (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinic acid methyl ester.

[0506] Step 2: (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3- Preparation of triazol-4-yl)nicotinic acid (intermediate 3A)

[0507] Methyl (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinic acid (0.432 mmol) dissolved in tetrahydrofuran (3 mL) was treated with 2 M lithium hydroxide solution (1.40 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate and washed with 1 N HCl solution. The organic layer was then washed with brine, dried over sodium sulfate, and concentrated to give crude (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinic acid (intermediate 3A).

[0508] Step 3: (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(5-(pyridin-4-ylcarbamoyl)pyridine) Preparation of pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Method A)

[0509] (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinic acid (0.0621 mmol) dissolved in dichloromethane (1 mL) was treated with pyridine-4-amine (0.159 mmol), HATU (0.106 mmol), and N,N-diisopropylethylamine (0.172 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated. The residue was purified by HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl(1-methyl-4-(5-(pyridin-4-ylcarbamoyl)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate. 1H NMR (400MHz, methanol-d4) δ9.15 (dd, J=2.4, 0.8Hz, 1H), 8.75-8.68 (m, 2H), 8.47-8.38 (m, 3H), 8.33 (s, 1H), 8.18 ( dd, J=8.4, 0.9Hz, 1H), 8.07 (d, J=18.7Hz, 1H), 7.47 (s, 1H), 6.1l (q, J=6.6Hz, 1H), 4.03 (s, 3H), 1.63 (s, 3H). LCMS m / z479.1M+1.

[0510] Example 5: Preparation of compounds 2 to 17

[0511] Compounds 2 to 17 are generally synthesized using methods A, B, or C according to step 4 of scheme B. For example, (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((3-chlorobicyclo[1.1.1]pent-1-yl)carbamoyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (compound 2) is prepared by method A as follows.

[0512]

[0513] (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinic acid (0.0745 mmol) dissolved in dichloromethane (1 mL) was treated with 3-chlorobicyclo[1.1.1]pentane-1-amine hydrochloride (0.149 mmol), HATU (0.149 mmol), and N,N-diisopropylethylamine (0.230 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated. The residue was purified by HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(((3-chlorobicyclo[1.1.1]pent-1-yl)carbamoyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (compound 2). 1H NMR (400MHz, methanol-d4) δ9.04-8.92 (m, 1H), 8.38-8.29 (m, 1H), 8.25 (dd, J=8.4, 2.2Hz, 1H), 8.06 (d, J=8.3Hz, 2H), 7.44 (s, 1H), 6.08 (q, J=6.6Hz, 1H), 4.00 (s, 3H), 2.54 (s, 6H), 1.61 (s, 3H). LCMS m / z 502.1 M+1.

[0514] According to step 4 of scheme B, compound 2-compound 17 (Table 1) is prepared similarly by reacting (intermediate 3A) (Example 5) with the reagent listed in Table 1 that replaces 3-chlorobicyclo[1.1.1]pentane-1-amine hydrochloride using the method described above.

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521] Example 6: (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-((3-cyanobicyclo[1.1.1]pentane-1- Synthesis of (18) carbamoyl (pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl) carbamate

[0522]

[0523] Step 1: 4-(5-(methoxycarbonyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-carboxylic acid

[0524] 4-Bromo-1-methyl-1H-1,2,3-triazol-5-carboxylic acid (49 mmol) was dissolved in 500 mL of tetrahydrofuran and immersed in a bath at -78 °C for 15 min. Under nitrogen atmosphere, a 1 M solution of bis(trimethylsilyl)aminolithium in tetrahydrofuran (53 mmol) was added dropwise over 15 min. A 2.5 M solution of n-butyllithium (102 mmol) in hexane was added dropwise over 20 min, and the mixture was stirred for another 1 h. A 1.9 M solution of zinc chloride (102 mmol) in 2-methyltetrahydrofuran was added dropwise over 15 min. The reaction mixture was heated to ambient temperature by immersion in a water bath and stirred for 30 min. The resulting mixture was bubbled with argon for 10 min, then methyl 6-bromopyridine-3-carboxylate (53 mmol) and a complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (5 mmol) were added. The reaction was heated at 75 °C for 5 h, then cooled to ambient temperature. The reaction was quenched with 100 mL of saturated sodium bicarbonate aqueous solution and 100 mL of water and stirred vigorously. 200 mL of MTBE was added dropwise, and the product was extruded. The product was filtered and washed with MTBE and water. The crude product was used for the next step without further purification.

[0525] Step 2: (R)-6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1, 2,3-Triazol-4-yl)nicotinic acid methyl ester

[0526] 11.6 mmol of 4-(5-(methoxycarbonyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-carboxylic acid was suspended in 100 mL of THF, and a 50% solution of 1-propanephosphonic anhydride (14.5 mmol) in THF, triethylamine (58 mmol), and trimethylsilane azide (10.4 mmol) were added to the reaction mixture. The resulting solution was stirred at room temperature for 30 min. The reaction was heated to 70°C and held for 30 min, and then (1R)-1-(2,5-difluoro-3-pyridyl)ethanol (23.2 mmol) was added at the same temperature. The reaction was heated at 70°C for 24 h. The reaction mixture was warmed and diluted with isopropyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, concentrated, and purified by silica gel chromatography.

[0527] Step 3: (R)-6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1, 2,3-Triazol-4-yl)nicotinic acid (intermediate 3B)

[0528] (R)-6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinic acid methyl ester (6.5 mmol) was dissolved in THF (25 mL), and 1 M NaOH (30 mL) was added, followed by vigorous stirring for 15 min. The reaction mixture was diluted with MTBE (25 mL) and the organic matter was discarded. The aqueous phase was then acidified with concentrated HCl until the pH was adjusted to 4. The resulting precipitate was filtered and dried under vacuum to provide the desired product (intermediate 3B).

[0529] Step 4: (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-((3-cyanobicyclo)) obtained by method A [1.1.1]Pent-1-yl)carbamoyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate

[0530] (R)-6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinic acid (0.25 mmol) dissolved in dichloromethane (3 mL) was treated with 3-aminobicyclo[1.1.1]pentane-1-carboxynitrile (0.32 mmol), HATU (0.37 mmol), and N,N-diisopropylethylamine (0.75 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated. The residue was purified by HPLC to provide the title compound. ¹H NMR (400 MHz, methanol-d⁴) δ 9.05–8.91 (m, ¹H), 8.35 (dd, J = 8.4, 2.2 Hz, ¹H), 8.15–8.00 (m, 2H), 7.88 (s, ¹H), 5.96 (q, J = 6.7 Hz, ¹H), 4.02 (s, 3H), 2.68 (s, 6H), 1.63 (s, 3H). LCMS m / z 495.1 M+1.

[0531] Example 7: Preparation of compounds 19 to 44

[0532] Compounds 19 to 44 are generally synthesized using methods A, B, or C according to step 4 of scheme A. For example, (R)-1-(2,5-difluoropyridin-3-yl)ethyl(1-methyl-4-(5-((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (compound 19) is prepared by method B as follows.

[0533]

[0534] (R)-6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinic acid (0.371 mmol) suspended in pyridine (3 mL) was treated with 2-(trifluoromethyl)pyridin-4-amine (0.493 mmol), followed by treatment with EDCI (0.742 mmol). The reaction mixture was heated at 50 °C overnight. The reaction mixture was concentrated. The residue was purified by HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl(1-methyl-4-(5-((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate. 1H NMR (400MHz, methanol-d4) δ9.13 (s, 1H), 8.65 (d, J = 5.6Hz, 1H), 8.43 (dd, J = 8.3, 2.2Hz, 1H), 8.33 (d, J = 2.0Hz, 1H), 8. 17 (d, J=8.4Hz, 1H), 8.06 (dd, J=5.7, 2.2Hz, 2H), 7.89 (s, 1H), 5.97 (q, J=6.6Hz, 1H), 4.03 (s, 3H), 1.64 (s, 3H). LCMS m / z 549.1 M+1.

[0535] According to step 4 of scheme A, compounds 19-44 (Table 2) were similarly prepared by reacting (intermediate 3B) (Example 6) with the reagents listed in Table 2 that replace 2-(trifluoromethyl)pyridine-4-amine using the method described above.

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546] Example 8: Preparation of compounds 45 to 54

[0547] Compounds 45 to 54 are generally synthesized according to scheme A using methods A, B, or C. For example, (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(1-methyl-4-(5-((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (compound 45) is prepared as follows.

[0548]

[0549] Step 1: (R)-6-(5-(((1-92-chloro-5-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H- 1,2,3-Triazol-4-yl)nicotinic acid methyl ester

[0550] 11.6 mmol of 4-(5-(methoxycarbonyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-carboxylic acid was suspended in 100 mL of THF, and a 50% solution of 1-propanephosphonic anhydride (14.5 mmol) in THF, triethylamine (58 mmol), and trimethylsilane azide (10.4 mmol) were added to the reaction mixture. The resulting solution was stirred at room temperature for 30 min. The reaction was heated to 70°C and held for 30 min, and then (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethanol-1-ol (23.2 mmol) was added at the same temperature. The reaction was heated at 70°C for 24 h. The reaction mixture was heated and diluted with isopropyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, concentrated, and purified by silica gel chromatography.

[0551] Step 2: (R)-6-(5-(((1-(2-chloro-5-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H- 1,2,3-Triazol-4-yl)nicotinic acid (intermediate 3C)

[0552] (R)-6-(5-(((1-(2-chloro-5-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinic acid methyl ester (6.5 mmol) was dissolved in THF (25 mL), and 1 M NaOH (30 mL) was added, followed by vigorous stirring for 15 min. The reaction mixture was diluted with MTBE (25 mL), and organic matter was discarded. The aqueous phase was then acidified with concentrated HCl until the pH was adjusted to 4. The resulting precipitate was filtered and dried under vacuum to provide the desired product.

[0553] Step 3: (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(1-methyl-4-(5-) ( (2-(trifluoromethyl)pyridine- 4-yl)carbamoyl)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Method C)

[0554] (R)-6-(5-(((1-(2-chloro-5-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinic acid (0.095 mmol) suspended in dichloromethane (1 mL) was treated with 2-(trifluoromethyl)pyridin-4-amine (0.123 mmol), followed by treatment with pyridine (0.496 mmol), and then phosphoryl chloride (0.235 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was quenched by slowly adding saturated sodium bicarbonate solution. It was then diluted with dichloromethane and the layers were separated. The organic layer was then washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by HPLC to give (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl(1-methyl-4-(5-((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate. 1H NMR (400MHz, methanol-d4) δ9.16 (d, J=2.3Hz, 1H), 8.65 (d, J=5.6Hz, 1H), 8.44 (dd, J=8.3, 2.3Hz, 1H), 8.36-8.23 (m, 2H ), 8.21-8.13 (m, 1H), 8.05 (dd, J=5.6, 2.1Hz, 1H), 7.89 (s, 1H), 6.06 (q, J=6.6Hz, 1H), 4.03 (s, 3H), 1.63 (s, 3H). LCMS m / z 565.1 M+1.

[0555] According to step 4 of scheme A, compounds 45-54 (Table 3) are prepared similarly by reacting (intermediate 3C) (Example 6) with the reagents listed in Table 2 that replace 2-(trifluoromethyl)pyridine-4-amine using methods A, B or C.

[0556]

[0557]

[0558]

[0559]

[0560] Example 9: Preparation of compounds 55 to 57

[0561] Compounds 55 to 57 are generally synthesized according to scheme B using methods A, B, or C. For example, (R)-1-(2-fluoropyridin-3-yl)ethyl(4-(5-((3-chlorobicyclo[1.1.1]pent-1-yl)carbamoyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (compound 55) is prepared as follows.

[0562]

[0563] Step 1: (R)-6-(5-(((1-(2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3- Triazol-4-yl)nicotinic acid methyl ester

[0564] (R)-1-(2-fluoropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (4.36 mmol) dissolved in tetrahydrofuran (30 mL) was cooled to -78 °C and treated with 1 M bis(trimethylsilyl)aminolithium solution (4.80 mmol). The reaction mixture was stirred at -78 °C for 15 min, and then 1.6 M n-butyllithium solution (9.12 mmol) was added. After stirring at -78 °C for another 30 min, 1.9 M zinc chloride solution (12.5 mmol) was added. The reaction mixture was warmed to room temperature after 5 min. Then methyl 6-bromonicotinic acid (4.17 mmol) was added to the reaction mixture, followed by XPhosPd G3 (0.443 mmol). The reaction mixture was heated at 70 °C for 1 h. After cooling to room temperature, the reaction mixture was quenched with 1 N HCl solution and extracted with ethyl acetate. The organic layer was then washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography to give (R)-6-(5-(((1-(2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinic acid methyl ester.

[0565] Step 2: (R)-6-(5-(((1-(2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3- Triazol-4-yl ) Nicotinic acid (intermediate 3D)

[0566] Methyl (R)-6-(5-(((1-(2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinic acid (0.157 mmol) was dissolved in THF (2 mL), and 2 M lithium hydroxide solution (0.500 mmol) was added. The mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 1 N HCl solution. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give crude (R)-6-(5-(((1-(2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinic acid.

[0567] Step 3: (R)-1-(2-fluoropyridin-3-yl)ethyl(4-(5-((3-chlorobicyclo[1.1.1]pent-1-yl)aminomethyl) Acyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate

[0568] (R)-6-(5-(((1-(2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinic acid (0.155 mmol) dissolved in dichloromethane (1 mL) was treated with 3-chlorobicyclo[1.1.1]pentane-1-amine hydrochloride (0.214 mmol), HATU (0.255 mmol), and N,N-diisopropylethylamine (0.459 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated. The residue was purified by HPLC to provide the title compound. 1HNMR (400MHz, methanol-d4) δ9.01-8.91 (m, 1H), 8.28 (d, J=8.5Hz, 1H), 8.16 (s, 1H), 8.07 (d, J =8.3Hz, 2H), 7.35 (s, 1H), 6.00 (q, J = 6.6Hz, 1H), 4.01 (s, 3H), 2.55 (s, 6H), 1.63 (s, 3H). LCMS m / z486.1M+1.

[0569] According to step 4 of scheme B, compounds 55-57 (Table 4) are prepared similarly by reacting (intermediate 3D) (Example 9) with the reagents listed in Table 4 that replace 3-chlorobicyclo[1.1.1]pentane-1-amine hydrochloride using methods A, B or C.

[0570]

[0571]

[0572] Example 10: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((3-chlorobicyclo[1.1.1]pent-1-yl)amino Synthesis of (formyl)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (compound 58)

[0573]

[0574] Step 1: (R)-6-(5- ( ((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3- Triazolyl-4-yl)-2-methylnicotinate methyl ester

[0575] (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (1.11 mmol) dissolved in tetrahydrofuran (7 mL) was cooled to -78 °C and treated with bis(trimethylsilyl)aminolithium solution (1.20 mmol). The reaction mixture was stirred at -78 °C for 15 min, and then n-butyllithium solution (2.24 mmol) was added. After stirring at -78 °C for another 30 min, zinc chloride solution (3.23 mmol) was added. The reaction mixture was warmed to room temperature after 5 min. Then methyl 6-bromo-2-methylnicotinate (1.09 mmol) was added to the reaction mixture, followed by XPhos Pd G3 (0.115 mmol). The reaction mixture was heated at 70 °C for 1 h. After cooling to room temperature, the reaction mixture was quenched with 1N HCl solution and extracted with ethyl acetate. The organic layer was then washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylnicotinic acid methyl ester.

[0576] Step 2: (R)-6-(5-(((-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3- Triazol-4-yl)-2-methylnicotinic acid

[0577] Methyl (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylnicotinic acid (0.302 mmol) was dissolved in THF (2 mL) and methanol (500 μL), and 2 M lithium hydroxide solution (0.960 mmol) was added. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated. The residue was diluted with ethyl acetate and washed with 1 N HCl solution. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give crude (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylnicotinic acid.

[0578] Step 3: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((3-chlorobicyclo[1.1.1]pent-1-yl)aminomethyl Acyl)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate

[0579] (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylnicotinic acid (0.098 mmol) dissolved in dichloromethane (1 mL) was treated with 3-chlorobicyclo[1.1.1]pentane-1-amine hydrochloride (0.214 mmol), HATU (0.162 mmol), and N,N-diisopropylethylamine (0.287 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated. The residue was purified by HPLC to provide the title compound. 1HNMR (400MHz, methanol-d4) δ 8.33 (s, 1H), 8.10-7.83 (m, 3H), 7.44 (s, 1H), 6.1l (d, J = 6.8Hz, 1H), 4.02 (s, 3H), 2.64 (s, 3H), 2.54 (s, 6H), 1.61 (s, 3H). LCMS m / z 516.1M+1.

[0580] Example 11: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((3-cyanobicyclo[1.1.1]pent-1-yl)amino Preparation of (-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (compound 59)

[0581]

[0582] Step 1: (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3- Triazol-4-yl)-5-fluoronicotinic acid

[0583] Under an argon atmosphere, (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (1.4 mmol) and 30 mL of THF were added to a 100 mL round-bottom flask, and the flask was cooled to -78 °C. While maintaining the temperature below -70 °C, LiHMDS (3.4 mL, 1 M in THF) was added dropwise, stirred for 5 min, and then added dropwise. nBuLi (2.3 mL, 2.5 M in hexane). After stirring for another 5 min, ZnCl2 (3.1 mL, 1.9 M in 2-Me-THF) was added dropwise. After the addition was complete, the reaction mixture was warmed to 0 °C in an ice / water bath and stirred for 10 min. Then, methyl 6-bromo-5-fluoronicotinic acid (3.1 mmol), (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (1.4 mmol) and Pd-Xphos G2 (0.28 mmol) were added to the reaction mixture, followed by heating at 65 °C for 2 h. The reaction was then cooled to room temperature, silica (15 wt.) was added, and the crude mixture was concentrated under vacuum to dryness, followed by purification by silica gel column chromatography (DCM / MeOH 0% to 25%). The purified material was then dissolved in 4 mL of THF, and 12 mL of 0.5 M NaOH solution was added and stirred for 1 h. After complete hydrolysis of the ester, the solution was acidified to pH 3 with 4 M HCl. The solution was then diluted with 20 mL of water and 20 mL of brine, and extracted three times with 30 mL of EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated under vacuum to dryness to obtain the desired acid.

[0584] Step 2: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((3-cyanobicyclo[1.1.1]pent-1-yl)amino (formyl)-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate

[0585] Add 0.17 mmol of 3-aminobicyclo[1.1.1]pentane-1-carboxynitrile and 0.17 mmol of N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride to a mixture of (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-5-fluoronicotinic acid (0.08 mmol) in pyridine (0.5 mL). Stir the reaction mixture magnetically for 2 h, then add water (1 mL) and purify the crude mixture by HPLC. 1H NMR (400MHz, methanol-d4) δ8.82 (t, J=1.6Hz, 1H), 8.51-8.25 (m, 1H), 7.99 (dd, J=10.9, 1. 8Hz, 2H), 7.46 (s, 1H), 6.03 (q, J=6.6Hz, 1H), 4.02 (s, 3H), 2.68 (s, 6H), 1.59 (s, 3H). LCMS m / z 511.079M+1.

[0586] Example 12: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(6-chloro-5-((3-fluorobicyclo[1.1.1]pent-1- Preparation of (compound 60) carbamate (pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate

[0587]

[0588] Step 1: (R)-2-chloro-6-(5-(((1-92-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H- 1,2,3-Triazol-4-yl)nicotinic acid

[0589] Under an argon atmosphere, (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (2.77 mmol) and 20 mL of THF were added to a 100 mL round-bottom flask, and the flask was cooled to -78 °C. While maintaining the temperature below -70 °C, LiHMDS (3.4 mL, 1 M in THF) was added dropwise, and the mixture was stirred for 5 min. Then, LiHMDS was added dropwise. n BuLi (2.4 mL, 2.5 M in hexane). After stirring for another 5 min, ZnCl2 (3.1 mL, 1.9 M in 2-Me-THF) was added dropwise. After the addition was complete, the reaction mixture was warmed to 0 °C in an ice / water bath and stirred for 10 min. Then methyl 6-bromo-2-chloronicotinate (2.77 mmol) and Pd-Xphos G2 (0.28 mmol) were added to the reaction mixture, followed by heating at 65 °C for 2 h. The reaction was then cooled to room temperature, silica (15 wt.) was added, and the crude mixture was concentrated under vacuum to dryness, followed by purification by silica gel column chromatography (DCM / MeOH 0% to 25%). The purified material was then dissolved in 4 mL of THF, and NaOH (12 mL, 0.5 M) solution was added and stirred for 1 h. After complete hydrolysis of the ester, the solution was acidified to pH 3 with 4 M HCl. The solution was then diluted with 20 mL of water and 20 mL of brine, and extracted three times with 30 mL of EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated under vacuum to dryness to obtain the desired acid.

[0590] Step 2: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(6-chloro-5-((3-fluorobicyclo[1.1.1]pent-1-yl)amino (pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate

[0591] Add 3-fluorobicyclo[1.1.1]pentane-1-amine (0.11 mmol) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.07 mmol) to a mixture of (R)-2-chloro-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinic acid (0.06 mmol) in pyridine (0.5 mL). Stir the reaction mixture magnetically for 2 h, then add water (1 mL) and purify the crude mixture by preparative HPLC. 1H NMR (400MHz, methanol-d4) δ 8.32 (d, J=4.6Hz, 1H), 8.22-7.83 (m, 3H), 7.45 (s, 1H), 6.13 (q, J=6.6Hz, 1H), 4.00 (s, 3H), 2.49 (d, J=2.1Hz, 6H), 1.63 (s, 3H). LCMS m / z 519.998M+1.

[0592] Example 13: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((3-cyanobicyclo[1.1.1]pent-1-yl)amino Preparation of (-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (compound 61)

[0593]

[0594] Step 1: (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3- Triazol-4-yl)-4-fluoronicotinic acid

[0595] Under an argon atmosphere, (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (1.4 mmol) and 10 mL THF were added to a 100 mL round-bottom flask, and the flask was cooled to -78 °C. While maintaining the temperature below -70 °C, LiHMDS (1.7 mL, 1 M in THF) was added dropwise, and the mixture was stirred for 5 min. Then, LiHMDS was added dropwise. nBuLi (1.2 mL, 2.5 M in hexane). After stirring for another 5 min, ZnCl2 (1.5 mL, 1.9 M in 2-Me-THF) was added dropwise. After the addition was complete, the reaction mixture was warmed to 0 °C in an ice / water bath and stirred for 10 min. Then methyl 6-chloro-4-fluoronicotinic acid (1.53 mmol) and Pd-Xphos G2 (0.1 mmol) were added to the reaction mixture, followed by heating at 65 °C for 2 h. The reaction was then cooled to room temperature, silica (15 wt.) was added, and the crude mixture was concentrated to dryness under vacuum, followed by purification by silica gel column chromatography (DCM / MeOH 0% to 25%). The purified material was then dissolved in 4 mL of THF, and NaOH (12 mL, 0.5 M) solution was added and stirred for 1 h. After complete hydrolysis of the ester, the solution was acidified to pH 3 with 4 M HCl. The solution was then diluted with 20 mL of water and 20 mL of brine, and extracted three times with 30 mL of EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated under vacuum to dryness to obtain the desired acid.

[0596] Step 3: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((3-cyanobicyclo[1.1.1]pent-1-yl)amino (formyl)-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate

[0597] Add 3-aminobicyclo[1.1.1]pentane-1-carboxynitrile (0.17 mmol) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 mmol) to a mixture of (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-4-fluoronicotinic acid (0.08 mmol) in pyridine (0.5 mL). Stir the reaction mixture magnetically for 2 h, then add water (1 mL) and purify the crude mixture by HPLC. ¹H NMR (400 MHz, methanol-d⁴): δ 8.79 (d, J = 10.0 Hz, ¹H), 8.44–8.22 (m, ¹H), 7.82 (d, J = 11.4 Hz, 2H), 7.46 (s, ¹H), 6.09 (q, J = 6.4 Hz, 1H), 3.99 (s, 3H), 2.68 (s, 6H), 1.61 (s, 3H). LCMS m / z 511.062 M⁺¹.

[0598] Example 14: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((3-cyanobicyclo[1.1.1]pent-1-yl)amino (-6-(trifluoromethyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (compound) Preparation of 62)

[0599]

[0600] Step 1: (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3- Triazol-4-yl)-2-(trifluoromethyl)nicotinic acid

[0601] Under an argon atmosphere, (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (2.77 mmol) and 20 mL of THF were added to a 100 mL round-bottom flask, and the flask was cooled to -78 °C. While maintaining the temperature below -70 °C, LiHMDS (3.4 mL, 1 M in THF) was added dropwise, and the mixture was stirred for 5 min. Then, LiHMDS was added dropwise. n BuLi (2.4 mL, 2.5 M in hexane). After stirring for another 5 min, ZnCl2 (3.1 mL, 1.9 M in 2-Me-THF) was added dropwise. After the addition was complete, the reaction mixture was warmed to 0 °C in an ice / water bath and stirred for 10 min. Then, methyl 6-chloro-2-(trifluoromethyl)pyridine-3-carboxylate (2.77 mmol) and Pd-Xphos G2 (0.28 mmol) were added to the reaction mixture, followed by heating at 65 °C for 2 h. The reaction was then cooled to room temperature, silica (15 wt.) was added, and the crude mixture was concentrated under vacuum to dryness, followed by purification by silica gel column chromatography (DCM / MeOH 0% to 25%). The purified material was then dissolved in 4 mL of THF, and NaOH (12 mL, 0.5 M) solution was added and stirred for 1 h. After complete hydrolysis of the ester, the solution was acidified to pH 3 with 4 M HCl. The solution was then diluted with 20 mL of water and 20 mL of brine, and extracted three times with 30 mL of EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated under vacuum to dryness to obtain the desired acid.

[0602] Step 2: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((3-cyanobicyclo[1.1.1]pentan-1-yl)amino (formyl)-6-(trifluoromethyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate

[0603] Add 3-aminobicyclo[1.1.1]pentane-1-carboxynitrile (0.11 mmol) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.07 mmol) to a mixture of (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-l-methyl-lH-1,2,3-triazol-4-yl)-2-(trifluoromethyl)nicotinic acid (0.06 mmol) in pyridine (0.5 mL). Stir the reaction mixture magnetically for 2 h, then add water (1 mL) and purify the crude mixture by preparative HPLC. 1H NMR (400MHz, methanol-d4) δ 8.31 (d, J=8.2Hz, 2H), 8.03 (d, J=8.1Hz, 2H), 7.44 (s, 1H), 6.09 (q, J=6.6Hz, 1H), 4.01 (s, 3H), 2.66 (s, 6H), 1.61 (s, 3H). LCMS m / z 561.037M+1.

[0604] Example 15: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(6-fluoro-5-((3-fluorobicyclo[1.1.1]pent-1- Preparation of (compound 63) carbamate (pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate

[0605]

[0606] Step 1: (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3- Triazol-4-yl)-2-fluoronicotinic acid

[0607] Under a nitrogen atmosphere, (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (1 mmol) and 15 mL of THF were added to a 40 mL vial, and the solution was cooled to -78 °C. While maintaining the temperature below -70 °C, 1.2 mL of LiHMDS (1 M in THF) was added dropwise, and the mixture was stirred for 5 min. Then, the solution was added dropwise. n BuLi (1.1 mL, 2.5 M in hexane). After stirring for another 5 min, ZnCl2 (1.3 mL, 1.9 M in 2-Me-THF) was added dropwise. After the addition was complete, the reaction mixture was warmed to 0 °C in an ice / water bath and stirred for 10 min. Then, 6-bromo-2-fluoronicotinic acid (1.2 mmol) and Pd(dppf)Cl2-DCM (0.28 mmol) were added to the reaction mixture, followed by heating at 765 °C for 2 h. The reaction was then cooled to room temperature and quenched by adding acetic acid (2 mL) and a solution of dichloromethane containing 10% methanol (10 mL). The crude reactant was filtered through a silica stopper, concentrated under vacuum to dryness, and used for the next step without further purification.

[0608] Step 2: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(6-fluoro-5-((3-fluorobicyclo[1.1.1]pent-1-yl)amino (pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate

[0609] To a mixture of (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-2-fluoronicotinic acid (0.1 mmol) in DCM (0.5 mL), 3-fluorobicyclo[1.1.1]pentane-1-amine (0.2 mmol), HATU (0.14 mmol), and N,N-diisopropylethylamine (0.3 mmol) were added. The reaction mixture was magnetically stirred for 16 h, then diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution and brine. The organic layer was separated, dried over sodium sulfate, concentrated, and purified by reversed-phase HPLC. 1H NMR (400MHz, methanol-d4) δ8.42-8.29 (m, 1H), 8.25 (dd, J=9.4, 7.8Hz, 1H), 8.19-7.93 (m, 2H), 7 .58-7.32 (m, 1H), 6.11 (q, J=6.5Hz, 1H), 3.99 (s, 3H), 2.50 (d, J=2.1Hz, 6H), 1.63 (s, 3H). LCMS m / z 503.95M+1.

[0610] Example 16: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(3-fluoro-5-((3-fluorobicyclo[1.1.1]pent-1- Preparation of (compound 64) carbamate (pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate

[0611]

[0612] Step 1: (R)-6-(5-((91-92-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3- Triazol-4-yl)-5-fluoronicotinic acid

[0613] Under a nitrogen atmosphere, (R)-1-(2-chloropyridin-3-yl)ethyl(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (1 mmol) and 15 mL of THF were added to a 40 mL vial, and the solution was cooled to -78 °C. While maintaining the temperature below -70 °C, 1.2 mL of LiHMDS (1 M in THF) was added dropwise, and the mixture was stirred for 5 min. Then, the solution was added dropwise. n BuLi (1.1 mL, 2.5 M in hexane). After stirring for another 5 min, ZnCl2 (1.3 mL, 1.9 M in 2-Me-THF) was added dropwise. After the addition was complete, the reaction mixture was warmed to 0 °C in an ice / water bath and stirred for 10 min. Then, 6-bromo-2-fluoronicotinic acid (1.2 mmol) and Pd(dppf)Cl2-DCM (0.28 mmol) were added to the reaction mixture, followed by heating at 765 °C for 2 h. The reaction was then cooled to room temperature and quenched by adding acetic acid (2 mL) and a solution of dichloromethane containing 10% methanol (10 mL). The crude reactant was filtered through a silica stopper, concentrated under vacuum to dryness, and used for the next step without further purification.

[0614] Step 2: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(3-fluoro-5-((3-fluorobicyclo[1.1.1]pent-1-yl)amino (pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate

[0615] To a mixture of (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-2-fluoronicotinic acid (0.1 mmol) in DCM (0.5 mL), 3-fluorobicyclo[1.1.1]pentane-1-amine (0.2 mmol), HATU (0.14 mmol), and N,N-diisopropylethylamine (0.3 mmol) were added. The reaction mixture was magnetically stirred for 16 h, then diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution and brine. The organic layer was separated, dried over sodium sulfate, concentrated, and purified by reversed-phase HPLC. 1H NMR (400MHz, methanol-d4) δ8.85 (s, 1H), 8.33 (d, J=4.7Hz, 1H), 8.01 (dd, J=10.9, 1.8Hz, 2H) , 7.47 (s, 1H), 6.04 (q, J=6.6Hz, 1H), 4.03 (s, 3H), 2.51 (d, J=2.1Hz, 6H), 1.59 (s, 3H). LCMS m / z 503.98M+1.

[0616] Example 17: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(6-chloro-5-((3-cyanobicyclo[1.1.1]pentane-1- Preparation of (compound 65) carbamate (pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate

[0617]

[0618] Using 3-aminobicyclo[1.1.1]pentane-1-carboxylonitrile (0.114 mmol) instead of 3-fluorobicyclo[1.1.1]pentane-1-amine, the procedure described in Example 12 for the synthesis of (R)-1-(2-chloropyridin-3-yl)ethyl(4-(6-chloro-5-((3-fluorobicyclo[1.1.1]pent-1-yl)carbamoyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (compound 60) was followed to obtain (R)-1-(2-chloropyridin-3-yl)ethyl(4-(6-chloro-5-((3-cyanobicyclo[1.1.1]pent-1-yl)carbamoyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (compound 65). 1HNMR (400MHz, methanol-d4) δ8.32 (d, J=4.6Hz, 1H), 7.98 (dd, J=49.0, 7.9Hz, 3H) , 7.45 (s, 1H), 6.12 (q, J=6.6Hz, 1H), 3.99 (s, 3H), 2.67 (s, 6H), 1.63 (s, 3H). LCMS m / z 526.99M+1.

[0619] Example 18: (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((3-fluorobicyclo[1.1.1]pent-1-yl)amino (formyl)-6-(trifluoromethyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (compound 66) Preparation

[0620]

[0621] 3-Fluorobicyclo[1.1.1]pentane-1-amine (0.106 mmol) was used instead of 3-aminobicyclo[1.1.1]pentane-1-carboxynitrile, according to Example 14, for (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((3-cyanobicyclo[1.1.1]pent-1-yl)carbamoyl)-6-(trifluoromethyl)pyridin-2-yl)-1-methyl-1H The synthetic procedure described for (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-((3-fluorobicyclo[1.1.1]pent-1-yl)carbamoyl)-6-(trifluoromethyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamoyl (compound 66) was obtained. LCMS m / z 554.037M+1. 1 ¹H NMR (400 MHz, methanol-d⁴) δ 8.32 (d, J = 8.1 Hz, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.44 (s, 1H), 6.10 (q, J = 6.6 Hz, 1H), 4.01 (s, 3H), 2.48 (d, J = 2.1 Hz, 6H), 1.61 (s, 3H).

[0622] Example 19: Calcium Determination

[0623] In vitro LPAR1 activity was measured in an intracellular calcium mobilization assay.

[0624] CHO-K1 EDG2 cells (DiscoverX, catalog number 93-0644C2) expressing human LPAR1 (NM_001401.3) were seeded at 15,000 cells / well into 25 μL of Dulbecco modified Eagle medium (DMEM) in 384-well tissue culture plates (Grenier#781091) and incubated overnight at 37°C. This medium contained 10% fetal bovine serum, 1x PenStrepGlutamine, 300 μg / mL hygromycin, and 800 μg / mL G418. Before the test, add 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 balanced salt solution (Corning #21-023-CV), 20 mM HEPES (Corning #25-060-CI), and 0.1% bovine serum albumin (Sigma-Aldrich #A7906-500G) to the cells and incubate at 37°C for 60 minutes.

[0625] Record agonist dose profiles for LPA 18∶2 (Avanti Polar Lipids, catalog number 857138, 0.5 nM to 10 μM) to determine the LPA 18∶2 EC5. 80 For subsequent antagonist assays, 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 HBSS solution / 20 mM Hepes / 0.1% bovine serum albumin (BSA) in 6X LPA was added to the cells 5 seconds before the start of the assay.

[0626] 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 LPA at a concentration (100 nM). 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 min. Antagonist activity was measured on a FLIPR Tetra. Calcium mobilization was monitored for 3.5 min, and 10 μL of 6X EC was added 5 seconds before the start of the assay. 80 LPA was added to cells in HBSS solution, 20 mM HEPES, and 0.1% BSA. The signal amplitude (maximum minus minimum) was plotted against logarithmically using a dose-response tool (Gilead Sciences Inc.).10 Plotting antagonist concentrations to determine EC 50 .

[0627] To evaluate the antagonistic potential of the exemplary compounds, the EC50 of compounds 1 through 66 was determined in an LPAR1 calcium mobilization assay. 50 Values. The results are shown in Table 5 (LPAR1 EC). 50 The compound numbers correspond to the compound numbers in Examples 1 through 18. N / A = Not applicable.

[0628] Table 5

[0629]

[0630]

[0631] ***

[0632] Unless otherwise defined, 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 pertains.

[0633] Therefore, it should be understood that although this disclosure has been specifically disclosed through preferred embodiments and optional features, modifications, improvements, and variations of the disclosure implemented herein can be made by those skilled in the art, and such modifications, improvements, and variations are considered to be within the scope of this disclosure. The materials, methods, and embodiments provided herein represent preferred embodiments, are exemplary, and are not intended to limit the scope of this disclosure.

[0634] This disclosure has been described broadly and generally. Each narrower species and subgenus group falling within the general disclosure also forms part of this disclosure. This includes the general description of this disclosure, whose preconditions or negative limitations remove any subject matter from that genus, regardless of whether the removed material is specifically described herein.

[0635] Furthermore, when features or aspects of this disclosure are described in accordance with the Markush Group, those skilled in the art will recognize that this disclosure is also described in accordance with any individual member or subgroup of the Markush Group.

[0636] It should be understood that although this disclosure has been described in conjunction with the above embodiments, the foregoing description and examples are intended to illustrate and not limit the scope of this disclosure. Other aspects, advantages, and modifications within the scope of this disclosure will be apparent to those skilled in the art to which this disclosure pertains.

Claims

1. A compound of formula (I), (I) Or its pharmaceutically acceptable salt. in: R 1 C 3-10 Cycloalkyl groups, having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, consisting of 3- to 10-membered heterocyclic groups, 6- to 10-membered aryl groups, or having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R... 1A Instead, the R 1A They can be the same or different, where each R 1A Independently selected from halogen, cyano, oxo, C 1-4 Alkyl, C 3-10 Cycloalkyl groups, consisting of 3- to 10-membered heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6- to 10-membered aryl groups, consisting of 5- to 10-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; -OR 1B1 , and -S(O) 0-2 R 1B1 , where R 1B1 Independently hydrogen or C 1-6 alkyl, Each R 1A Alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 1 to 4 R groups. 1C Replace these R 1C They can be the same or different, and each of R... 1C Independently for C 1-4 Alkyl, halogen, or -OR 1D1 , where R 1D1 Independently hydrogen or C 1-6 alkyl; or R 2 It is hydrogen; R 3 Selected from hydrogen, deuterium, halogens, or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 3 substituents, which may be the same or different and are independently selected from halogens; Each R 4 Independently selected from deuterium and halogens; n is 0 or 1; R 5 -CH3; Each Y 1 and Y 2 C is independently hydrogen, deuterium, or optionally substituted with 1 to 3 substituents. 1-6 Alkyl groups, wherein the substituents may be the same or different, and are independently selected from deuterium, halogen, cyano, C 2-3 alkynyl group, C 1-4 Alkoxy groups and -C(O)NH-(C 1-4 H 3-9 );and Z is , , or .

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

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each Y 1 and Y 2 C is independently hydrogen, deuterium, or optionally substituted with 1 to 3 substituents. 1-6 Alkyl groups, wherein the substituents may be the same or different, and each is independently selected from halogens, cyano groups, C6 groups, etc. 2-3 alkynyl group, C 1-4 Alkoxy groups and -C(O)NH-(C 1-4 H 3-9 ).

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y 1 C is optionally substituted with 1 to 3 substituents 1-4 Alkyl groups, wherein the substituents may be the same or different, and each is independently selected from halogens, cyano groups, and C. 1-4 alkoxy groups, and Y 2 It is hydrogen.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y 1 The methyl group is optionally substituted with 1 to 3 substituents, which may be the same or different and are each independently selected from -F, -Cl, -CN and -O-CH3.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y 1 It is -CH3.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y 2 It is hydrogen.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y 1 It is -CH3, and Z is , , or .

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has formula (II): (II)。 10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) has formula (IIa): (IIa)。 11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 To be arbitrarily assigned to 1 to 4 R 1A Replacement C 3-10 cycloalkyl, the R 1A They can be the same or different, where each R 1A Independently selected from halogen, cyano, oxo, C 1-4 Alkyl, C 3-10 Cycloalkyl groups, consisting of 3- to 10-membered heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6- to 10-membered aryl groups, consisting of 5- to 10-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; -OR 1B1 , and -S(O) 0-2 R 1B1 , where R 1B1 Independently hydrogen or C 1-6 alkyl, Each R 1A Alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 1 to 4 R groups. 1C Replace these R 1C They can be the same or different, and each of R... 1C Independently for C 1-4 Alkyl, halogen, cyano or -OR 1D1 , where R 1D1 Independently hydrogen or C 1-6 alkyl.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is cyclopropyl or cyclobutyl, wherein each of the cyclopropyl or cyclobutyl groups is optionally surrounded by one or two R groups. 1A Instead, the R 1A Independently selected from -F and phenyl, wherein each phenyl group is optionally surrounded by 1 to 4 R groups. 1C Instead, the R 1C They can be the same or different, and each of R... 1C Independently for C 1-4 Alkyl groups, halogens.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 for , or .

14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the C 3-10 Cycloalkyl group is C 5-10 Bicyclic cycloalkyl.

15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein the C 5-10 The bicyclic cycloalkyl group is C 5-8 Bridged bicyclic cycloalkyl groups.

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein the C 5-8 The bridged bicyclic cycloalkyl group is a bicyclopentyl group, each optionally substituted with 1 to 3 substituents, which may be the same or different, and each independently selected from -F, -Cl, -CN, -CH3, -CH2-OH, -CHF2, -CF3, -O-CH3, -CO2-CH3, -SO2-CH3 and phenyl.

17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 for , , , , , , , , , , or .

18. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 To be arbitrarily assigned to 1 to 4 R 1A The substituted 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 1A They can be the same or different, where each R 1A Independently selected from halogen, cyano, oxo, C 1-4 Alkyl, C 3-10 Cycloalkyl groups, consisting of 3- to 10-membered heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6- to 10-membered aryl groups, consisting of 5- to 10-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; -OR 1B1 , and -S(O) 0-2 R 1B1 , where R 1B1 Independently hydrogen or C 1-6 alkyl, Each R 1A Alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 1 to 4 R groups. 1C Instead, the R 1C They can be the same or different, and each of R... 1C Independently for C 1-4 Alkyl, halogen or -OR 1D1 , where R 1D1 Independently hydrogen or C 1-6 alkyl.

19. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 To be arbitrarily assigned to 1 to 4 R 1A Substituted tetrahydropyranyl, said R 1A They may be the same or different, and each can be independently selected from -F, -Cl, -OH, -CN, -CH3, -CH2F, -CHF2, -CF3 and -O-CH3.

20. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 for .

21. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 To be arbitrarily assigned to 1 to 4 R 1A The substituted 6- to 10-membered aryl group, said R 1A They can be the same or different, where each R 1A Independently selected from halogen, cyano, oxo, C 1-4 Alkyl, C 3-10 Cycloalkyl groups, consisting of 3- to 10-membered heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6- to 10-membered aryl groups, consisting of 5- to 10-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; -OR 1B1 , and -S(O) 0-2 R 1B1 , where R 1B1 Independently hydrogen or C 1-6 alkyl, Each R 1A Alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 1 to 4 R groups. 1C Instead, the R 1C They can be the same or different, and each of R... 1C Independently for C 1-4 Alkyl, halogen, or -OR 1D1 , where R 1D1 Independently hydrogen or C 1-6 alkyl.

22. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 To be arbitrarily assigned to 1 to 4 R 1A Substituted phenyl, said R 1A They can be the same or different, where each R 1A Independently selected from halogen, cyano, C 1-3 Alkyl, C 1-4 An alkoxy group, a 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each alkyl, heterocyclic, and heteroaryl group is optionally surrounded by 1 to 4 R... 1C Instead, the R 1C They can be the same or different, and each of R... 1C Independently halogen or C 1-4 alkyl.

23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 To be arbitrarily assigned to 1 to 4 R 1A Substituted phenyl, said R 1A They can be the same or different, where each R 1A Independently selected from cyano, -CF3, -F, -Cl, morpholino, phenyl, pyridyl, and oxadiazolyl, wherein each morpholino, phenyl, pyridyl, and oxadiazolyl is optionally surrounded by 1 to 4 R groups. 1C Instead, the R 1C They can be the same or different, and each of R... 1C Independently halogen or C 1-4 alkyl.

24. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 for 、 、 、 、 、 、 、 or .

25. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 To be arbitrarily assigned to 1 to 4 R 1A The substituted 5- to 10-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the R 1A They can be the same or different, where each R 1A Independently selected from halogen, cyano, oxo, C 1-4 Alkyl, C 3-10 Cycloalkyl groups, consisting of 3- to 10-membered heterocyclic groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6- to 10-membered aryl groups, consisting of 5- to 10-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; -OR 1B1 , or -S(O) 0-2 R 1B1 , where R 1B1 Independently hydrogen or C 1-6 alkyl, Each R 1A Alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 1 to 4 R groups. 1C Instead, the R 1C They can be the same or different, and each of R... 1C Independently for C 1-4 Alkyl, halogen, or -OR 1D1 , where R 1D1 Independently hydrogen or C 1-6 alkyl.

26. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 The radical group is thiazolyl, oxazolyl, pyridyl, pyrimidinyl, or pyridazinyl, each optionally surrounded by 1 to 4 R groups. 1A Instead, the R 1A They can be the same or different, where each R 1A Independently selected from halogen, cyano, oxo, C 1-4 Alkyl, C 3-10 Cycloalkyl groups, having 1 to 4 independent heterocyclic groups selected from nitrogen and oxygen, ranging from 3 to 10 members, -OR 1B1 and -S(O) 0-2 R 1B1 , where R 1B1 Independently hydrogen or C 1-6 alkyl, Each R 1A Alkyl, cycloalkyl, and heterocyclic groups are optionally surrounded by 1 to 4 R groups. 1C Instead, the R 1C They can be the same or different, and each of R... 1C Independently for C 1-4 Alkyl or halogen.

27. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 The group is thiazolyl, oxazolyl, pyridyl, pyrimidinyl, or pyridazinyl, each optionally substituted with 1 to 3 substituents, which may be the same or different, and each independently selected from -F, -Cl, -CN, -CHF2, -CF3, -OCH3, -OCHF2, or... .

28. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 for , , , , , , , , , , , , , , , , or .

29. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 It is hydrogen.

30. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 C is selected from halogens or optionally substituted with 1 to 3 halogens. 1-3 alkyl.

31. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from -F, -Cl, -CH3 or -CF3.

32. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 4 It is a halogen.

33. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 4 It is -F.

34. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 0.

35. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 1.

36. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R 6 It can be -F or -Cl.

37. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R 7 It can be hydrogen or -F.

38. A compound selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , Or its pharmaceutically acceptable salt.

39. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 。 40. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 。 41. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 。 42. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 。 43. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 。 44. A pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 43, and a pharmaceutically acceptable excipient.

45. The pharmaceutical composition of claim 44, wherein the pharmaceutical composition further comprises an additional therapeutic agent.

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

47. The use according to claim 46, wherein the LPAR1-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.

48. The use according to claim 46, wherein the LPAR1-mediated disease or condition is interstitial lung disease (ILD).

49. The use according to claim 48, wherein the interstitial lung disease (ILD) is nonspecific interstitial pneumonia (NSIP), sarcoidosis, asbestosis, occupational exposure-related ILD, progressive fibrotic ILD, idiopathic interstitial pneumonia (IIP), connective tissue disease-related interstitial lung disease (CTD-ILD), rheumatoid arthritis-related ILD, scleroderma-related ILD, or extrinsic alveolitis.

50. The use according to claim 46, wherein the LPAR1-mediated disease or condition is chronic kidney disease (CKD).

51. The use according to claim 50, wherein the CKD is complement glomerulonephropathy, membranous glomerulonephropathy, polycystic kidney disease, IgA nephropathy, focal segmental glomerulosclerosis (FSGS), or Alport syndrome.

52. The use according to claim 50 or 51, wherein the LPAR1-mediated disease or condition includes fibrosis.

53. The use according to claim 52, wherein the fibrosis is pulmonary fibrosis, renal fibrosis, liver fibrosis, ocular fibrosis, myocardial fibrosis, or systemic sclerosis.

54. The use according to claim 53, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF) or progressive fibrotic interstitial lung disease (PF-ILD).

55. The use according to claim 53, wherein the pulmonary fibrosis is secondary to a systemic inflammatory disease.

56. The use according to claim 55, wherein the systemic inflammatory disease is rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrotic 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 syndrome.

57. The use according to claim 53, wherein the renal fibrosis is associated with diabetic nephropathy.

58. The use according to claim 46, wherein the LPAR1-mediated disease or condition is liver disease.

59. The use according to claim 58, wherein the liver disease includes liver fibrosis.

60. The use according to claim 58 or 59, wherein the liver disease includes non-alcoholic fatty liver disease (NAFLD).

61. The use according to claim 58 or 59, wherein the liver disease includes steatosis.

62. The use according to claim 61, wherein the liver disease includes non-alcoholic steatohepatitis (NASH).

63. The use according to claim 58 or 59, wherein the liver disease includes cirrhosis.

64. The use according to claim 63, wherein the cirrhosis is compensated cirrhosis.

65. The use according to claim 63, wherein the cirrhosis is decompensated cirrhosis.

66. The use according to claim 58 or 59, wherein the liver disease includes hepatocellular carcinoma (HCC).

67. The use according to claim 58 or 59, wherein the liver disease includes primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC).

68. The use according to claim 58 or 59, wherein the liver disease includes portal hypertension.

69. The use according to claim 46, wherein the compound or a pharmaceutically acceptable salt thereof is administered in combination with an additional therapeutic agent.

70. The pharmaceutical composition of claim 45 or the use of claim 69, wherein the additional therapeutic agent is one, two, three or four additional therapeutic agents.

71. The pharmaceutical composition of claim 45 or the use of claim 69, wherein the additional therapeutic agent comprises an acetyl-CoA carboxylase (ACC) inhibitor, an apoptosis signal-regulated 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 α (PPARα) agonist, or a TGFβ antagonist.

72. The pharmaceutical composition or use according to claim 71, wherein the ACC inhibitor is firsocostat.

73. The pharmaceutical composition or use according to claim 71, wherein the ASK1 inhibitor is selonsertib.

74. The pharmaceutical composition or use according to claim 71, wherein the FXR agonist is cilofexor.

75. The pharmaceutical composition or use according to claim 71, wherein the PPARα agonist is fibrate.

76. The pharmaceutical composition or use according to claim 71, wherein the fish oil is ethyl eicosapentaenoate.

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

78. The pharmaceutical composition or use according to claim 71, wherein the TGFβ antagonist is an anti-TGFβ1 specific antibody.

79. The pharmaceutical composition or use according to claim 71, wherein the TGFβ antagonist is a TGFβ receptor.

80. The pharmaceutical composition or use according to claim 71, wherein the additional therapeutic agent comprises fexococcal and silofex.

81. The pharmaceutical composition or use according to claim 71, wherein the additional therapeutic agent comprises fexococcal and liraglutide or smegglutide.

82. The pharmaceutical composition or use according to claim 71, wherein the additional therapeutic agent comprises fibrate or ethyl eicosapentaenoate.

83. The pharmaceutical composition or use according to claim 71, wherein the additional therapeutic agent comprises silofexo and liraglutide or smegglutide.

84. The pharmaceutical composition of claim 45 or the use of claim 69, wherein the additional therapeutic agent comprises a VEGFR inhibitor, an FGFR inhibitor, a PDGFR inhibitor, an autotoxin inhibitor, a GPR84 agonist, a PASK inhibitor, a CFTR agonist, a JAK1 inhibitor, an ADAMTS5 inhibitor, a TOL2 / 3 inhibitor, a CTGF inhibitor, soluble PTX2, an anti-galactoglobulin 3 antibody, or integrin α. V -β6 / α V -β1 antagonists, JNK1 inhibitors, mineralocorticoid receptor antagonists, Nrf2 activators, chymotrypsin inhibitors, PDE inhibitors, NOX1 / 4 inhibitors, leukotriene / thromboxane receptor antagonists, SLC22A12 inhibitors, sGC inhibitors, or xanthine oxidase inhibitors.

85. The pharmaceutical composition of claim 45 or the use of claim 69, wherein the additional therapeutic agent is selected from the group consisting of: nintedanib, pirfenidone, pamrevlumab, PRM-151, GB-0139, PLN-74809, CC-90001, finerenone, BAY1142524, PCS-499, setanaxib, SER150, RDEA3170, praliciguat, TMX-049, GLPG1690, GLPG1205, GLPG1972, GLPG4059, GLPG2737, GLPG3970, and filgotinib.

86. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 43 for the manufacture of a medicament for treating LPAR1-mediated diseases or conditions.

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