LPA receptor antagonists and their use

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. The compounds are useful for the treatment of diseases and / or conditions mediated by LPAR1 binding, including fibrosis and liver diseases, such as nonalcoholic steatohepatitis (NASH), interstitial lung disease (ILD), or chronic kidney disease (CKD).

Description

Technical Field

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 188,281, filed May 13, 2021, under 35 U.S.C. § 119(e), the entire content of which is incorporated herein by reference.

[0002] The present disclosure relates to compounds that bind to lysophosphatidic acid (LPA) receptors, such as LPAR1, and act as antagonists thereof. The present disclosure further relates to the use of the compounds for the treatment and / or prevention of diseases and / or conditions associated with one or more LPA receptors, such as LPAR1-related diseases or conditions.

Background Art

[0003] Lysophosphatidic acid (mono-acyl-glycerol-3-phosphate, LPA) is a class of biologically active phospholipids that can be generated, for example, from lysophosphatidyl choline (LPC) by the enzyme autotaxin. 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 arachidonyl LPA (20:4). LPA exerts a wide range of cellular responses such as proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis through a family of rhodopsin-like G protein-coupled receptors (GPCRs). Six LPA receptors have been characterized and found to differ in their tissue distribution and downstream signaling pathways. These six LPA receptors are often referred to interchangeably as LPAR1-6 (genes) or LPA1-6 (proteins). LPA receptor-mediated signaling has been shown to affect many biological processes such as wound healing, immunity, carcinogenesis, angiogenesis, and neurogenesis.

[0004] In vivo studies with LPA receptor-deficient mice or certain tool compounds have suggested the potential of LPA receptors as drug targets in a variety of diseases including cancer, fibrosis, inflammation, pain, and cardiovascular diseases. More recently, LPAR1 antagonists have been clinically studied in relation to fibrotic disease states such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis.

[0005] There remains a need for LPA antagonists with desirable selectivity, potency, metabolic stability, or reduced adverse effects. SUMMARY OF THE INVENTION

[0006] The present disclosure provides compounds useful as inhibitors of Lysophosphatidic Acid Receptor 1 (LPAR1). The present disclosure further relates to the use of the compounds for the treatment and / or prevention of diseases and / or conditions through the binding of LPAR1 by the compounds.

[0007] In one embodiment, provided herein is a compound of formula (I),

Chemical formula

[0008] In some embodiments, a pharmaceutical composition comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier is provided herein. 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.

[0009] In some embodiments, the pharmaceutical composition provided herein further comprises one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents, or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents, or pharmaceutically acceptable salts thereof.

[0010] In some embodiments, the present disclosure provides a method of doing so in a subject in need of inhibition of LPAR1 activity, the method 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.

[0011] In some embodiments, the present disclosure provides a method of treating a patient having an LPAR1-mediated condition, the method comprising 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 DESCRIPTION OF THE INVENTION

[0012] The present disclosure relates to LPA receptor antagonists such as antagonists of LPAR1. The present disclosure also relates to compositions and methods related to LPAR1 antagonists, and to the use of such compounds for the treatment and / or prevention of LPAR1-mediated diseases and conditions. The present disclosure also relates to compositions and methods for treating and / or preventing liver diseases comprising an LPAR1 antagonist in combination with one or more additional therapeutic agents.

[0013] It is generally contemplated that treatment with an LPAR1 antagonist and optionally one or more additional therapeutic agents may be beneficial for patients having certain LPAR1-mediated diseases such as cancer, fibrosis, inflammation, pain, and cardiovascular diseases, or liver diseases including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[0014] Definitions and General Parameters The following description is to be read with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated. Headings used throughout this disclosure are for convenience only and are in no way to be construed as limiting the claims. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

[0015] 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 should be noted that as used in this specification and the appended claims, the singular forms “a,” “and,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound” includes a plurality of such compounds, and reference to “an assay” includes reference to one or more assays known to those of ordinary skill in the art and equivalents thereof.

[0016] As used herein, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used suggests otherwise.

[0017] A dash (“-”) not between two letters or symbols is used to indicate the point of attachment for a substituent. For example, -CONH 2 is attached through a carbon atom. Dashes at the front or end of a chemical group are for convenience, and the chemical group may be shown with or without one or more dashes without losing their ordinary meaning. A wavy line drawn across a line in a structure indicates the point of attachment of a group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality. A solid line protruding from the center of a ring indicates that the point of attachment of a substituent in that ring can be at any ring atom. For example, R in the following structure aIt can be bonded to any of the five carbocyclic atoms, or the hydrogen bonded to the nitrogen ring atom can be replaced by R a : [Chemical formula] is as follows.

[0018] The prefix "C u~v " indicates that the following group has u - v carbon atoms. For example, "C 1~6 alkyl group" indicates that the alkyl group has 1 - 6 carbon atoms. Similarly, the term "x - y membered" ring where x and y are numerical ranges (e.g., "3 - 12 membered heterocyclyl", etc.) means a ring having x - y atoms (e.g., 3 - 12), and up to 80% of these atoms may be heteroatoms such as N, O, S, P, etc., and the remaining atoms are carbon.

[0019] Also, certain commonly used alternative chemical names may or may not be used. For example, divalent groups such as divalent "alkyl" groups and divalent "aryl" groups may also be referred to as "alkylene" groups or "alkylenyl" groups, or alkyllyl groups, "arylene" groups or "arylenyl" groups, or aryllyl groups, respectively.

[0020] "The compounds disclosed herein" or "the compounds of the present disclosure" or "the compounds provided herein" or "the compounds described herein" refer to the compounds of (I), (Ia), (II), or (IIa). Specific compounds 1 - 66 provided herein (e.g., Examples 1 - 18) are also included.

[0021] References to values or parameters prefaced by "about" in this specification include (and describe) embodiments that relate to the value or parameter itself. In certain embodiments, the term "about" includes the recited amount plus or minus 10%. In other embodiments, the term "about" includes the recited amount plus or minus 5%. In certain other embodiments, the term "about" includes the recited amount plus or minus 1%. Also, for the term, "about X" includes the description of "X". Also, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "an assay" includes reference to one or more assays known to those skilled in the art and their equivalents.

[0022] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C 1~20 alkyl), 1 to 8 carbon atoms (i.e., C 1~8 alkyl), 1 to 6 carbon atoms (i.e., C 1~6 alkyl), 1 to 4 carbon atoms (i.e., C 1~4 alkyl), or 1 to 3 carbon atoms (i.e., C 1~3 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl group having a specific number of carbons is designated by a chemical name or identified by a molecular formula, all positional isomers having that number of carbons may be included. Thus, for example, "butyl" includes n-butyl (i.e., -(CH 2 ) 3 CH 3 ), sec-butyl (i.e., -CH(CH 3 )CH 2 CH 3 ), isobutyl (i.e., -CH 2 CH(CH 3 ) 2), and tert-butyl (i.e., -C(CH 3 ) 3 ) is included, and "propyl" includes n-propyl (i.e., -(CH 2 ) 2 CH 3 ) and isopropyl (i.e., -CH(CH 3 ) 2 ).

[0023] "Alkenyl" contains at least one carbon-carbon double bond and has 2 to 20 carbon atoms (i.e., C 2~20 alkenyl), 2 to 8 carbon atoms (i.e., C 2~8 alkenyl), 2 to 6 carbon atoms (i.e., C 2~6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2~4 alkenyl), and refers to an aliphatic group. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0024] "Alkynyl" contains at least one carbon-carbon triple bond and has 2 to 20 carbon atoms (i.e., C 2~20 alkynyl), 2 to 8 carbon atoms (i.e., C 2~8 alkynyl), 2 to 6 carbon atoms (i.e., C 2~6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2~4 alkynyl), and refers to an aliphatic group. The term "alkynyl" also includes an alkynyl group having one triple bond and one double bond.

[0025] "Alkoxy" refers to an "alkyl-O-" group. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0026] "Acyl" refers to a -C(=O)R group, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may optionally be substituted as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0027] "Amino" refers to a -NR y R z group, where R y and R z are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which may optionally be substituted.

[0028] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or a polyring containing a fused system (e.g., bicyclic or tricyclic). As used herein, aryl has 6 to 20 carbocyclic atoms (i.e., C 6~20 aryl), 6 to 12 carbocyclic atoms (i.e., C 6~12 aryl), or 6 to 10 carbocyclic atoms (i.e., C 6~10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not in any way encompass heteroaryl as defined below and does not overlap with this heteroaryl. When one or more aryl groups are fused to a heteroaryl ring, the resulting ring system is heteroaryl.

[0029] "Cyano" or "carbonitrile" refers to a -CN group.

[0030] "Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having a monocyclic or polycyclic ring including a fused ring system, a bridged ring system, and a spiro ring system. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl has 3 to 20 ring carbon atoms (i.e., C 3~20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3~8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3~6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0031] "Fused" refers to a ring that is bonded to an adjacent ring. In some embodiments, the fused ring system is heterocyclyl. In some embodiments, the fused ring system is oxabicyclohexanyl. In some embodiments, the fused ring system is

Chemical formula

[0032] "Bridged" refers to a ring condensation in which non-adjacent atoms on the ring are joined by a divalent substituent such as an alkenylenyl group, an alkenylenyl group containing one or two heteroatoms, or a single heteroatom. Quinuclidinyl and adamantanyl are examples of bridged ring systems. In some embodiments, the bridged ring is bicyclopentanyl (bicycle[1.1.1]pentanyl] or bicyclooctanyl (bicycle[2.2.2]octanyl). In some embodiments, the bridged ring is

Chemical formula

[0033] "Spiro" refers to a ring substituent that is bonded by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, where cyclopentane and piperidine are spiro substituents, respectively. In some embodiments, the spiro substituent is spiropentanyl (spiro[a.b]pentanyl), spirohexanyl, spiroheptanyl, or spirodecanyl. In some embodiments, the spiro substituent is

Chemical Formula

[0034] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodo.

[0035] "Heteroaryl" refers to an aromatic group having a monocyclic, polycyclic, or fused polycyclic ring having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl has 1 to 20 carbocyclic atoms (i.e., C 1~20 heteroaryl), 3 to 12 carbocyclic atoms (i.e., C 3~12 heteroaryl), or 3 to 8 carbocyclic atoms (i.e., C 3~8 heteroaryl), and includes 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not include aryl as defined above and does not overlap with aryl.

[0036] "Heterocyclyl" or "heterocyclic ring" or "heterocycle" refers to a non-aromatic cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, "heterocyclyl" or "heterocyclic ring" or "heterocycle" refers to a ring that is saturated or partially saturated unless otherwise indicated. For example, in some embodiments, "heterocyclyl" or "heterocyclic ring" or "heterocycle" refers to a ring that is partially saturated when so specified. The term "heterocyclyl" or "heterocyclic ring" or "heterocycle" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond). Heterocyclyl can be monocyclic or polycyclic, and polycycles can be fused, bridged, or spiro. As used herein, heterocyclyl has 2 to 20 carbon ring atoms (i.e., C 2~20 heterocyclyl), 2 to 12 carbon ring atoms (i.e., C 2~12 heterocyclyl), 2 to 10 carbon ring atoms (i.e., C 2~10 heterocyclyl), 2 to 8 carbon ring atoms (i.e., C 2~8 heterocyclyl), 3 to 12 carbon ring atoms (i.e., C 3~12 heterocyclyl), 3 to 8 carbon ring atoms (i.e., C 3~8 heterocyclyl), or 3 to 6 carbon ring atoms (i.e., C 3~6 heterocyclyl) and has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. As used herein, the terms "heterocycle", "heterocyclyl", and "heterocyclic ring" are used interchangeably.

[0037] "Hydroxy" or "hydroxyl" refers to the -OH group.

[0038] "Oxo" refers to the (=O) group or the (O) group.

[0039] "Sulfonyl" refers to -S(O) 2 R c group, where R c is alkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0040] Whenever a graphical representation of a group ends with a nitrogen atom singly bonded, that group represents -NH 2 group, unless otherwise indicated. Similarly, unless otherwise specified, hydrogen atoms are implied and considered to be present as necessary to complete the valence or provide stability, taking into account the knowledge of those skilled in the art.

[0041] The terms "optional" or "optionally" mean that the event or situation described thereafter may or may not occur, and that the description includes both the case where the event or situation occurs and the case where the event or situation does not occur. Also, the term "optionally substituted" means that any one or more hydrogen atoms on the specified atom or group may or may not be replaced by a moiety other than hydrogen.

[0042] The term "substituted" means that any one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents other than hydrogen, provided that the normal valence of the specified atom is not exceeded. Examples of one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidino, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar indefinite structures obtained by defining substituents with further substituents added ad infinitum (e.g., a substituted aryl having a substituted alkyl, where the substituted alkyl itself is substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of consecutive substitutions in the compounds described herein is 3. For example, consecutive substitution of a substituted aryl group by two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the foregoing definitions are not intended to include unacceptable substitution patterns (e.g., a methyl substituted with five fluorines 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 a chemical group, the term "substituted" can describe other chemical groups as defined herein. For example, the term "substituted aryl" includes, but is not limited to, "alkylaryl". Unless otherwise specified, when a group is described as optionally substituted, any substituent of the group is itself unsubstituted.

[0043] In some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents including hydroxyl, halo, amino, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In additional embodiments, "substituted cycloalkyl" refers to a cycloalkyl group having one or more substituents including alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amino, alkoxy, halo, oxo, and hydroxyl, "substituted heterocyclyl" refers to a heterocyclyl group having one or more substituents including alkyl, amino, haloalkyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl, "substituted aryl" refers to an aryl group having one or more substituents including halo, alkyl, amino, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano, "substituted heteroaryl" refers to a heteroaryl group having one or more substituents including halo, amino, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, and cyano, "substituted sulfonyl" refers to -S(O) 2 refers to an R group, where R is substituted with one or more substituents including alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, one or more of the substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0044] In some embodiments, a substituted cycloalkyl, substituted heterocyclyl, substituted aryl, and / or substituted heteroaryl includes a cycloalkyl, heterocyclyl, aryl, and / or heteroaryl having a substituent on a ring atom, and the cycloalkyl, heterocyclyl, aryl, and / or heteroaryl is attached to the remainder of the compound. For example, in the following moiety, cyclopropyl is substituted with a methyl group:

Chemical formula

[0045] The disclosure illustrated herein can be suitably practiced in the absence of any element or elements, limitation or limitations not specifically disclosed herein. Thus, for example, terms such as "comprising," "including," "containing," etc. are to be read expansively and not restrictively. Further, the terms and expressions used herein are used as terms of description and not of limitation, and there is no intention to exclude any equivalents of the features shown and described or portions thereof, although it is recognized that various modifications are possible within the scope of the claimed disclosure.

[0046] The compounds of the present disclosure can be in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. The compounds of the present disclosure can be in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. When the compounds of the present disclosure contain one or more acidic or basic groups, the present disclosure also includes the corresponding pharmaceutically or toxicologically acceptable salts of the compounds, particularly the pharmaceutically available salts of the compounds. Thus, compounds of the present disclosure containing acidic groups can exist in these groups and, in accordance with the present disclosure, can be used, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts. More specific examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine, amino acids, or other bases known to those skilled in the art. Compounds of the present disclosure containing one or more basic groups, i.e., groups that can be protonated, can exist and can be used in the form of these additional salts containing inorganic or organic acids, in accordance with the present disclosure. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art.

[0047] When the compounds of the present disclosure contain both acidic and basic groups in the molecule, the present disclosure also includes inner salts or betaines (zwitterions) in addition to the salt forms mentioned. Each salt can be obtained by conventional methods known to those skilled in the art, for example, by contacting these salts with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.

[0048] The present disclosure also includes all salts of the compounds of the present disclosure that, due to low physiological compatibility, are not directly suitable for use in pharmaceuticals but can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts. Acids and bases useful for reaction with the parent compound to form pharmaceutically acceptable salts (acid addition salts or base addition salts, respectively) are known to those of ordinary skill in the art. Similarly, methods for preparing pharmaceutically acceptable salts from the parent compound (at the time of disclosure) are known to those of ordinary skill in the art and are disclosed, for example, in Berge, at al. Journal of Pharmaceutical Science, Jan. 1977 vol. 66, No. 1, and other sources.

[0049] Furthermore, the compounds disclosed herein may be subject to the influence of tautomerism. When tautomerism, for example, keto-enol tautomerism of a compound or its prodrugs can occur, the individual forms, such as the keto form and the enol form, are each within the scope of the present disclosure, as well as mixtures thereof in any ratio. The same applies to stereoisomers, such as enantiomers, cis / trans isomers, diastereomers, conformational isomers, and the like.

[0050] The term "protecting group" refers to a moiety of a compound that shields or modifies the properties of a functional group or the compound as a whole. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See, for example, Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often used to shield the reactivity of a particular functional group to assist in the effectiveness of a desired chemical reaction, for example, to regularly and systematically form and cleave chemical bonds. The term "deprotection" refers to the removal of a protecting group.

[0051] If a list of alternative substituents includes members that cannot be used to replace a particular group due to the valence requirements of the members or other reasons, it is intended that the list be read by one of ordinary skill in the art to include only those members of the list that are suitable for replacing the particular group.

[0052] Furthermore, the compounds of the present disclosure may exist in the form of solvates, including solvated water or solvates such as pharmaceutically acceptable solvates with alcohols, particularly ethanol. A "solvate" is formed by the interaction of a solvent with a compound.

[0053] In certain embodiments, provided are optical isomers, racemic compounds, or other mixtures thereof or mixtures of the compounds or pharmaceutically acceptable salts thereof described herein. If desired, the isomers can be separated by methods well known in the art, such as liquid chromatography. In these situations, a single enantiomer or diastereomer, i.e., an optically active form, can be obtained by asymmetric synthesis or by resolution. Resolution can be achieved, for example, by crystallization in the presence of a resolving agent or by conventional methods such as chromatography using a chiral high-pressure liquid chromatography (HPLC) column.

[0054] "Stereoisomers" refer to compounds that are composed of the same atoms bonded by the same bonds but have different three-dimensional structures that are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.

[0055] The compounds disclosed herein and their pharmaceutically acceptable salts may, in some embodiments, contain chiral centers and thus can give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- with respect to absolute stereochemistry, or as (D)- or (L)- for amino acids. Some embodiments include all such possible isomers, as well as their racemic and optically pure forms. The optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using a chiral synthon or chiral reagent or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of a racemic compound (or a racemic compound of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). When the compounds described herein contain an olefinic double bond or other geometrically chiral center and are not otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0056] The compositions provided herein that contain a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, can include a racemic mixture, or a mixture containing an enantiomerically enriched one enantiomer or a single diastereomer, or a mixture of diastereomers. All such isomeric forms of these compounds are expressly included herein as if each and every isomeric form was specifically and individually recited.

[0057] Any formula or structure given herein is also intended to represent both unlabeled and isotopically labeled forms of the compound. An isotopically labeled compound has the structure shown by a formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present disclosure include, but are not limited to, 2 H (deuterium, D), 3H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I, etc., include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine. Various isotope-labeled compounds of the present disclosure are, for example, 3 H, 13 C and 14 C, etc., incorporated with radioactive isotopes. Such isotope-labeled compounds can be useful in detection techniques or imaging techniques including metabolic studies, reaction kinetics studies, positron emission tomography (PET), or single-photon emission computed tomography (SPECT) for tissue distribution assays of drugs or substrates, or in radiotherapy of patients. The isotope-labeled compounds and their prodrugs of the present disclosure can generally be prepared by substituting readily available isotope-labeled reagents for non-isotope-labeled reagents and by carrying out the procedures disclosed in the schemes or in the examples and preparations described below.

[0058] The present disclosure also includes "deuterated analogs" of the compounds disclosed herein in which 1 to n hydrogens bonded to a carbon atom are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds can exhibit increased resistance to metabolism and, thus, can be useful for increasing the half-life of any compound of formula (I) when administered to a mammal, for example, a human. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci. 5(12):524-527(1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens have been exchanged by deuterium.

[0059] The deuterium-labeled or deuterium-substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope such as deuterium can result in certain therapeutic advantages due to greater metabolic stability, such as an extended half-life in vivo, a reduced dosing requirement, and / or an improved therapeutic index. 18 F-labeled compounds may be useful in PET or SPECT studies.

[0060] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotope enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope represents any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as “H” or “hydrogen,” that position is understood to have hydrogen with the isotopic composition of the natural abundance ratio of hydrogen. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) means deuterium.

[0061] Furthermore, the present disclosure provides a pharmaceutical composition comprising, as an active ingredient, a compound of the present disclosure, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier.

[0062] “Pharmaceutical composition” means one or more active ingredients, and one or more inert ingredients that constitute a carrier, and any product directly or indirectly resulting from a combination, complex formation, or aggregation of any two or more of the ingredients, or from the dissociation of one or more of the ingredients, or from one or more other types of reaction or interaction of one or more of the ingredients. Thus, the pharmaceutical compositions of the present disclosure can include any composition produced by admixing at least one compound of the present disclosure with a pharmaceutically acceptable carrier.

[0063] As used herein, "pharmaceutically acceptable carrier" includes excipients or agents such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc., which are not harmful to the disclosed compounds or their use. The use of such carriers and agents for preparing compositions of pharmaceutically active substances is well known in the art (see, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.)).

[0064] "IC 50 " or "EC 50 " refers to the inhibitory concentration required to achieve 50% of the maximum desired effect. In many cases herein, the maximum desired effect is the inhibition of LPA-induced LPAR1 activation. This term is obtained using in vitro assays such as calcium mobilization assays that evaluate the concentration-dependent inhibition of LPA-induced LPAR1 activity.

[0065] "Treatment" or "treating" is an approach for obtaining a beneficial or desired result, including a clinical result. The beneficial or desired clinical result can include one or more of the following: namely, a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition and / or reducing the degree of the disease or condition), b) delaying or preventing the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition), and / or c) alleviating the disease, i.e., causing regression of the clinical symptoms (e.g., improving the disease state, providing partial or complete remission of the disease or condition, enhancing the effect of another agent, delaying the progression of the disease, improving the quality of life, and / or extending survival). In some embodiments, the term "treatment" or "treating" means administering a compound of formula (I), (Ia), (II), or (II), or a pharmaceutically acceptable salt thereof, for the purpose of (i) delaying the onset of a disease, i.e., preventing the clinical symptoms of the disease from occurring or delaying the onset of the disease, (ii) inhibiting the disease, i.e., preventing the onset of clinical symptoms, and / or (iii) alleviating the disease, i.e., causing regression of the clinical symptoms or their severity).

[0066] "Prevention" or "preventing" means any treatment of a disease or condition that does not cause the clinical symptoms of the disease or condition to occur. In some embodiments, the compound can be administered to a subject (including a human) at risk or having a family history of the disease or condition.

[0067] "Subject" refers to an animal such as a mammal (including humans) that may have been for the purpose of treatment, observation, or experiment. The methods described herein may be useful in human therapy and / or veterinary medicine. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0068] As used herein, the terms "therapeutically effective amount" or "effective amount" of a compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, mean an amount sufficient to provide a therapeutic benefit when administered to a subject, such as improvement of symptoms or retardation of disease progression. For example, a therapeutically effective amount can be an amount sufficient to reduce the symptoms of a disease or condition in response to an LPAR1 antagonist. The therapeutically effective amount can vary depending on the subject, the disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the mode of administration, and can be readily determined by one of ordinary skill in the art. [Table A]

[0069] As used herein, "LPAR1 inhibitor" refers to any agent that can bind to and inhibit LPAR1. LPA 1LPAR1, which is also known as such, 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 in Castelino et al., 2010 Arthritis Rheum. 2011 May;63(5):1405 - 1415 or Swaney et al., J Pharmacol Exp Ther. 2011 Mar;336(3):693 - 700.

[0070] As used herein, "ACC inhibitor" refers to any agent that can bind to and inhibit acetyl - CoA carboxylase (ACC). An ACC inhibitor can act as an inhibitor or partial inhibitor of ACC. The agent can be a chemical compound or a biological molecule (e.g., a protein or an antibody). The activity of an ACC inhibitor can be measured by methods known in the art, such as those described and cited in U.S. Patent No. 8,969,557 and / or U.S. Patent No. 10,208,063, which are hereby incorporated by reference in their entirety.

[0071] As used herein, an "ASK1 inhibitor" can be any agent that can inactivate apoptosis signal regulating kinase 1 (ASK1) protein. The agent can be a chemical compound or a biological molecule (e.g., a protein or an antibody). ASK1 protein activity can be measured by several different methods. For example, the activity of the ASK1 protein can be determined based on the ability of the ASK1 protein to phosphorylate a substrate protein. Methods for identifying ASK1 inhibitors are known (see, e.g., U.S. Patent Application Publication No. 2007 / 0276050). Exemplary ASK1 substrate proteins include MAPKK3, MAPKK4, MAPKK6, MAPKK7, or fragments thereof. ASK1 protein activity can also be measured by the phosphorylation level of the ASK1 protein, e.g., the phosphorylation level of the threonine residue in the ASK1 protein corresponding to threonine 838 (T838) of the human full-length ASK1 protein or threonine 845 (T845) of the mouse full-length ASK1 protein. For example, if the ASK1 protein contains the full-length human ASK1 protein sequence, an ASK1 inhibitor can attenuate the phosphorylation of T838 in the full-length human ASK1 protein sequence. Site-specific antibodies against human ASK1 T838 or mouse ASK1 T845 can be used to detect the phosphorylation level.

[0072] As used herein, "FXR agonist" refers to any agent that can bind to and activate the farnesoid X receptor (FXR), which may also be referred to as the bile acid receptor (BAR) or NR1H4 (nuclear receptor subfamily 1, group H, member 4). An FXR agonist can act as an agonist or partial agonist of FXR. The agent can be a chemical compound or a biological molecule (e.g., a protein or an antibody). The activity of an FXR agonist can be measured in vitro by several different methods, for example, in a fluorescence resonance energy transfer (FRET) cell-free assay as described in Pellicciari, et al. Journal of Medicinal Chemistry, 2002 vol.15, No.45:3569-72.

[0073] Compound In one embodiment, provided herein is a compound of formula (I),

Chemical Structure

[0074] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound of formula (Ia), [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, R 2 is hydrogen.

[0076] In some embodiments of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, each Y 1 and Y 2 is independently hydrogen, deuterium, or C 2~3 alkynyl, C 1~4 alkoxy, and -C(O)NH-(C 1~4 H 3-9 ) optionally substituted with 1 to 3 same or different substituents each independently selected from C 1~6 alkyl.

[0077] In some embodiments of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, Y 1 is C 1~4 alkyl optionally substituted with 1 to 3 same or different substituents each independently selected from halogen, cyano, and C 1~4 alkoxy, and Y 2 is hydrogen.

[0078] In some embodiments of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, Y 1 is methyl optionally substituted with 1 to 3 same or different substituents each independently selected from -F, -Cl, -CN, and -O-CH 3 .

[0079] In some embodiments of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, Y 1 is -CH 3 .

[0080] In some embodiments of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, Y 2 is hydrogen.

[0081] In some embodiments of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, Z is a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the heteroaryl is optionally substituted with 1 to 3 substituents, the same or different, each independently selected from halogen and C 1~4 alkyl.

[0082] In some embodiments of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, Z is pyridyl optionally substituted with 1 or 2 substituents each independently selected from -F and -Cl.

[0083] In some embodiments of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, Z is

Chemical formula

[0084] In some embodiments of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, Y 1 is -CH 3 , and Z is

Chemical formula

[0085] In some embodiments of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, R 5 is halogen, cyano, C1~4 Alkoxy, -C(O)N(R 5A1 ), and -N(R 5A1 )(R 5A2 ), independently selected from the same or different 1 to 3 substituents, is optionally substituted C 1~6 alkyl, and each R 5A1 and R 5A2 is independently H, C 1~6 alkyl, or C 3~10 cycloalkyl.

[0086] In some embodiments of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, R 5 is -CH 3 .

[0087] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound of formula (II),

Chemical formula

[0088] In some embodiments, the compound of formula (I), (Ia), or (II), or a pharmaceutically acceptable salt thereof, is of formula (IIa):

Chemical formula

[0089] In some embodiments of the compounds of formula (I), (Ia), (II), and (IIa), or a pharmaceutically acceptable salt thereof, R 1 is C 1A cycloalkyl optionally substituted with 1 to 4 R 3~10 which are the same or different, and each R 1A is halogen, cyano, oxo, nitro, C 1~4 alkyl, C 3~10A 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected from cycloalkyl, nitrogen, oxygen, and sulfur, a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, -N(R 1B1 )(R 1B2 ), -O-R 1B1 , -S-R 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) 2 N(R 1B1 )(R 1B2 ), and -N(R 1B1 )S(O) 2 R 1B2 , independently selected, wherein each R 1B1 , R 1B2 , and R 1B3 is independently hydrogen, C 1~6 alkyl, or C 3~6 cycloalkyl, each R 1A alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be the same or different and may be optionally substituted with 1 to 4 R 1C , each R 1C is independently C 1~4 alkyl, halogen, cyano, -O-R 1D1 , or -N(R 1D1 )(R 1D2 ), wherein each R 1D1 and R 1D2 is independently hydrogen or C 1~6 alkyl, and each R 1B1 as well as R 1B2 alkyl and cycloalkyl are optionally substituted with 1 to 3 halogens.

[0090] In some embodiments of the compounds of formula (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, R1 is one or two Rs independently selected from -F and phenyl 1A each being cyclopropyl or cyclobutyl optionally substituted with R, and each phenyl being optionally substituted with 1 to 4 Rs which may be the same or different 1C optionally substituted with R, and each R 1C is independently C 1~4 alkyl, halogen. In some embodiments of the compounds of formulas (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, R 1 is

Chemical formula

[0091] In some embodiments of the compounds of formulas (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, R 1 C 3~10 cycloalkyl is C 5~10 bicyclic cycloalkyl. In some embodiments of the compounds of formulas (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, C 5~10 bicyclic cycloalkyl is C 5~8 bridged bicyclic cycloalkyl.

[0092] In some embodiments of the compounds of formulas (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, C 5~8 bridged bicyclic cycloalkyl is -F, -Cl, -CN, -CH 3 -, -CH 2 -OH, -CHF 2 -, -CF 3 -, -O-CH 3 -, -CO 2 -CH 3 -, -SO 2 -CH 3 -, and phenyl, each optionally substituted with 1 to 3 substituents independently selected from each other and which may be the same or different. In some embodiments of the compounds of formulas (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, C5~8 The bridged bicyclic cycloalkyl is [Chemical formula] as follows.

[0093] In some embodiments of the compounds of formula (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, R 1 is a 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with 1 to 4 R 1A which may be the same or different, and each R 1A is halogen, cyano, oxo, nitro, C 1~4 alkyl, C 3~10 cycloalkyl, a 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, -N(R 1B1 )(R 1B2 ), -O-R 1B1 , -S-R 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) 2 N(R 1B1 )(R 1B2 ), and -N(R 1B1 )S(O) 2 R 1B2 independently selected from, wherein each R 1B1 , R 1B2 , and R 1B3 is independently hydrogen, C 1~6 alkyl, or C 3~6 cycloalkyl, and each R 1AAlkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be the same or different and are each optionally substituted with 1 to 4 R 1C and each R 1C is independently C 1~4 alkyl, halogen, cyano, -O-R 1D1 , or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 is independently hydrogen or C 1~6 alkyl, and each R 1B1 as well as R 1B2 alkyl and cycloalkyl are each optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of formula (I), (Ia), (II), or (IIa), or a pharmaceutically acceptable salt thereof, R 1 is tetrahydropyranyl optionally substituted with 1 to 4 R 3 that are each independently selected from -F, -Cl, -OH, -CN, -CH 2 , -CH 2 F, -CHF 3 , -CF 3 , and -O-CH 1A . In some embodiments of the compounds of formula (I), (Ia), (II), and (IIa), or a pharmaceutically acceptable salt thereof, R 1 is

Chemical formula

[0094] In some embodiments of the compounds of formula (I), (Ia), (II), and (IIa), or a pharmaceutically acceptable salt thereof, R 1 is a 6- to 10-membered aryl optionally substituted with 1 to 4 R 1A and each R 1A is halogen, cyano, oxo, nitro, C 1~4 alkyl, C 3~10A 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected from cycloalkyl, nitrogen, oxygen, and sulfur, a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, -N(R 1B1 )(R 1B2 ), -O-R 1B1 ), -S-R 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) 2 N(R 1B1 )(R 1B2 ), and -NR 1B1 S(O) 2 R 1B2 , independently selected, wherein each R 1B1 , R 1B2 , and R 1B3 is independently hydrogen, C 1~6 alkyl, or C 3~6 cycloalkyl, each R 1A alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be the same or different and may be optionally substituted with 1 to 4 R 1C , each R 1C is independently C 1~4 alkyl, halogen, cyano, -O-R 1D1 , or -N(R 1D1 )(R 1D2 ), wherein each R 1D1 and R 1D2 is independently hydrogen or C 1~6 alkyl, and each R 1B1 as well as R 1B2 alkyl and cycloalkyl are optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of formula (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, R 1 may be the same or different and may be 1 to 4 R 1Ais phenyl optionally substituted with, each R 1A is independently selected from halogen, cyano, C 1~3 alkyl, C 1~4 alkoxy, 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and each alkyl, heterocyclyl, and heteroaryl is optionally substituted with 1 to 4 R 1C and each R 1C is independently cyano, halogen, or C 1~4 alkyl. In some embodiments of the compounds of formulas (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, R 1 is phenyl optionally substituted with 1 to 4 R 1A wherein each R 1A is independently selected from cyano, -CF 3 , -F, -Cl, morpholinyl, phenyl, pyridyl, oxadiazolyl, and each morpholinyl, phenyl, pyridyl, and oxadiazolyl is optionally substituted with 1 to 4 R 1C and each R 1C is independently cyano, halogen, or C 1~4 alkyl. In some embodiments of the compounds of formulas (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, R 1 is [Chemical formula] .

[0095] In some embodiments of the compounds of formulas (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, R 1 is 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with 1 to 4 R 1A wherein each R1A is independently selected from halogen, cyano, oxo, nitro, C 1~4 alkyl, C 3~10 cycloalkyl, a 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, -N(R 1B1 )(R 1B2 ), -O-R 1B1 , -S-R 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) 2 N(R 1B1 )(R 1B2 ), and -NR 1B1 S(O) 2 R 1B2 , where each R 1B1 , R 1B2 , and R 1B3 is independently hydrogen, C 1~6 alkyl, or C 3~6 cycloalkyl, each R 1A alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be the same or different and may be optionally substituted with 1 to 4 R 1C , each R 1C is independently C 1~4 alkyl, halogen, cyano, -O-R 1D1 , or -N(R 1D1 )(R 1D2 ), where each R 1D1 and R 1D2 is independently hydrogen or C 1~6 alkyl, and each R 1B1 as well as R 1B2Alkyl and cycloalkyl are optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of formula (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, R 1 is thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, or pyridazinyl, each optionally substituted with 1 to 4 R 1A which may be the same or different, and each R 1A is halogen, cyano, oxo, C 1~4 alkyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen and oxygen, -N(R 1B1 )(R 1B2 ), -O-R 1B1 , and -S(O) 0-2 R 1B1 independently selected from, wherein each R 1B1 and R 1B2 is independently hydrogen or C 1~6 alkyl, and each R 1A alkyl, cycloalkyl, and heterocyclyl are optionally substituted with 1 to 4 R 1C which may be the same or different, and each R 1C is independently C 1~4 alkyl, halogen, or cyano, and each R 1B1 as well as R 1B2 alkyl and cycloalkyl are optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of formula (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, R 1 is

Chemical formula

[0096] In some embodiments of the compounds of formula (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, R 3 is hydrogen.

[0097] In some embodiments of the compounds of formula (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, R 3 is selected from deuterium, halogen, C 1~6 alkyl, C 3~6 cycloalkyl, -O-R 3A1 , and -N(R 3A1 )(R 3A2 ), C 1~6 alkyl is optionally substituted with the same or different one to three substituents independently selected from C 1~4 alkoxy and halogen, and each R 3A1 and R 3A2 is independently hydrogen or C 1~4 alkyl optionally substituted with the same or different one to three halogens. In some embodiments of the compounds of formula (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, R 3 is selected from halogen or C 1~3 alkyl optionally substituted with one to three halogens. In some embodiments, the halogen is -F. In some embodiments of the compounds of formula (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, R 3 is selected from -F, -Cl, -CH 3 , or -CF 3 .

[0098] In some embodiments of the compounds of formula (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, each R 4 is independently selected from deuterium, halogen, C 1~6 alkyl, C 3~6 cycloalkyl, -O-R 4A1 , and -N(R 4A1 )(R 4A2 ), C 1~6 alkyl is optionally substituted with the same or different one to three substituents independently selected from C 1~4 alkoxy and halogen, and each R 4A1 and R 4A2is independently hydrogen or C optionally substituted with hydrogen, or one to three identical or different halogens 1~4 alkyl. In some embodiments of the compounds of formulas (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, each R 4 is halogen. In some embodiments of the compounds of formulas (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, each R 4 is -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.

[0099] In some embodiments of the compounds of formulas (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, R 6 is hydrogen, halogen, cyano, C 1~4 alkyl, C 1~4 alkoxy, or C 3~6 cycloalkyl, where C 1~4 alkyl is optionally substituted with one to three identical or different substituents selected from C 1~4 alkoxy and halogen. In some embodiments of the compounds of formulas (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, R 6 is halogen. In some embodiments of the compounds of formulas (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, it is -F or -Cl.

[0100] In some embodiments of the compounds of formulas (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, R 7is hydrogen, halogen, cyano, C 1~4 alkyl, C 1~4 alkoxy, or C 3~6 cycloalkyl, and C 1~4 alkyl is optionally substituted with 1 to 3 same or different substituents selected from C 1~4 alkoxy and halogen. In some embodiments of the compounds of formula (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, R 7 is hydrogen or halogen. In some embodiments of the compounds of formula (I), (Ia), (II), and (IIa), or pharmaceutically acceptable salts thereof, R 7 is hydrogen or -F.

[0101] In some embodiments, the compound of formula (I), (Ia), (II), or (IIa), or a pharmaceutically acceptable salt thereof is selected from the group consisting of.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0102] In some embodiments, the compound of formula (I), (Ia), (II), or (IIa), or a pharmaceutically acceptable salt thereof is

Chemical formula

[0103] In some embodiments, the compound of formula (I), (Ia), (II), or (IIa), or a pharmaceutically acceptable salt thereof, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the compound of formula (I), (Ia), (II), or (IIa), or a pharmaceutically acceptable salt thereof, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments, the compound of formula (I), (Ia), (II), or (IIa), or a pharmaceutically acceptable salt thereof, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the compound of formula (I), (Ia), (II), or (IIa), or a pharmaceutically acceptable salt thereof, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0107] Pharmaceutical Compositions and Modes of Administration Furthermore, the present disclosure provides a pharmaceutical composition comprising, at least, a compound of the present disclosure, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient, together with a pharmaceutically acceptable carrier.

[0108] The pharmaceutical composition of the present disclosure may further comprise one or more other compounds as active ingredients, such as prodrug compounds or other enzyme inhibitors.

[0109] The composition is suitable for oral administration, rectal administration, topical administration, parenteral administration (including subcutaneous administration, intramuscular administration, and intravenous administration), intraocular administration (ophthalmic administration), pulmonary administration (nasal administration or buccal inhalation administration) or nasal administration. However, the most suitable route in any given case depends on the nature and severity of the condition being treated and the nature of the active ingredient. The composition can be conveniently presented in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art.

[0110] In actual use, the compounds of the present disclosure can be combined as active ingredients in a homogeneous admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a variety of forms depending on the form of the preparation desired for administration, for example, oral or parenteral (including intravenous). When preparing a composition for an oral dosage form, for example, in the case of oral liquid preparations such as suspensions, elixirs, and solutions, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., or, for example, in the case of oral solid preparations such as powders, hard capsules, soft capsules, and tablets, carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc., any of the usual pharmaceutical media can be used, and solid oral preparations are preferred over liquid preparations.

[0111] For ease of their administration, tablets and capsules represent the most advantageous oral unit dosage forms, in which case a solid pharmaceutical carrier is used. If desired, the tablets can be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of the active compound. The proportion of the active compound in these compositions can, of course, vary widely and can conveniently be from about 2 percent to about 60 percent by unit weight. The amount of the active compound in such therapeutically useful compositions is an amount such that an effective dosage is obtained. The active compound can also be administered nasally, for example, as droplets or a spray.

[0112] Tablets, pills, capsules, etc. may also contain binders such as gum tragacanth, acacia, corn starch, or gelatin, excipients such as dicalcium phosphate, disintegrants such as corn starch, potato starch, alginic acid, lubricants such as magnesium stearate, and sweeteners such as sucrose, lactose, or saccharin. When the unit dosage form is a capsule, it may contain a liquid carrier such as fatty oil in addition to the materials of the above types.

[0113] Various other materials may be present as coatings or to improve the physical form of the unit dosage form. For example, tablets may be coated with shellac, sugar, or both. Syrups or elixirs may contain, in addition to the active ingredient, sucrose as a sweetener, methylparaben and propylparaben as preservatives, dyes, and flavoring agents such as cherry or orange flavor.

[0114] In some embodiments, the compounds of the present disclosure may also be used as salts having various counter cations to obtain orally available formulations.

[0115] The compounds of the present disclosure may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can be prepared in glycerol in oil, liquid polyethylene glycols, and mixtures thereof. Under normal conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms.

[0116] Pharmaceutical forms suitable for use in injection include sterile aqueous solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that it can be easily placed in a syringe. The form must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0117] Any suitable route of administration can be used to provide a mammalian, particularly a human, with an effective dose of the compounds of the present disclosure. For example, oral, rectal, topical, parenteral, intraocular, intralung, intranasal, etc. can be used. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc. In some embodiments, the compounds of the present disclosure are administered orally.

[0118] Kit Also provided herein are kits comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and a suitable package. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit comprises a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and a label and / or instructions for use of the compound in the treatment of an indication comprising a disease or condition described herein.

[0119] Also provided herein are articles of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, in a suitable container. The container can be a vial, a bottle, an ampule, a filled syringe, and an infusion bag.

[0120] Therapeutic Methods and Uses The present disclosure further relates to the use of the compounds disclosed herein for the treatment and / or prevention of diseases and / or conditions through binding of LPAR1 by the compounds. Further, the present disclosure relates to the use of the compounds for the preparation of a medicament for the treatment and / or prevention of diseases and / or conditions through binding of LPAR1 by the compounds.

[0121] The medicaments referred to herein can be prepared by conventional processes comprising a combination of a compound according to the present disclosure and a pharmaceutically acceptable carrier.

[0122] In some embodiments, provided herein is a method of doing so in a patient in need of treatment and / or prevention of an LPAR1-mediated disease or condition, 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.

[0123] In some embodiments, LPAR1-mediated diseases or conditions include those in which there is an absolute or relative excess amount of LPA present and / or observed.

[0124] In some embodiments, LPAR1-mediated diseases or conditions include fibrosis, wound healing, cancer, pain, respiratory disorders, allergic disorders, nervous system disorders, cardiovascular disorders, or inflammatory disorders.

[0125] In some embodiments, the LPAR1-mediated disease or condition is interstitial lung disease (ILD). In some embodiments, the interstitial lung disease (ILD) is nonspecific interstitial pneumonitis (NSIP), sarcoidosis, asbestosis, ILD associated with occupational exposure, progressive fibrotic ILD, idiopathic interstitial pneumonia (IIP), connective tissue disease-associated interstitial lung disease (CTD-ILD), rheumatoid arthritis-associated ILD, scleroderma-associated ILD, or exogenous alveolitis.

[0126] In some embodiments, the LPAR1-mediated disease or condition is chronic kidney disease (CKD). In some embodiments, the chronic kidney disease is complement glomerulopathy, membranous glomerulopathy, polycystic kidney disease, IgA nephropathy, focal segmental glomerulosclerosis (FSGS), or Alport syndrome.

[0127] In some embodiments, the LPAR1-mediated disease or condition includes fibrosis. In some embodiments, the fibrosis includes pulmonary fibrosis, renal fibrosis, hepatic fibrosis, ocular fibrosis, or cardiac fibrosis.

[0128] In some embodiments, the LPAR1-mediated disease or condition includes pulmonary fibrosis. In some embodiments, the pulmonary fibrosis includes idiopathic pulmonary fibrosis (IPF). In some embodiments, the pulmonary fibrosis includes Progressive Fibrotic interstitial lung disease (PF-ILD). In some embodiments, the pulmonary fibrosis includes secondary pulmonary fibrosis secondary to systemic inflammatory diseases such as rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrosing alveolitis, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, chronic asthma, silicosis, asbestos-induced lung or pleural fibrosis, acute lung injury and acute respiratory distress (including those induced by bacterial pneumonia, trauma, viral pneumonia, ventilator-induced, non-pulmonary sepsis-induced, and aspiration-induced).

[0129] In some embodiments, the LPAR1-mediated disease or condition includes renal fibrosis. In some embodiments, the renal fibrosis includes chronic kidney disease (renal fibrosis) associated with injury / fibrosis, such as glomerulonephritis secondary to systemic inflammatory diseases such as lupus and scleroderma, diabetes, IgA nephropathy, hypertension, allografts, and Alport; intestinal fibrosis, such as scleroderma and radiation-induced intestinal fibrosis.

[0130] In some embodiments, the LPAR1-mediated disease or condition includes liver fibrosis. In some embodiments, the liver fibrosis includes cirrhosis, alcohol-induced liver fibrosis, non-alcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis, infectious diseases, or virus-induced liver fibrosis (e.g., chronic HCV infection), and autoimmune hepatitis.

[0131] In some embodiments, the LPAR1-mediated disease or condition includes, for example, radiation-induced head and neck fibrosis.

[0132] In some embodiments, the LPAR1-mediated disease or condition includes, for example, LASIK (laser-assisted in situ keratomileusis), corneal transplantation, or trabeculectomy. In some embodiments, the compounds of formula (I), (Ia), (II), or (IIa), or a pharmaceutically acceptable salt thereof, are used to improve corneal sensitivity reduction caused by corneal surgery such as LASIK or cataract surgery, corneal sensitivity reduction caused by corneal degeneration, and dry eye symptoms caused thereby. In some embodiments, the compounds of formula (I), (Ia), (II), or (IIa), or a pharmaceutically acceptable salt thereof, are used in the treatment or prevention of eye inflammation and allergic conjunctivitis, vernal conjunctivitis, and papillary conjunctivitis. In some embodiments, the compounds of formula (I), (Ia), (II), or (IIa), or a pharmaceutically acceptable salt thereof, are used in the treatment or prevention of Sjogren's disease or inflammatory diseases associated with dry eye.

[0133] In some embodiments, the LPAR1-mediated disease or condition includes, for example, hypertrophic scars and keloids of burns or surgery, sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, mixed connective tissue disease, and other fibrotic conditions such as Peyronie's disease.

[0134] In some embodiments, the LPAR1-mediated disease or condition includes pain. In some embodiments, the pain includes neuropathic pain. In some embodiments, the pain includes acute pain. In some embodiments, the pain includes chronic pain.

[0135] In some embodiments, the LPAR1-mediated disease or condition includes cancer. In some embodiments, the cancer includes ovarian cancer, colon cancer, prostate cancer, breast cancer, melanoma, head and neck cancer, intestinal cancer (colorectal cancer), and thyroid cancer. In some embodiments, the cancer includes solid tumors or hematological tumors (such as leukemia) of (at any stage of the disease regardless of the presence or absence of metastasis) the bladder, intestine, brain, breast, endometrium, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas, or other endocrine organs (thyroid), prostate, skin (melanoma or basal cell carcinoma), etc. In some embodiments, the cancer includes acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brainstem glioma, brain tumor, brain and spinal cord tumor, breast cancer, bronchial tumor, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, fetal tumor, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromaltumors, GIST), gastrointestinal stromal tumors, germ cell tumors, gliomas, hairy cell leukemia, head and neck cancers, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi sarcoma, kidney 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, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenström macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, oral cancer, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, low malignant potential ovarian tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, moderately differentiated pineal parenchymal tumor, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasma cell tumor / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, Kaposi, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell cancer, stomach (gastric) cancer, supratentorial primitive, neuroectodermal tumor, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic cancer, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, and Wilms tumor.

[0136] In some embodiments, the LPAR1-mediated disease or condition includes a respiratory or allergic disorder. In some embodiments, the respiratory or allergic disorder includes asthma, peribronchiolar fibrosis, bronchiolitis obliterans, and chronic obstructive pulmonary disease (COPD). In some embodiments, COPD includes chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or airway inflammation, and cystic fibrosis. In some embodiments, the respiratory disease includes adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, hyperventilation with hypocapnia, childhood-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, and hypoxia.

[0137] In some embodiments, the LPAR1-mediated disease or condition includes a neurological disorder. In some embodiments, the neurological disorder includes Alzheimer's disease, cerebral edema, cerebral ischemia, stroke, multiple sclerosis, neuropathy, Parkinson's disease, neurological conditions found after blunt or surgical trauma (including postoperative cognitive dysfunction and spinal cord or brainstem injury), and the neurological aspects of disorders such as degenerative disc disease and sciatica.

[0138] In some embodiments, the LPAR1-mediated disease or condition includes a cardiovascular disorder. In some embodiments, the cardiovascular disorder includes arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina pectoris; cardiac dysfunction; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis; stroke; peripheral obstructive arterial disease of the limb, organ, or tissue; reperfusion injury after ischemia of the brain, heart, or other organ or tissue; endotoxin, surgical, or traumatic shock; hypertension; valvular heart disease; heart failure; abnormal blood pressure; shock; vasoconstriction (including those related to migraine); vascular abnormalities, and cardiovascular insufficiency limited to a single organ or tissue.

[0139] In some embodiments, the LPAR1-mediated disease or condition includes pulmonary fibrosis, renal fibrosis, liver fibrosis, scarring, asthma, rhinitis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, interstitial lung fibrosis, arthritis, allergy, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, pain, proliferative disorders, and inflammatory conditions.

[0140] In some embodiments, the LPAR1-mediated disease or condition is a metabolic disorder or a liver disease. In some embodiments, the liver disease is hepatitis C, liver cancer, familial combined hyperlipidemia, non-alcoholic fatty liver disease (NAFLD), progressive familial intrahepatic cholestasis, primary biliary cirrhosis (PBC), or primary sclerosing cholangitis (PSC). In some embodiments, the liver disease is PSC. In some embodiments, the liver disease includes portal hypertension. In some embodiments, liver cancer includes hepatocellular carcinoma (HCC), cholangiocarcinoma, angiosarcoma, or hemangiosarcoma. In some embodiments, liver cancer 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 embodiments, the liver disease is NASH.

[0141] In some embodiments, provided herein is a method of treating and / or preventing NAFLD or NASH in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (II), 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 comprises liver fibrosis. In some embodiments, NAFLD or NASH comprises cirrhosis. In some embodiments, the cirrhosis is compensated cirrhosis. In some embodiments, the cirrhosis is decompensated cirrhosis. In some embodiments, NAFLD or NASH comprises HCC.

[0142] In some embodiments, provided herein is a method of preventing a liver disease or condition in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (II), 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.

[0143] In some embodiments, the present disclosure relates to the use of a compound according to formula (I), (Ia), (II), or (IIa), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention and / or treatment of an LPAR1-mediated disease or condition disclosed herein.

[0144] Dosage The effective dosage of the active ingredient used may vary depending on the particular compound used, the mode of administration, the condition being treated, and the severity of the condition being treated. Such dosages can be readily ascertained by one of ordinary skill in the art.

[0145] When treating or preventing an LPAR1-mediated disease or condition for which a compound of the present disclosure is needed, generally satisfactory results are obtained when the compound of the present disclosure is administered at a daily dosage of about 0.1 milligram to about 300 milligrams per kilogram of body weight of the animal. In some embodiments, the compound of the present disclosure is administered as a single daily dose or as divided doses 2 to 6 times a day, or in a sustained release form. For most large mammals, the total daily dosage is from about 1 milligram to about 1000 milligrams, or from about 1 milligram to about 50 milligrams. In the case of a 70 kg adult human, the total daily dosage will generally be from about 0.1 milligram to about 200 milligrams. This dosage regimen can be adjusted to provide an optimal therapeutic response. In some embodiments, the total daily dosage is from about 1 milligram to about 900 milligrams, from about 1 milligram to about 800 milligrams, from about 1 milligram to about 700 milligrams, from about 1 milligram to about 600 milligrams, from about 1 milligram to about 400 milligrams, from about 1 milligram to about 300 milligrams, from about 1 milligram to about 200 milligrams, from about 1 milligram to about 100 milligrams, from about 1 milligram to about 50 milligrams, from about 1 milligram to about 20 milligrams, or from about 1 milligram to about 10 milligrams.

[0146] The compound or composition thereof of the present application can be administered once, twice, three times, or four times a day using any of the suitable modes described above. Also, the administration or treatment with the compound can be continued for several days. For example, usually, the treatment will continue for at least 7 days, 14 days, or 28 days for one treatment cycle. The treatment cycles will periodically alternate with a rest period of about 1 to 28 days, usually about 7 days or about 14 days, between cycles. The treatment cycles can also be continuous in other embodiments.

[0147] In some embodiments, the method comprises administering an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose in increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dose can be increased daily, every other day, twice a week, or once a week.

[0148] Combination In some embodiments, a compound of formula (I), (Ia), (II), or (IIa) provided herein, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more additional therapeutic agents for treating or preventing a disease or condition disclosed herein. In some embodiments, the one or more additional therapeutic agents are 1, 2, 3, or 4 additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are 1 additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are 2 additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are 3 additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are 4 additional therapeutic agents.

[0149] In some embodiments, a pharmaceutical composition provided herein comprises 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 1, 2, 3, or 4 additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are 1 additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are 2 additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are 3 additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are 4 additional therapeutic agents.

[0150] In some embodiments, one or more additional therapeutic agents are angiotensin converting enzyme (ACE) inhibitors, adenosine A3 receptor agonists, adiponectin receptor agonists, AKT protein kinase inhibitors, AMP kinase activators, AMP-activated protein kinase (AMPK) activators, amylin receptor agonists, angiotensin II AT-1 receptor antagonists, androgen receptor agonists, apoptosis signal-regulating kinase 1 (ASK1) inhibitors, ATP citrate lyase inhibitors, apolipoprotein C3 (APOC3) antagonists, autophagy protein modulators, autotaxin inhibitors, Axl tyrosine kinase receptor inhibitors, Bax protein stimulators, bioactive lipids, calcitonin agonists, cannabinoid receptor modulators, caspase inhibitors, caspase-3 stimulators, cathepsin inhibitors (e.g., cathepsin B inhibitors), caveolin-1 inhibitors, CCR2 chemokine antagonists, CCR3 chemokine antagonists, CCR5 chemokine antagonists, CD3 antagonists, chloride channel stimulators, cholesterol solubilizers, CNR1 inhibitors, cyclin D1 inhibitors, cytochrome P450 7A1 inhibitors, cytochrome P450 2E1 (CYP2E1) inhibitors, diacylglycerol O acyltransferase 1 (DGAT1) inhibitors, diacylglycerol O acyltransferase 1 (DGAT2) inhibitors, CXCR4 chemokine antagonists, dipeptidyl peptidase IV inhibitors, endosialin modulators, endothelial nitric oxide synthase stimulators, eotaxin ligand inhibitors, extracellular matrix protein modulators, farnesoid X receptor agonists, fatty acid synthase inhibitors, FGF1 receptor agonists, fibroblast activationprotein, fibroblast activation protein (FAP) inhibitor, fibroblast growth factor receptor ligand (e.g., FGF-15, FGF-19, FGF-21), fish oil, galectin-3 inhibitor, glucagon receptor agonist, glucagon-like peptide 1 receptor agonist, glucocorticoid receptor antagonist, glucose 6-phosphate 1-dehydrogenase inhibitor, glutaminase inhibitor, glutathione precursor, G protein-coupled bile acid receptor 1 agonist, G protein-coupled receptor 84 antagonist, Hedgehog (Hh) modulator, hepatitis C virus NS3 protease inhibitor, hepatocyte nuclear factor 4 alpha modulator (HNF4A), hepatocyte growth factor modulator, histone deacetylase inhibitor, HMG CoA reductase inhibitor, 11β-hydroxysteroid dehydrogenase (11β-HSD1) inhibitor, hypoxia-inducible factor-2 alpha inhibitor, IL-1β antagonist, IL-6 receptor agonist, IL-10 agonist, IL-11 antagonist, IL-17 antagonist, ileal sodium-bile acid cotransporter inhibitor, insulin sensitizer, insulin ligand agonist, insulin receptor agonist, integrin modulator, integrin antagonist interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, Jak2 tyrosine kinase inhibitor, ketohexokinase (KHK) inhibitor, Klotho beta stimulator, leptin, leptin analog, 5-lipoxygenase inhibitor, lipoprotein lipase inhibitor, liver X receptor, LPL gene stimulator, lysophosphatidate-1 receptor (LPAR-1) antagonist, lysyl oxidase homolog 2 (LOXL2) inhibitor, LXR inverse agonist, macrophage mannose receptor 1 modulator, matrix metalloproteinase (Matrixmetalloproteinase, MMP) inhibitor, MCH receptor-1 antagonist, MEKK-5 protein kinase inhibitor, membrane copper amine oxidase (VAP-1) inhibitor, methionine aminopeptidase-2 inhibitor, methyl CpG binding protein 2 modulator, MicroRNA-132 (miR-132) antagonist, MicroRNA-21 (miR-21) inhibitor, mitochondrial uncoupler, mixed lineage kinase-3 inhibitor, myelin basic protein stimulator, NACHT LRR PYD domain protein 3 (NACHT LRR PYD domain protein 3, NLRP3) inhibitor, NAD-dependent deacetylase sirtuin-1 stimulator, NADPH oxidase inhibitor (NADPH oxidase, NOX), nicotinic acid receptor 1 agonist, P2X7 purinergic receptor modulator, P2Y13 purinergic receptor stimulator, PDE 3 inhibitor, PDE 4 inhibitor, PDE 5 inhibitor, PDGF receptor beta modulator, peptidyl-prolyl cis-trans isomerase A inhibitor, phenylalanine hydroxylase stimulator, phospholipase C inhibitor, PPAR alpha agonist, PPAR gamma agonist, PPAR delta agonist, PPAR gamma modulator, PPAR alpha / delta agonist, PPAR alpha / gamma / delta agonist, protease-activated receptor 2 antagonist, protein kinase modulator, Rho associated protein kinase 2 (ROCK2) inhibitor, S-nitrosoglutathione reductase (Snitrosoglutathione reductase, GSNOR) enzyme inhibitor, sodium glucose transporter-2 (Sodium glucose transporter-2, SGLT2) inhibitor, SREBP transcription factor inhibitor, STAT-1 inhibitor, STAT-3 modulator, stearoyl CoA desaturase-1 inhibitor, S-nitrosoglutathione reductase (GSNOR) enzyme inhibitor, suppressor of cytokine signaling-1 stimulator, suppressor of cytokine signaling-3 stimulator, spleen tyrosine kinase (Spleen tyorosineSelected from kinase, SYK inhibitor, transforming growth factor β (TGF-β), TGF-β antagonist (e.g., TGF-β1 antagonist, TGF-β2 antagonist, TGF-β3 antagonist, latent TGF-β complex modulator), TGF-β receptor antagonist, transforming growth factor β activated kinase 1 (TAK1), thyroid hormone receptor beta agonist, Toll-like receptor (TLR)-4 antagonist, transglutaminase inhibitor, tumor necrosis factor alpha (TNFα) ligand inhibitor, tumor progression locus 2 (Tpl2) kinase inhibitor, tyrosine kinase receptor modulator, GPCR modulator, nuclear hormone receptor modulator, WNT modulator, YAP / TAZ modulator, and zonulin inhibitor.

[0151] Non-limiting examples of one or more additional therapeutic agents include the following. ACE inhibitors such as enalapril; Acetyl-CoA carboxylase (ACC) inhibitors such as NDI-010976 (firsocostat), DRM-01, gemcabene, PF-05175157, QLT-091382, or PF-05221304; Acetyl-CoA carboxylase / diacylglycerol O-acyltransferase 2 inhibitors such as PF-07055341; Aldehyde dehydrogenase inhibitors such as ADX-629; Adenosine receptor agonists such as CF-102 (namodenoson), CF-101, CF-502, or CGS21680; Adiponectin receptor agonists such as ADP-355 or ADP-399; Amylin / calcitonin receptor agonists such as KBP-042 or KBP-089; AMP-activated protein kinase stimulators such as PXL-770 or O-304; AMP kinase activators / ATP citrate lyase inhibitors such as bempedoic acid (ETC-1002, ESP-55016); AMP-activated protein kinase / endothelial nitric oxide synthase / NAD-dependent deacetylase sirtuin-1 stimulators such as NS-0200 (leucine + metformin + sildenafil); Androgen receptor agonists such as LPCN-1144; Angiotensin II AT-1 receptor antagonists such as irbesartan; Angiopoietin-related protein-3 inhibitors such as IONIS-ANGPTL3-LRx; Autotaxin inhibitors such as PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, AM-063, or BBT-877; Axl tyrosine kinase receptor inhibitors such as bemcentinib (BGB-324, R-428); Bax protein stimulators such as CBL-514; Bioactive lipids such as DS-102; Type 1 cannabinoid receptor (CNR1) inhibitors such as namasizumab, GWP-42004, REV-200, or CRB-4001; Caspase inhibitors such as emricasan; Total cathepsin B inhibitors such as VBY-376; Total cathepsin inhibitors such as VBY-825; CCR2 / CCR5 chemokine antagonists such as cenicriviroc, maraviroc, CCX-872, or WXSH-0213; CCR2 chemokine antagonists such as propelargonin; CCR2 chemokine / angiotensin II AT-1 receptor antagonists such as DMX-200 or DMX-250; CCR2 / CCR5 chemokine antagonists such as LJC-242 (tropifexor + cenicriviroc) and FXR agonists; CCR3 chemokine antagonists such as belinostat; Chloride channel stimulants such as cobiprostone or lubiprostone; CD3 antagonists such as NI-0401 (foralumab); CXCR4 chemokine antagonists such as AD-214; Diacylglycerol acyltransferase 1 (DGAT1) inhibitors such as GSK-3008356; Diacylglycerol O-acyltransferase 1 (DGAT1) / cytochrome P450 2E1 (CYP2E1) inhibitors such as SNP-610, Diacylglycerol acyltransferase 2 (DGAT2) inhibitors such as IONIS-DGAT2Rx, or PF-06865571; Dipeptidyl peptidase IV inhibitors such as linagliptin or evogliptin; Eotaxin ligand inhibitors such as belinostat or CM-101; Extracellular matrix protein modulators such as CNX-024; Farnesoid X receptor (FXR) agonists such as AGN-242266, AGN-242256, EP-024297, RDX-023, BWL-200, AKN-083, EDP-305, GNF-5120, GS-9674, LMB-763, obeticholic acid, Px-102, Px-103, M790, M780, M450, M-480, MET-409, PX20606, EYP-001, TERN-101, TC-100, INT-2228; Farnesoid X receptor (FXR) / G protein-coupled bile acid receptor 1 (TGR5) agonists such as INT-767, Fatty acid synthase inhibitors such as TVB-2640; FGF receptor agonists / Klotho beta stimulants such as BFKB-8488A (RG-7992); Fibroblast growth factor 19 (rhFGF19) / cytochrome P450 (CYP) 7A1 inhibitors such as NGM-282; Fibroblast growth factor 21 (FGF-21) ligands such as BMS-986171, BIO89-100, B-1344, or BMS-986036; Fibroblast growth factor 21 (FGF-21) / glucagon like peptide 1 (GLP-1) agonists such as YH-25723 (YH-25724, YH-22241) or AKR-001; Fish oil compositions such as ethyl eicosapentaenoate (Vascepa (registered trademark)); Galectin-3 inhibitors such as GR-MD-02, GB-1107 (Gal-300), or GB1211 (Gal-400); 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; Glucocorticoid receptor antagonists such as CORT-118335 (millicortilant); Glucose 6-phosphate 1-dehydrogenase inhibitors such as ST001; G protein-coupled bile acid receptor 1 (TGR5) agonists such as RDX-009 or INT-777; Heat shock protein 47 (HSP47) inhibitors such as ND-L02-s0201; HMG CoA reductase inhibitors such as atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin; Hypoxia-inducible factor-2 alpha inhibitors such as PT-2567; IL-10 agonists such as peg-ilodecakin; Ileal sodium-bile acid cotransporter inhibitors such as odesivixibat (A-4250), polyxibat potassium ethanol adduct hydrate (SHP-262), GSK2330672, CJ-14199, or elobixibat (A-3309); Insulin sensitizers such as KBP-042, MSDC-0602K, MSDC-5514, Px-102, RG-125 (AZD4076), VVP-100X, CB-4211, or ETI-101; Insulin ligand / ds insulin receptor agonists such as ORMD-0801; Integrin antagonists such as IDL-2965; IL-6 receptor agonists such as KM-2702; Ketohexokinase (KHK) inhibitors such as PF-06835919; Beta Klotho (KLB)-FGF1c agonists such as MK-3655 (NGM-313); 5-Lipoxygenase inhibitors such as tepelukast (MN-001), DS-102 (AF-102); Lipoprotein lipase inhibitors such as CAT-2003; LPL gene stimulants such as alipogene tiparvovec; Liver X receptor (LXR) modulators such as PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, or SR-9238; Lysophosphatidic acid-1 receptor antagonists such as BMT-053011, UD-009 (CP-2090), AR-479, ITMN-10534, BMS-986020, or KI-16198; Lysyl oxidase homolog 2 inhibitors such as simtuzumab or PXS-5382A (PXS-5338); Macrophage mannose receptor 1 modulators such as tilmanocept-Cy3 (technetium Tc 99m tilmanocept); Membrane copper amine oxidase (VAP-1) inhibitors such as TERN-201; Inhibitors of MEKK-5 protein kinase (ASK-1), such as GS-4997, SRT-015, or GS-444217, GST-HG-151; MCH receptor-1 antagonists, such as CSTI-100 (ALB-127158); Methionine aminopeptidase-2 inhibitors, such as ZGN-839, ZGN-839, or ZN-1345; Methyl CpG-binding protein 2 modulators, such as mercaptamine; Mitochondrial uncoupling agents, such as 2,4-dinitrophenol or HU6; Mixed lineage kinase-3 inhibitors, such as URMC-099-C; Myelin basic protein stimulants, such as olesoxime; NADPH oxidase 1 / 4 inhibitors, such as GKT-831 or APX-311; Nicotinic acid receptor 1 agonists, such as ARI-3037MO; Nitazoxinide; NACHT LRR PYD domain-containing protein 3 (NLRP3) inhibitors, such as KDDF-201406-03, NBC-6, IFM-514, or JT-194 (JT-349); Nuclear receptor modulators, such as DUR-928 (DV-928); P2X7 purinergic receptor modulators, such as SGM-1019; P2Y13 purinergic receptor stimulants, such as CER-209; PDE 3 / 4 inhibitors, such as tipepidast (MN-001); PDE 5 inhibitors, such as sildenafil or MSTM-102; PDGF receptor β modulators, such as BOT-191 or BOT-509; Peptidyl-prolyl cis-trans isomerase inhibitors, such as CRV-431 (CPI-432-32), NVP-018, or NV-556 (NVP-025); Phenylalanine hydroxylase stimulants, such as HepaStem; PPAR agonists such as elafibranor (GFT-505), MBX-8025, deuterated pioglitazone R-enantiomer, pioglitazone, DRX-065, saroglitazar, or IVA-337 (including PPAR alpha agonists, PPAR alpha / delta agonists, PPAR alpha / delta / gamma agonists, PPAR delta agonists); aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, pemafibrate, ronifibrate, simfibrate, omega-3 fatty acids (fish oil, e.g., eicosapentaenoic acid ethyl (Vascepa®), or docosahexaenoic acid), pirinixic acid, GW409544, AZ 242, LY518674, NS-220, AVE8134, BMS-711939, aleglitazar, muraglitzar, or saroglitazar, etc., PPAR alpha agonists; PPAR alpha / delta agonists such as elafibranor; PPAR alpha / delta / gamma agonists such as lanifibranor; PPAR delta agonists such as seladelpar; Protease-activated receptor-2 antagonists such as PZ-235; Protein kinase modulators such as CNX-014; Rho-associated protein kinase (ROCK) inhibitors such as REDX-10178 (REDX-10325) or KD-025; Semicarbazide-sensitive amine oxidase / vascular adhesion protein-1 (SSAO / VAP-1) inhibitors such as PXS-4728A; S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors such as SL-891; Sodium-glucose transporter-2 (SGLT2) inhibitors such as ipragliflozin, remogliflozin etabonate, ertugliflozin, dapagliflozin, tofogliflozin, or sotagliflozin; SREBP transcription factor inhibitors such as CAT-2003 or MDV-4463; Stearoyl-CoA desaturase-1 inhibitors such as Arachidonic acid; Thyroid hormone receptor (THR) beta agonists such as Resmetrio (MGL-3196), MGL-3745, or VK-2809; TLR-2 / TLR-4 antagonists such as VB-201 (CI-201); TLR-4 antagonists, for example, JKB-121; Tyrosine kinase receptor modulators such as CNX-025 or GFE-2137 (repurposed nitazoxanide); GPCR modulators, for example, CNX-023; Nuclear hormone receptor modulators such as Px-102; Xanthine oxidase / urate anion exchanger 1 (URAT1) inhibitors such as RLBN-1001, RLBN-1127; and Zonulin inhibitors such as Lorazotide acetate (INN-202).

[0152] Additional non-limiting examples of one or more additional therapeutic agents include the following. ACE inhibitors such as Benzepril, Imidapril, etc., Adenosine A3 receptor antagonists such as FM-101, Adropin stimulants such as RBT-2, Albumin modulators such as SYNT-002, Adenosine / mineralocorticoid receptor antagonists such as MT-3995, Allogeneic bone marrow-derived mesenchymal stromal cell therapies such as ORBCEL-M, Allogeneic expanded adipose-derived stem cell therapies such as Elixcyte™, AMP-activated protein kinase stimulators / preprotein convertase PC9 inhibitors such as O-304, AMP-activated protein kinase stimulators such as DZCY-01, MK-8722, PXL-770; Angiotensin II AT-1 receptor / CCR2 chemokine antagonists such as DMX-200, Angiotensin II AT-2 receptor antagonists such as MOR-107, irbesartan, Angiotensin II receptor antagonists such as losartan, Angiotensinogen ligand inhibitors such as ALN-AGT, Anti-C1 antibodies such as BIVV-009 (stimuvumab), Anti-CB1 antibodies, e.g., GFB-024; Anti-CX3CR1 nanobodies such as BI-655088, Anti-IL-6 antibodies, e.g., COR-001; Anti-VEGF-B antibodies such as CSL-346, APOA1 gene stimulators / bromodomain-containing protein 2 / bromodomain-containing protein 4 inhibitors such as apabetalone, Bone morphogenetic protein-7 ligand modulators such as BMP-7, Calcium channel inhibitors such as TBN (xiaotongqin), Cannabinoid CB1 receptor antagonists such as JNJ-2463, CB1 inverse agonists such as CRB-4001, Chymase inhibitors such as flasimirstat (BAY-1142524), Cyclooxygenase 1 inhibitors such as GLY-230, Cyclooxygenase 2 / epoxide hydrolase inhibitors such as COX-2 / soluble epoxide hydrolase, Cytochrome P450 11B2 inhibitors such as aldosterone synthase inhibitors, Ectonucleotide pyrophosphatase-PDE-2 inhibitors such as BLD-0409, Endothelin ET-A / endothelin ET-B receptor antagonists such as aprocitentan, Enteropeptidase inhibitors such as SCO-792, Erythropoietin receptor antagonists such as EPO-018B, Farnesoid X receptor agonists such as LMB-763, FGF / PDGF / beta receptor antagonists / p38 MAP kinase inhibitors such as pirfenidone, GHR / IGF1 gene inhibitors such as atesidorsen sodium, GPR40 antagonists / GPR84 antagonists such as PBI-4050, G protein beta subunit inhibitors such as gallon, G protein-coupled receptor 84 modulators such as PBI-4425, Growth hormone ligands / growth hormone receptor agonists such as Jintropin AQ(trademark), Growth hormone receptor agonists such as LAT-8881, Guanylate cyclase receptor agonists / guanylate cyclase stimulants such as praliciguat, Guanylate cyclase stimulants such as MRL-001 and lanciguat, Heme oxygenase 1 modulators such as RBT-1, HIF prolyl hydroxylase inhibitors such as TRGX-154, Insulin sensitizers / kallikrein 1 modulators such as DM-199, Integrin alpha-V / beta-3 antagonists such as VPI-2690B, Interleukin 33 ligand inhibitors such as MEDI-3506, Kelch-like ECH-associated protein 1 modulators / nuclear erythroid 2-related factor 2 stimulants such as SFX-01, LDHA gene inhibitors such as nedoceran, 5-Lipoxygenase activating protein inhibitors such as AZD-5718, Lysophosphatidic acid-1 receptor antagonists such as BMS-002 and EPGN-696, Matrix extracellular phosphoglycoprotein modulators / phosphatonin receptor agonists such as TPX-200, MEKK-5 protein kinase inhibitors such as seronesertib, Membrane copper amine oxidase inhibitors such as UD-014, Midkine ligand inhibitors such as CAB-101, Mineralocorticoid receptor antagonists such as AZD-9977, esaxerenone, finerenone, KBP-5074, etc., Myosin 2 inhibitors such as DeciMab (trademark), NADPH oxidase 1 inhibitors / NADPH oxidase 4 inhibitors such as setanaxib, NADPH oxidase inhibitors such as APX-115, NK1 receptor antagonists / opioid receptor kappa agonists / opioid receptor mu antagonists such as AV-104, Nuclear erythroid 2-related factor 2 stimulants / TGF beta ligand inhibitors such as CU01-1001, Nuclear factor kappa B inhibitors such as mefenidone, bardoxolone methyl (NSC-713200), etc., PDE 4 inhibitors such as ART-648, PCS-499, etc., PDGF receptor beta modulators such as BOT-191, PDGF / VEGF receptor antagonists such as ANG-3070, PR84 antagonists / GPR40 (FFAR1) / GPR120 (FFAR4) agonists / and partial activators of peroxisome proliferator-activated receptor (PPAR) such as PBI-4547, PRKAA2 gene stimulants / AMPK activators such as PF-06679142, PF-06685249, etc., Prostacyclin (PGI2) agonists such as YS-1402, Protein C activators / glycoprotein Ib (GPIb) antagonists such as AB-002, Protein NOV homolog modulators such as BLR-200, Protein tyrosine phosphatase-1B inhibitors such as MSI-1436, Reactive oxygen species modulator inhibitors such as SUL-121, Renin inhibitors such as Imarilquine hydrochloride, Rho-related protein kinase 2 inhibitors such as ANG-4201 and RXC-007, Sodium glucose transporter-2 inhibitors such as Canagliflozin, Dapagliflozin propanediol, and Empagliflozin, Thromboxane A2 receptor antagonists / thromboxane synthesis inhibitors such as SER-150, Tissue transglutaminase inhibitors such as ZED-1227, TRP cation channel C5 inhibitors such as GFB-887, TRP cation channel C6 inhibitors such as ALGX-2224, Cell adhesion molecule inhibitors such as glycoside bacterial adhesin antagonists, Urate anion exchanger 1 (URAT1) / SLC22A12 inhibitors such as Berinurad (RDEA3170), VIP1 / VIP2 receptor agonists such as LBT-3627, and Xanthine oxidase inhibitors such as TMX-049 and TMX-049DN.

[0153] In some embodiments, one or more additional therapeutic agents are A-4250, AC-3174, acetylsalicylic acid, AK-20, alipogene tiparvovec, AMX-342, AN-3015, alamecol, ARI-3037MO, ASP-8232, AZD-2693, belimumab, betaine anhydrous, BI-1467335, BMS-986036, BMS-986171, BMT-053011, BOT-191, BTT-1023, CAT-2003, cenicriviroc, CBW-511, CER-209, CF-102, CGS21680, CNX-014, CNX-023, CNX-024, CNX-025, cobiprostone, colesevlam, dapagliflozin, DCR-LIV1, deuterated pioglitazone R-enantiomer, 2,4-dinitrophenol, DRX-065, DS-102, DUR-928, EDP-305, elafibranor (GFT-505), emricasan, enalapril, ertugliflozin, evogliptin, F-351, flurasterone (ST-002), FT-4101, GKT-831, GNF-5120, GRI-0621, GR-MD-02, GS-300, GS-4997, GS-9674, HTD-1801, HST-202, HST-201, hydrochlorothiazide,icosabutate (PRC-4016), ethyl ester of icosapent acid, IMM-124-E, INT-767, INV-240, IONIS-DGAT2Rx, ipragliflozin, irbesartan, propagermanium, IVA-337, JKB-121, KB-GE-001, KBP-042, KD-025, M790, M780, M450, metformin, sildenafil, LC-280126, linagliptin, liraglutide, LJN-452 (tropifexor), LM-011, LM-002 (CVI-LM-002), LMB-763, LYN-100, MBX-8025, MDV-4463, mercaptamine, MGL-3196, MGL-3745, MP-301, MSDC-0602K, namilumab, 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),Selected from 25HC3S, olesoxime, PAT-505, PAT-048, PBI-4547, peg-ilodecakin, pioglitazone, pirfenidone, PRI-724, PX20606, Px-102, PX-L603, PX-L493, PXS-4728A, PZ-235, RDX-009, lesmoglibose etabonate, RG-125 (AZD4076), RPI-500, saroglitazar, semaglutide, simtuzumab, solithromycin, sotagliflozin, statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), symbiotic agents, TCM-606F, TEV-45478, TQA-3526, tipepidust (MN-001), TLY-012, TRX-318, TVB-2640, UD-009, ursodeoxycholic acid, VBY-376, VBY-825, VK-2809, besimodegib, bolixibat potassium ethanol adduct hydrate (SHP-626), VVP-100X, WAV-301, WNT-974, XRx-117, ZGN-839, ZG-5216, ZSYM-008, ZYSM-007.

[0154] In some embodiments, the methods and pharmaceutical compositions provided herein include a therapeutically effective amount of apoptosis signal-regulating kinase 1 (ASK1) inhibitor and a therapeutically effective amount of an LPAR1 antagonist, and the LPAR1 antagonist is a compound of formula (I), (Ia), (II), or (IIa) provided herein, or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the ASK1 inhibitor is GS-4997 (seroncertib, SEL).

[0156] The ASK1 inhibitor can be synthesized and characterized using methods known to those skilled in the art, such as those described in US Patent Application Publication No. 2007 / 0276050, US Patent Application Publication No. 2011 / 0009410, and US Patent Application Publication No. 2013 / 0197037.

[0157] 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.

[0158] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the ACC inhibitor is GS-0976 (firsocostat, FIR).

[0159] The ACC inhibitor can be synthesized and characterized using methods known to those of skill in the art, such as those described in U.S. Patent No. 9,453,026 and U.S. Patent No. 10,183,951.

[0160] In some embodiments, the methods and compositions provided herein include a therapeutically effective amount of a PPAR agonist (e.g., a PPAR alpha agonist, a PPAR alpha / delta agonist, a PPAR alpha / delta / gamma agonist, a PPAR delta agonist) or fish oil, a therapeutically effective amount of an acetyl-CoA carboxylase (ACC) inhibitor such as GS-0976 (firsocostat, FIR), and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of formula (I), (Ia), (II), or (IIa) provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the PPAR agonist is a PPAR alpha agonist. In some embodiments, the PPAR alpha agonist is selected from aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, pemafibrate, lonafibrate, simfibrate, pirinixic acid, GW409544, AZ 242, LY518674, NS-220, AVE8134, BMS-711939, aleglitazar, muraglitazar, and saroglitazar. In some embodiments, the PPAR agonist (e.g., a PPAR alpha agonist) is a fibrate. In some embodiments, the PPAR agonist (e.g., a PPAR alpha agonist) is fenofibrate. In some embodiments, the PPAR agonist is a PPAR alpha / delta agonist (e.g., elafibranor). In some embodiments, the PPAR agonist is a PPAR alpha / delta / gamma agonist (e.g., lanifibranor). In some embodiments, the PPAR agonist is a PPAR delta agonist (e.g., seladelpar). In some embodiments, the fish oil is omega-3 fatty acid or docosahexaenoic acid. In some embodiments, the fish oil is eicosapentaenoic acid ethyl (e.g., Vascepa®).

[0161] 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.

[0162] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the FXR agonist is GS-9674 (cilofexor, CILO).

[0163] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the FXR agonist is a compound having the following structure,

Chemical formula

[0164] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of a GLP-1 receptor agonist and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of formula (I), (Ia), (II), or (IIa) provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is liraglutide or semaglutide. In some embodiments, the GLP-1 receptor agonist is semaglutide.

[0165] 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. The TGFβ-specific antibody can be prepared and characterized using methods known to those of skill in the art, such as those described in PCT International Publication No. WO 2018 / 129329 and U.S. Patent No. 9,518,112. In some embodiments, the TGFβ antagonist binds to a TGFβ latency-associated peptide (LAP), such as TGFβ1-LAP. The TGFβ1-LAP-specific antibody can be prepared and characterized using methods known to those of skill 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 a context-independent manner (e.g., independent of the presentation of TGFβ in a particular tissue or organ). In some embodiments, the TGFβ antagonist binds to TGFβ (e.g., TGFβ1) in a context-dependent manner. In some embodiments, the TGFβ antagonist blocks the activation of latent TGFβ (e.g., latent TGFβ1) localized in the extracellular matrix, such as the connective tissue of the liver. In some embodiments, the TGFβ antagonist blocks the activation of latent TGFβ (e.g., latent TGFβ1) localized in the thymus, lymph nodes, or tumor microenvironment (e.g., in a patient with liver cancer). In some embodiments, the TGFβ antagonist blocks the activation of latent TGFβ (e.g., latent TGFβ1) by a latent TGFβ binding protein (LTBP).In some embodiments, the TGFβ antagonist blocks the activation of latent TGFβ (e.g., latent TGFβ1) by Glycoprotein-A Repetitions Predominant protein (GARP), as described, for example, in U.S. Patent No. 10,000,572. In some embodiments, the TGFβ antagonist is ARGX-115. In some embodiments, the TGFβ antagonist is an anti-latency-associated 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 the extracellular matrix (ECM) of connective tissue in the liver, for example. 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, in the tumor microenvironment, for example. In some embodiments, the anti-LAP antibody is the TLS-01 antibody. In some embodiments, the anti-LAP antibody specifically binds to the LAP-TGFβ complex in any context. In some embodiments, the anti-LAP antibody is the 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 comprising a TGFβ receptor. TGFβ antagonists comprising a TGFβ receptor that may be useful in connection with the compositions and methods provided herein are described, for example, in PCT International Publication Nos. 2019 / 113123 (A1) and 2019 / 113464 (A1).

[0166] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of an LPAR1 antagonist and an ACE inhibitor, an adenosine A3 receptor antagonist, an adiponectin stimulator, an albumin modulator, an aldosterone antagonist, an AMP-activated protein kinase stimulator, an angiotensin II AT-2 receptor agonist, an angiotensin II receptor antagonist, an angiotensinogen ligand inhibitor, an APOA1 gene stimulator, an apolipoprotein L1 modulator, a bone morphogenetic protein-7 ligand modulator, a bromodomain-containing protein 2 inhibitor, a bromodomain-containing protein 4 inhibitor, a calcium channel inhibitor, a cannabinoid CB1 receptor antagonist, a CB1 inverse agonist, a CCR2 chemokine antagonist, a chymase inhibitor, a complement C1s subcomponent inhibitor, a CX3CR1 chemokine antagonist, a cyclooxygenase 1 inhibitor, a cyclooxygenase 2 inhibitor, a cytochrome P45011B2 inhibitor, ectonucleotide pyrophosphatase-PDE-2 inhibitor, endothelin ET-A receptor antagonist, endothelin ET-B receptor antagonist, enteropeptidase inhibitor, epoxide hydrolase inhibitor, erythropoietin receptor antagonist, farnesoid X receptor agonist, FGF receptor antagonist, free fatty acid receptor 1 agonist, GHR gene inhibitor, glycoprotein Ib (GPIb) antagonist, GPR40 agonist, GPR84 antagonist, G protein beta subunit inhibitor, G protein-coupled receptor 120 agonist, G protein-coupled receptor 84 modulator, growth hormone ligand, growth hormone receptor agonist, guanylate cyclase receptor agonist, guanylate cyclase stimulator, heme oxygenase 1 modulator, HIF prolyl hydroxylase inhibitor, IGF1 gene inhibitor, IgG receptor FcRn large subunit p51 modulator, IL-6 receptor antagonist, integrin alpha-V / beta-3 antagonist, interleukin 33 ligand inhibitor, Kelch-like ECH-associated protein 1 modulator, LDHA gene inhibitor, 5-lipoxygenase activating protein inhibitor, lysophosphatidic acid-1 receptor antagonist, matrix extracellular phosphoglycoprotein modulator, membrane copper amine oxidase inhibitor, midkine ligand inhibitor, mineralocorticoid receptor antagonist, myosin 2 inhibitor, NADPH oxidase 1 inhibitor, NADPH oxidase 4 inhibitor, NADPH oxidase inhibitor, NK1 receptor antagonist, nuclear erythroid 2-related factor 2 stimulator, nuclear factor kappa B inhibitor, opioid receptor kappa agonist, opioid receptor mu antagonist p38A therapeutically effective amount of an additional therapeutic agent selected from a MAP kinase inhibitor, a PDE4 inhibitor, a PDGF receptor antagonist, a PDGF receptor beta modulator, a phosphatonin receptor agonist, a PRKAA2 gene stimulator, a proprotein convertase PC9 inhibitor, a prostacyclin (PGI2) agonist, a protein C activator, a protein NOV homolog modulator, a protein tyrosine phosphatase-1B inhibitor, a reactive oxygen species modulator inhibitor, a renin inhibitor, a Rho-associated protein kinase 2 inhibitor, an SLC22A12 inhibitor, a sodium glucose transporter-2 inhibitor, a solute carrier family inhibitor, a TGF beta ligand inhibitor, a TGF beta receptor antagonist, a thromboxane A2 receptor antagonist, a thromboxane synthesis inhibitor, a tissue transglutaminase inhibitor, a TRP cation channel C5 inhibitor, a TRP cation channel C6 inhibitor, a tryptophanase inhibitor, an unspecified cell adhesion molecule inhibitor, a urate anion exchanger 1 inhibitor, a vasopressin V1a receptor antagonist, a VEGF receptor antagonist, a VIP1 receptor agonist, a VIP2 receptor agonist, and a xanthine oxidase inhibitor.

[0167] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of an LPAR1 antagonist and a therapeutically effective amount of an additional therapeutic agent selected from a VEGFR inhibitor, an FGFR inhibitor, a PDGFR inhibitor, an autotaxin 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-galectin-3 antibody, an integrin-α V -β 6 / α V -β 1 antagonist, a JNK1 inhibitor, a mineralocorticoid receptor antagonist, an Nrf2 activator, a kinase inhibitor, a PDE inhibitor, a NOX1 / 4 inhibitor, a leukotriene / thromboxane receptor antagonist, an SLC22A12 inhibitor, an sGC inhibitor, and a xanthine oxidase inhibitor.

[0168] In some embodiments, the methods and compositions provided herein include a therapeutically effective amount of an LPAR1 antagonist and a therapeutically effective amount of an additional therapeutic agent selected from nintedanib, pirfenidone, pembrolizumab, PRM-151, GB-0139, PLN-74809, CC-90001, finerenone, BAY1142524, PCS-499, cetnarib, SER150, RDEA3170, praliciguat, TMX-049, GLPG1690, GLPG1205, GLPG1972, GLPG4059, GLPG2737, GLPG3970, and filgotinib.

[0169] In some embodiments, the methods and compositions provided herein include a therapeutically effective amount of an LPAR1 antagonist and a therapeutically effective amount of an additional therapeutic agent selected from A-717, ACF-TEI, alanyl-glutamine, ALLN-346, anti-SCF248 antibody, anti-TAGE monoclonal antibody, anti-TGF beta antibody, AST-120, BAY-2327949, BI-685509, DP-001, DZ-4001, GDT-01, LNP-1892, MEDI-8367, microRNA target antisense oligonucleotide therapy, MK-2060, MPC-300-IV, NAV-003, Neo-Kidney Augment (NKA), NP-135, NP-160, NP-251, NRF-803, PBI-4610, PHN-033, R-HSC-010, salvianolic acid, SGF-3, SPD-01, Sugaheal variant, SZ-005, TCF-12, UMC119-06, VAR-400, bevirimer, VS-105, and XRx-221.

Example

[0170] The following examples are included to demonstrate specific embodiments of the present disclosure. It should be understood by those skilled in the art that the techniques disclosed in the following examples represent techniques that function well in the implementation of the present disclosure and, therefore, can be considered to constitute specific modes for their implementation. However, those skilled in the art should understand that, in light of the present disclosure, these examples are illustrative and not exhaustive. Without departing from the spirit and scope of the present disclosure, many modifications can be made in the specific embodiments disclosed and still obtain similar or analogous results.

[0171] The compounds disclosed herein can be prepared using suitable materials according to the procedures of the following schemes and examples, and are further illustrated by the following specific examples. Additionally, by using the procedures described herein in combination with ordinary techniques in the relevant art, additional compounds of the present disclosure claimed herein can be readily prepared. The examples further illustrate the details of the preparation of the compounds of the present disclosure. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparation procedures can be used to prepare these compounds. To synthesize the compounds that are embodiments described in the present disclosure, examination of the structure of the compound being synthesized provides the identity of each substituent. In some cases, the identity of the final product can be clarified by the examination process of the identity of the required starting materials, considering the examples herein. The compounds can be isolated in the form of their pharmaceutically acceptable salts, such as those described above. The compounds described herein are typically stable and isolable at room temperature and pressure.

[0172] Examples of the preparation of the compounds disclosed in this specification are shown below. Unless otherwise indicated, the variables have the same meaning as above. The examples presented below are intended to illustrate specific embodiments of the present disclosure. Suitable starting materials, building blocks, and reagents used in the syntheses as described below are commercially available, for example, from AbovChem, Acros Organics, Astatech, Combi Blocks, Oakwood Chemical, or Sigma-Aldrich, or can be routinely prepared by procedures described in the literature, for example, "March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 5 th Edition; John Wiley & Sons or T. Eicher, S. Hauptmann "The Chemistry of Heterocycles; Structures, Reactions, Synthesis and Application", 2 nd edition, Wiley-VCH 2003; Fieser et al. "Fiesers’ Reagents for organic Synthesis" John Wiley & Sons 2000.

[0173] General Scheme

Chemical formula

[0174] Step 2 describes the general synthesis of heteroaryl triazole carbamate (V). The heteroaryl triazole carboxylic acid (II) undergoes a Curtius rearrangement when treated with diphenylphosphoryl azide (DPPA) or alternatively with a solution of 1-propanephosphonic anhydride (T3P) and azidotrimethylsilane. The intermediate isocyanate is then trapped with an alcohol (IV) to provide the desired heteroaryl triazole carbamate (V).

[0175] Step 3 describes the general synthesis of heteroaryl triazole carbamate (VI). The heteroaryl triazole carbamate ester (V) can be hydrolyzed by treatment with a base such as sodium hydroxide or lithium hydroxide to provide the corresponding heteroaryl triazole carbamate carboxylic acid (VI).

[0176] Step 4 describes the general synthesis of triazole carbamate aryl and heteroaryl amides (VII). Heteroaryl triazole carbamate carboxylic acid (VI) can be treated with 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-oxide hexafluorophosphate (HATU) in combination with an amine to provide the corresponding triazole carbamate heteroaryl amide (VII). Alternatively, heteroaryl triazole carbamate carboxylic acid (VI) can be first converted to an acid chloride, for example, by treatment with phosphoryl chloride, and then coupled with the desired amine to provide the corresponding triazole carbamate heteroaryl amide (VII).

[0177]

Chemical formula

[0178] Step 2 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 species via lithium-halogen exchange and trapping with zinc chloride. Next, a Negishi cross-coupling with heteroaryl halide (I) provides the desired heteroaryl triazole carbamate (V). Alternatively, heteroaryl halide (I) can first be converted to the corresponding boronic acid ester, such as a pinacol boronate, via Miyaura borylation, and then subjected to Suzuki reaction conditions using bromotriazole carbamate VIII to complete the desired heteroaryl triazole carbamate (V). When Y = H, Step 3 can be omitted.

[0179] Step 3 describes the general synthesis of heteroaryl triazole carbamate (VI). Hydrolysis of heteroaryl triazole carbamate ester (V) by treatment with a base such as sodium hydroxide or lithium hydroxide can provide the corresponding heteroaryl triazole carbamate carboxylic acid (VI).

[0180] Step 4 describes the general synthesis of triazole carbamate aryl and heteroaryl amides (VII). Treatment of heteroaryl triazole carbamate carboxylic acid (VI) with 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-oxide hexafluorophosphate (HATU) in combination with an amine provides the corresponding triazole carbamate heteroaryl amide (VII). Alternatively, heteroaryl triazole carbamate carboxylic acid (VI) can first be converted to an acid chloride, for example, by treatment with phosphoryl chloride, and then coupled with the desired amine to provide the corresponding triazole carbamate heteroaryl amide (VII).

[0181] Example 1: Preparation of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1): [Chemical formula] Step 1: 4,5-dibromo-2H-1,2,3-triazole Bromine (2.8 mol) was added to a solution of 2H-1,2,3-triazole (1.4 mol) in water (600 mL) at 40 °C. The resulting mixture was stirred at 40 °C for 2 hours. After cooling to room temperature, the precipitate was collected by filtration. The solid was washed with water (2 × 300 mL) and dried under vacuum to obtain 4,5-dibromo-2H-1,2,3-triazole.

[0182] Step 2: 4,5-dibromo-1-methyl-1H-1,2,3-triazole Iodomethane (1.0 mol) was added to a mixture of 4,5-dibromo-2H-1,2,3-triazole (704 mmol) and K 2 CO 3 (1.4 mol) in THF (1000 mL). The mixture was stirred at room temperature for 12 hours. The mixture was filtered, the filter cake was washed with ethyl acetate (2 × 500 mL), and the filtrate was concentrated at 40 °C to obtain a crude product, which was purified by column chromatography to obtain 4,5-dibromo-1-methyl-1H-1,2,3-triazole.

[0183] Step 3: 4-bromo-1-methyl-1H-1,2,3-triazole-5-carbaldehyde Isopropylmagnesium chloride (252.0 mmol) was added to a solution of 4,5-dibromo-1-methyl-1H-1,2,3-triazole (168.0 mmol) in THF (600 mL) at -10 °C. The mixture was stirred for 15 minutes, and DMF (840 mmol) was added. After 1 hour, the mixture was treated with 250 mL of saturated ammonium chloride and extracted with DCM (2 × 350 mL). The combined organic matter was washed with 250 mL of brine and Na 2 SO 4It was dried, filtered, and concentrated to obtain 4-bromo-1-methyl-1H-1,2,3-triazole-5-carbaldehyde.

[0184] Step 4: 4-Bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid Oxone (651 mmol) was added to a solution of 4-bromo-1-methyl-1H-1,2,3-triazole-5-carbaldehyde (536 mmol) in DMF (800 mL), and the resulting suspension was stirred at room temperature overnight. The mixed reaction was diluted with H 2 O (1000 mL), adjusted to pH 3 with 1N HCl, and the aqueous phase was extracted with ethyl acetate (3 × 800 mL). The combined organics were washed with saturated Na 2 CO 3 (2 × 500 mL), and the aqueous phase was adjusted to pH 3 with 1N HCl. The precipitate was isolated by filtration and dried under reduced pressure to afford 4-bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1).

[0185] Example 2: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2B):

Chemical formula

[0186] Example 3: Preparation of (R)-1-(2-fluoropyridin-3-yl)ethyl (4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 2C):

Chemical formula

[0187]

Chemical formula

[0188] Step 2: Preparation of (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinic acid (Intermediate 3A) Methyl (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinate (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 hours. The reaction mixture was diluted with ethyl acetate and washed with 1 N HCl solution. Then, the organic layer was washed with brine, dried over sodium sulfate, and concentrated to obtain 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).

[0189] Step 3: Preparation of (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 (Method A) (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 pyridin-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 hour. 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 (400 MHz, methanol-d4) δ 9.15 (dd, J = 2.4, 0.8 Hz, 1H), 8.75 - 8.68 (m, 2H), 8.47 - 8.38 (m, 3H), 8.33 (s, 1H), 8.18 (dd, J = 8.4, 0.9 Hz, 1H), 8.07 (d, J = 18.7 Hz, 1H), 7.47 (s, 1H), 6.11 (q, J = 6.6 Hz, 1H), 4.03 (s, 3H), 1.63 (s, 3H). LCMS m / z 479.1 M+1.

[0190] Example 5: Preparation of Compounds 2 - 17 Compounds 2 - 17 were generally synthesized according to Scheme B, Step 4 using Method A, B, or C. For example, (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-((3-chlorobicyclo[1.1.1]pentan-1-yl)carbamoyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 2) was prepared as follows by Method A.

Chemical formula

[0191] (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]pentan-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]pentan-1-yl)carbamoyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 2). 1H NMR (400 MHz, methanol-d4) δ 9.04 - 8.92 (m, 1H), 8.38 - 8.29 (m, 1H), 8.25 (dd, J = 8.4, 2.2 Hz, 1H), 8.06 (d, J = 8.3 Hz, 2H), 7.44 (s, 1H), 6.08 (q, J = 6.6 Hz, 1H), 4.00 (s, 3H), 2.54 (s, 6H), 1.61 (s, 3H). LCMS m / z 502.1 M+1.

[0192] Compounds 2 - 17 (Table 1) were similarly prepared by reacting (Intermediate 3A) (Example 5) with the reagents listed in Table 1 in place of 3-chlorobicyclo[1.1.1]pentan-1-amine hydrochloride using the method described according to Scheme B, Step 4.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

[0193] Example 6: Synthesis of (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-((3-cyanobicyclo[1.1.1]pentan-1-yl)carbamoyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 18) [Chemical formula] Step 1: 4-(5-(Methoxycarbonyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid 4-Bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (49 mmol) was dissolved in 500 mL of tetrahydrofuran and submerged in a -78 °C bath for 15 minutes. Under nitrogen, a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (53 mmol) was added dropwise over 15 minutes. A 2.5 M solution of n-butyllithium in hexane (102 mmol) was added dropwise over 20 minutes and stirred for an additional 1 hour. A 1.9 M solution of zinc chloride (102 mmol) in 2-methyltetrahydrofuran was added dropwise over 15 minutes. The reaction mixture was warmed to ambient temperature by submerging it in a water bath and stirred for 30 minutes. The resulting mixture was sparged with argon gas for 10 minutes, then methyl 6-bromopyridine-3-carboxylate (53 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex (5 mmol) with dichloromethane were added. The reaction was heated at 75 °C for 5 hours and then cooled to ambient temperature. The reaction was quenched with 100 mL of saturated aqueous sodium bicarbonate and 100 mL of water and stirred vigorously. 200 mL of MTBE was added dropwise and the product was triturated. The product was filtered and washed with MTBE and water. The crude product was used without further purification in the next step.

[0194] Process 2: Methyl (R)-6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinate 4-(5-(Methoxycarbonyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (11.6 mmol) was suspended in THF (100 mL), and a 50% solution of 1-propanephosphonic anhydride in THF (14.5 mmol), triethylamine (58 mmol), and azidotrimethylsilane (10.4 mmol) were charged into the reaction. The resulting solution was stirred at room temperature for 30 minutes. The reaction was heated to 70 °C for 30 minutes, after which (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 hours. The reaction was warmed, diluted in isopropyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, concentrated, and purified by silica gel chromatography.

[0195] Process 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) Methyl (R)-6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinate (6.5 mmol) was dissolved in THF (25 mL), 1 M NaOH (30 mL) was added, and the mixture was stirred vigorously for 15 minutes. The reaction mixture was diluted with MTBE (25 mL), and the organic layer was discarded. The aqueous layer was treated with concentrated HCl until the pH was adjusted to 4. The resulting precipitate was filtered and dried in vacuo to afford the desired product (Intermediate 3B).

[0196] Step 4: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(5-((3-cyanobicyclo[1.1.1]pentan-1-yl)carbamoyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (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-carbonitrile (0.32 mmol), HATU (0.37 mmol), and N,N-diisopropylethylamine (0.75 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was purified by HPLC to afford 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.

[0197] Example 7: Preparation of Compounds 19 - 44 Compounds 19 - 44 were generally synthesized according to Step 4 of Scheme A using Method A, B, or C. 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) was prepared as follows by Method B.

Chem.

[0198] (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 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 (400 MHz, methanol-d4) δ 9.13 (s, 1H), 8.65 (d, J = 5.6 Hz, 1H), 8.43 (dd, J = 8.3, 2.2 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.06 (dd, J = 5.7, 2.2 Hz, 2H), 7.89 (s, 1H), 5.97 (q, J = 6.6 Hz, 1H), 4.03 (s, 3H), 1.64 (s, 3H). LCMS m / z 549.1 M+1.

[0199] Compounds 19 - 44 (Table 2) were similarly prepared by reacting (Intermediate 3B) (Example 6) with the reagents listed in Table 2 in place of 2-(trifluoromethyl)pyridin-4-amine using the method described according to Scheme A, Step 4.

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

[0200] Example 8: Preparation of Compounds 45 - 54 Compounds 45 - 54 were generally synthesized according to Scheme A using Method 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) was prepared as follows.

Chemical Structure

[0201] 4-(5-(Methoxycarbonyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (11.6 mmol) was suspended in THF (100 mL), and a 50% solution of 1-propanephosphonic anhydride in THF (14.5 mmol), triethylamine (58 mmol), and azidotrimethylsilane (10.4 mmol) were charged into the reaction. The resulting solution was stirred at room temperature for 30 minutes. After heating the reaction to 70 °C for 30 minutes, (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethan-1-ol (23.2 mmol) was added at the same temperature. The reaction was heated at 70 °C for 24 hours. The reaction was warmed, diluted in isopropyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, concentrated, and purified by silica gel chromatography.

[0202] 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) Methyl (R)-6-(5-(((1-(2-chloro-5-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinate (6.5 mmol) was dissolved in THF (25 mL), 1 M NaOH (30 mL) was added, and the mixture was stirred vigorously for 15 minutes. The reaction mixture was diluted with MTBE (25 mL), and the organic matter was discarded. The aqueous layer was treated with concentrated HCl until the pH was adjusted to 4. The resulting precipitate was filtered and dried in vacuo to give the desired product.

[0203] Step 3: (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 (Method C) (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 pyridine (0.496 mmol), and phosphoryl chloride (0.235 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 30 minutes and quenched by slowly adding saturated sodium bicarbonate solution. It was then diluted with dichloromethane and the layers were separated. The organic layer was 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 (400 MHz, methanol-d4) δ 9.16 (d, J = 2.3 Hz, 1H), 8.65 (d, J = 5.6 Hz, 1H), 8.44 (dd, J = 8.3, 2.3 Hz, 1H), 8.36 - 8.23 (m, 2H), 8.21 - 8.13 (m, 1H), 8.05 (dd, J = 5.6, 2.1 Hz, 1H), 7.89 (s, 1H), 6.06 (q, J = 6.6 Hz, 1H), 4.03 (s, 3H), 1.63 (s, 3H). LCMS m / z 565.1 M+1.

[0204] Compounds 45 - 54 (Table 3) were similarly prepared by reacting (Intermediate 3C) (Example 6) with the reagents listed in Table 2 using either Method A, B, or C according to Scheme A, Step 4, in place of 2-(trifluoromethyl)pyridin-4-amine.

Table 3-1

Table 3-2

Table 3-3

Table 3-4

[0205] Example 9: Preparation of Compounds 55 - 57 Compounds 55 - 57 were generally synthesized according to Scheme B using Method A, B, or C. For example, (R)-1-(2-fluoropyridin-3-yl)ethyl (4-(5-((3-chlorobicyclo[1.1.1]pentan-1-yl)carbamoyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 55) was prepared as follows.

Chemical Structure

[0206] Step 1: Methyl (R)-6-(5-(((1-(2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinate (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 lithium bis(trimethylsilyl)amide solution (4.80 mmol). The reaction mixture was stirred at -78 °C for 15 minutes, then 1.6 M n-butyllithium solution was added (9.12 mmol). Stirring was continued at -78 °C for an additional 30 minutes, then 1.9 M zinc chloride solution was added (12.5 mmol). After 5 minutes, the reaction mixture was warmed to room temperature. Subsequently, methyl 6-bromonicotinate (4.17 mmol) was added to the reaction mixture, followed by XPhos Pd G3 (0.443 mmol). The reaction mixture was heated at 70 °C for 1 hour. 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 methyl (R)-6-(5-(((1-(2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinate.

[0207] 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) Methyl (R)-6-(5-(((1-(2-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)nicotinate (0.157 mmol) was dissolved in THF (2 mL), 2 M lithium hydroxide solution (0.500 mmol) was added, and the mixture was stirred at room temperature overnight. 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.

[0208] Process 3: (R)-1-(2-Fluoropyridin-3-yl)ethyl (4-(5-((3-chlorobicyclo[1.1.1]pentan-1-yl)carbamoyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (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]pentan-1-amine hydrochloride (0.214 mmol), HATU (0.255 mmol), and N,N-diisopropylethylamine (0.459 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was purified by HPLC to afford the title compound. 1H NMR (400 MHz, methanol-d4) δ 9.01 - 8.91 (m, 1H), 8.28 (d, J = 8.5 Hz, 1H), 8.16 (s, 1H), 8.07 (d, J = 8.3 Hz, 2H), 7.35 (s, 1H), 6.00 (q, J = 6.6 Hz, 1H), 4.01 (s, 3H), 2.55 (s, 6H), 1.63 (s, 3H). LCMS m / z 486.1 M+1.

[0209] Compounds 55 - 57 (Table 4) were similarly prepared by reacting (Intermediate 3D) (Example 9) with the reagents listed in Table 4 using either Method A, B, or C according to Scheme B, Process 4, in place of 3-chlorobicyclo[1.1.1]pentan-1-amine hydrochloride.

Table 4

[0210] Example 10: Synthesis of (R)-1-(2-Chloropyridin-3-yl)ethyl (4-(5-((3-chlorobicyclo[1.1.1]pentan-1-yl)carbamoyl)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 58) [Chemistry] Step 1: Methyl (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylnicotinate (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 lithium bis(trimethylsilyl)amide solution (1.20 mmol). The reaction mixture was stirred at -78 °C for 15 minutes, then n-butyllithium solution was added (2.24 mmol). Stirring was continued at -78 °C for an additional 30 minutes, then zinc chloride solution was added (3.23 mmol). After 5 minutes, the reaction mixture was warmed to room temperature. 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 hour. 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 obtain methyl (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylnicotinate.

[0211] Step 2: (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylnicotinic acid Methyl (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylnicotinate (0.302 mmol) was dissolved in THF (2 mL) and methanol (500 μL), 2 M lithium hydroxide solution (0.960 mmol) was added, and the mixture was stirred at room temperature overnight. 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 obtain crude (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylnicotinic acid.

[0212] Step 3: (R)-1-(2-Chloropyridin-3-yl)ethyl (4-(5-((3-chlorobicyclo[1.1.1]pentan-1-yl)carbamoyl)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (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]pentan-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 hour. The reaction mixture was concentrated. The residue was purified by HPLC to give the title compound. 1H NMR (400 MHz, methanol-d4) δ 8.33 (s, 1H), 8.10 - 7.83 (m, 3H), 7.44 (s, 1H), 6.11 (d, J = 6.8 Hz, 1H), 4.02 (s, 3H), 2.64 (s, 3H), 2.54 (s, 6H), 1.61 (s, 3H). LCMS m / z 516.1 M+1.

[0213] Example 11: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-((3-cyanobicyclo[1.1.1]pentan-1-yl)carbamoyl)-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 59) [Chemical formula] 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 In a 100 mL round-bottom flask, 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 charged and cooled to -78°C. While maintaining a temperature below -70°C, LiHMDS (3.4 mL, 1 M in THF) was added dropwise, and after stirring for 5 minutes, n BuLi (2.3 mL, 2.5 M in hexane) was added dropwise. After further stirring for 5 minutes, ZnCl 2(1.9 M in 3.1 mL of 2-Me-THF) was added dropwise. Once the addition was complete, the reaction mixture was warmed to 0 °C in an ice / water bath and stirred for 10 minutes. Then, methyl 6-bromo-5-fluoronicotinate (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, and the mixture was subsequently heated at 65 °C for 2 hours. The reaction was then cooled to room temperature, silica (15 mass equivalents) was added, and the crude mixture was concentrated to dryness in vacuo, followed by purification by silica gel column chromatography (DCM / MeOH: 0–25%). The purified material was then dissolved in 4 mL of THF, to which NaOH (12 mL, 0.5 M) solution was added and stirred for 1 hour. Once the hydrolysis of the ester was complete, 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 to dryness in vacuo to afford the desired acid.

[0214] Step 2: (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-((3-cyanobicyclo[1.1.1]pentan-1-yl)carbamoyl)-3-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (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 a mixture of pyridine (0.5 mL) was added to 3-aminobicyclo[1.1.1]pentane-1-carbonitrile (0.17 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 mmol). The reaction mixture was left for 2 hours with magnetic stirring, at which point water (1 mL) was added and the crude mixture was purified by HPLC. 1H NMR (400 MHz, methanol-d4) δ 8.82 (t, J = 1.6 Hz, 1H), 8.51 - 8.25 (m, 1H), 7.99 (dd, J = 10.9, 1.8 Hz, 2H), 7.46 (s, 1H), 6.03 (q, J = 6.6 Hz, 1H), 4.02 (s, 3H), 2.68 (s, 6H), 1.59 (s, 3H). LCMS m / z 511.079 M+1.

[0215] Example 12: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(6-chloro-5-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 60)

Chemical formula

[0216] Step 2: (R)-1-(2-chloropyridin-3-yl)ethyl (4-(6-chloro-5-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (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 a mixture of pyridine (0.5 mL) was added to 3-fluorobicyclo[1.1.1]pentan-1-amine (0.11 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.07 mmol). The reaction mixture was left to stand for 2 hours with magnetic stirring, at which point water (1 mL) was added and the crude mixture was purified by preparative HPLC. 1H NMR (400 MHz, methanol-d4) δ 8.32 (d, J = 4.6 Hz, 1H), 8.22 - 7.83 (m, 3H), 7.45 (s, 1H), 6.13 (q, J = 6.6 Hz, 1H), 4.00 (s, 3H), 2.49 (d, J = 2.1 Hz, 6H), 1.63 (s, 3H). LCMS m / z 519.998 M+1.

[0217] Example 13: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-((3-cyanobicyclo[1.1.1]pentan-1-yl)carbamoyl)-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 61)

Chemical formula

[0218] Step 3: (R)-1-(2-Chloropyridin-3-yl)ethyl (4-(5-((3-cyanobicyclo[1.1.1]pentan-1-yl)carbamoyl)-4-fluoropyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (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) was added to 3-aminobicyclo[1.1.1]pentane-1-carbonitrile (0.17 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 mmol). The reaction mixture was left for 2 hours with magnetic stirring, at which point water (1 mL) was added and the crude mixture was purified 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.

[0219] Example 14: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-((3-cyanobicyclo[1.1.1]pentan-1-yl)carbamoyl)-6-(trifluoromethyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 62)

Chemical formula

[0220] Step 2: (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-((3-cyanobicyclo[1.1.1]pentan-1-yl)carbamoyl)-6-(trifluoromethyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(trifluoromethyl)nicotinic acid (0.06 mmol) in pyridine (0.5 mL) was added to 3-aminobicyclo[1.1.1]pentane-1-carbonitrile (0.11 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.07 mmol). The reaction mixture was left for 2 hours with magnetic stirring, at which point water (1 mL) was added and the crude mixture was purified by preparative HPLC. 1H NMR (400 MHz, methanol-d4) δ 8.31 (d, J = 8.2 Hz, 2H), 8.03 (d, J = 8.1 Hz, 2H), 7.44 (s, 1H), 6.09 (q, J = 6.6 Hz, 1H), 4.01 (s, 3H), 2.66 (s, 6H), 1.61 (s, 3H). LCMS m / z 561.037 M+1.

[0221] Example 15: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(6-fluoro-5-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 63)

Chemical formula

[0222] Step 2: (R)-1-(2-Chloropyridin-3-yl)ethyl (4-(6-fluoro-5-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate 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) were added 3-fluorobicyclo[1.1.1]pentan-1-amine (0.2 mmol), HATU (0.14 mmol), and N,N-diisopropylethylamine (0.3 mmol). The reaction mixture was left to stand for 16 hours with magnetic stirring, then diluted with ethyl acetate and washed with aqueous sodium bicarbonate and brine. The organic layer was separated, dried over sodium sulfate, concentrated, and purified by reverse phase HPLC. 1H NMR (400 MHz, methanol-d4) δ 8.42 - 8.29 (m, 1H), 8.25 (dd, J = 9.4, 7.8 Hz, 1H), 8.19 - 7.93 (m, 2H), 7.58 - 7.32 (m, 1H), 6.11 (q, J = 6.5 Hz, 1H), 3.99 (s, 3H), 2.50 (d, J = 2.1 Hz, 6H), 1.63 (s, 3H). LCMS m / z 503.95 M+1.

[0223] Example 16: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(3-fluoro-5-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 64)

Chemical formula

[0224] Step 2: (R)-1-(2-chloropyridin-3-yl)ethyl (4-(3-fluoro-5-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate 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]pentan-1-amine (0.2 mmol), HATU (0.14 mmol), and N,N-diisopropylethylamine (0.3 mmol) were added. The reaction mixture was left to stand for 16 hours with magnetic stirring, 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 reverse phase HPLC. 1H NMR (400 MHz, methanol-d4) δ 8.85 (s, 1H), 8.33 (d, J = 4.7 Hz, 1H), 8.01 (dd, J = 10.9, 1.8 Hz, 2H), 7.47 (s, 1H), 6.04 (q, J = 6.6 Hz, 1H), 4.03 (s, 3H), 2.51 (d, J = 2.1 Hz, 6H), 1.59 (s, 3H). LCMS m / z 503.98 M+1.

[0225] Example 17: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(6-chloro-5-((3-cyanobicyclo[1.1.1]pentan-1-yl)carbamoyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 65)

Chemical Structure

[0226] Example 18: Preparation of (R)-1-(2-Chloropyridin-3-yl)ethyl (4-(5-((3-Fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)-6-(trifluoromethyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 66) [Chemical formula] (R)-1-(2-Chloropyridin-3-yl)ethyl (4-(5-((3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)-6-(trifluoromethyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 66) was obtained according to the procedure described in Example 14 for the synthesis of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-((3-cyanobicyclo[1.1.1]pentan-1-yl)carbamoyl)-6-(trifluoromethyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 62), using 3-fluorobicyclo[1.1.1]pentan-1-amine (0.106 mmol) instead of 3-aminobicyclo[1.1.1]pentane-1-carbonitrile. LCMS m / z 554.037 M+1. 1 H NMR (400 MHz, methanol-d 4 ) 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).

[0227] Example 19: Calcium Assay In vitro LPAR1 activity was measured in an intracellular calcium mobilization assay.

[0228] CHO-K1 EDG2 cells (DiscoverX catalog number 93-0644C2) expressing human LPAR1 (NM_001401.3) were seeded at 15,000 cells / well in a total volume of 25 μL of Dulbecco's Modified Eagle Medium (DMEM) containing 10% fetal bovine serum, 1× PenStrepGlutamine, 300 μg / mL hygromycin, and 800 μg / mL G418 in a 384-well tissue culture plate (Grenier catalog number 781091) and incubated overnight at 37°C. Prior to the test, 25 μL of calcium-loaded dye component A (FLIPR Calcium 6 Assay Kit Molecular Devices catalog number R8190) and 2.5 mM probenecid (Invitrogen catalog number P36400, freshly prepared), 20 mM HEPES (Corning catalog number 25-060-CI), 0.1% bovine serum albumin (Sigma-Aldrich catalog number A7906-500G) in Hank's Balanced Salt Solution (Corning catalog number 21-023-CV) were added to the cells at 37°C for 60 minutes.

[0229] An agonist dose-response curve of LPA 18:2 (Avanti Polar Lipids catalog number 857138, 0.5 nM to 10 μM) was recorded to determine the EC 80 for subsequent antagonist assays. For the agonist dose-response curve, the cells were removed from the incubator 2 hours after dye loading and transferred to a FLIPR Tetra instrument (Molecular Devices, San Jose, CA). Calcium mobilization was monitored for 5 minutes and 10 μL of 6× LPA in HBSS / 20 mM HEPES / 0.1% bovine serum albumin (BSA) was added to the cells for 5 seconds during the assay.

[0230] To determine the LPAR1 antagonist activity of the test compound, the cells were pre-incubated with the test compound in the dose range of 0.5 nM to 10 μM and then the EC 80Cells were pre-incubated with LPA at a concentration of 100 nM. After dye loading, the cells were removed from the incubator and 0.3 μL of 200× antagonist was added. The cells were incubated at 37 °C for 60 minutes. Antagonist activity was measured using FLIPR Tetra. Calcium mobilization was monitored for 3.5 minutes and 10 μL of 6× EC in HBSS 80 LPA, 20 mM HEPES, and 0.1% BSA were added to the cells for 5 seconds during the assay. The signal amplitude (maximum minus minimum) values were plotted against the log of the antagonist concentration using a dose-response tool (Gilead Sciences Inc.) 10 to determine the EC 50 .

[0231] To evaluate the antagonist potential of the exemplified compounds, the EC 50 values were determined for Compounds 1 - 66 in the LPAR1 calcium mobilization assay. The results are shown in Table 5 (LPAR1 EC 50 ). The compound numbers correspond to the compound numbers of Examples 1 - 18. N / A means not applicable.

Table 5-1

Table 5-2

[0232] 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.

[0233] Accordingly, although the present disclosure has been specifically disclosed by way of preferred embodiments, any features, modifications, improvements, and variations of the disclosure embodied herein may be reused by those skilled in the art, and it should be understood that such modifications, improvements, and variations are considered to be within the scope of the present disclosure. The materials, methods, and examples provided herein are representative of the preferred embodiments, are illustrative, and are not intended as limitations on the scope of the present disclosure.

[0234] The present disclosure has been described herein in a broad and comprehensive manner. Each of the more narrow species and subgeneric groups falling within the comprehensive disclosure also forms part of the present disclosure. This includes a general description of the present disclosure with conditional or negative limitations removing any subject from the genus, whether or not the deleted material is specifically recited herein.

[0235] In addition, when a feature or aspect of the present disclosure is described in terms of a Markush group, those skilled in the art will recognize that the present disclosure is also described in terms of any individual member or subgroup of members of the Markush group.

[0236] The present disclosure has been described in conjunction with the above embodiments, but it should be understood that the foregoing description and examples are intended to be illustrative and not to limit the scope of the present disclosure. Other aspects, advantages, and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which the present disclosure pertains. The present invention provides, for example, the following items. (Item 1) A compound of formula (I),

Chemical Formula

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Chem.

Chem.

Chem.

Chem.

Chem.

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Chem.

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Chem.

Chem.

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Claims

1. A compound of formula (I), 【Chemical 49】 or a pharmaceutically acceptable salt thereof, wherein in the formula, R １ is cyclopropyl or cyclobutyl, each optionally substituted with one or two R1A independently selected from -F and phenyl, each phenyl optionally substituted with 1 to 4 R1C which may be the same or different, and each R1C is independently C1-4 alkyl, halogen, or R1 is 【Chemical Formula 56】 or R1 is tetrahydropyranyl optionally substituted with 1 to 4 R1A which are each independently selected from -F, -Cl, -OH, -CN, -CH3, -CH2F, -CHF2, -CF3, and -O-CH3, the same or different, or R1 is 【Chemical 57】 or R1 is phenyl optionally substituted with 1 to 4 R1A which may be the same or different, each R1A being independently selected from cyano, -CF3, -F, -Cl, morpholinyl, phenyl, pyridyl, oxadiazolyl, each morpholinyl, phenyl, pyridyl, and oxadiazolyl being optionally substituted with 1 to 4 R1C which may be the same or different, each R1C being independently cyano, halogen, or C1-4 alkyl, or R1 is 【Chemical 58】 or R1 is thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, or pyridazinyl optionally substituted with 1 to 4 R1A which may be the same or different, each R1A being independently selected from halogen, cyano, oxo, C1-4 alkyl, C3-10 cycloalkyl, 3-10 membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen and oxygen, -N(R1B1)(R1B2), -O-R1B1, and -S(O)0-2R1B1, wherein each R1B1 and R1B2 is independently hydrogen or C1-6 alkyl, each R1A alkyl, cycloalkyl, and heterocyclyl is optionally substituted with 1 to 4 R1C which may be the same or different, each R1C being independently C1-4 alkyl, halogen, or cyano, each R1B1 and R1B2 alkyl and cycloalkyl is optionally substituted with 1 to 3 halogens, or R1 is -F, -Cl, -CN, -CHF2, -CF3, -OCH3, -OCHF2, or 【Chemical 59】 thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, or pyridazinyl each optionally substituted with 1 to 3 substituents independently selected from the same or different, or R1 is 【Chemical Formula 60】 and R ２ is C optionally substituted with the same or different 1 to 3 substituents independently selected from hydrogen, halogen, cyano, C １～４ alkoxy, and C ３～１０ cycloalkyl, or １～６ is alkyl R ２ is optionally substituted with the same or different 1 to 3 substituents independently selected from halogen, cyano, C １～４ alkoxy, and C １～６ cycloalkyl, ３～６ and R ３ is selected from hydrogen, deuterium, halogen, C １～６ alkyl, C ３～６ cycloalkyl, -O-R ３Ａ１ , and -N(R ３Ａ１ )(R ３Ａ２ ), wherein the C １～６ alkyl is optionally substituted with one to three substituents, the same or different, independently selected from C １～４ alkoxy and halogen, and each R ３Ａ１ and R ３Ａ２ is independently hydrogen or C １～３ alkyl optionally substituted with one to three halogens, the same or different. Each R ４ is independently selected from deuterium, halogen, C １～６ alkyl, C ３～６ cycloalkyl, -O-R ４Ａ１ , and -N(R ４Ａ１ )(R ４Ａ２ ), and the C １～６ alkyl is optionally substituted with one to three substituents, the same or different, independently selected from C １～４ alkoxy and halogen, and each R ４Ａ１ and R ４Ａ２ is independently hydrogen or C １～３ alkyl optionally substituted with one to three halogens, the same or different. n is 0, 1, or 2, R ５ is optionally substituted with 1 to 3 same or different substituents independently selected from halogen, cyano, C １～４ alkoxy, -C(O)N(R ５Ａ１ ), and -N(R ５Ａ１ )(R ５Ａ２ ), and is C １～６ alkyl, each R ５Ａ１ and R ５Ａ２ is independently hydrogen, C １～６ alkyl, or C ３～１０ cycloalkyl, or R ５ is C ３～６ cycloalkyl, or 3- to 6-membered heterocyclyl having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur, said cycloalkyl or heterocyclyl being optionally substituted with one to three substituents, the same or different, independently selected from halogen, cyano, C １～４ alkyl, and C １～４ alkoxy, Each Y １ and Y ２ is independently optionally substituted with the same or different one to three substituents selected from hydrogen, deuterium, or deuterium, halogen, cyano, C ２～３ alkynyl, C １～４ alkoxy, and -C(O)NH-(C １～４ H ３－９ ) and is an optionally substituted C １～６ alkyl, and Z is C １～８ alkyl, C １～６ alkoxy, C ３～６ cycloalkyl, C ６～１２ aryl, nitrogen, oxygen, and sulfur, and is a 3- to 12-membered heterocyclyl having 1 to 4 heteroatoms independently selected therefrom, or a 5- to 12-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the alkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is each optionally substituted with 1 to 3 substituents, the same or different, independently selected from halogen, cyano, C １～４ alkyl, C １～４ alkoxy, and C ３～６ cycloalkyl, and the C １～４ alkyl is optionally substituted with 1 to 3 substituents, the same or different, selected from C １～４ alkoxy and halogen, or Y １ and Z, together with the carbon to which they are attached, form C ３～６ cycloalkyl, C ６～１２ aryl, nitrogen, oxygen, and sulfur independently selected from 1 to 4 heteroatoms having 3 to 12 membered heterocyclyl, or nitrogen, oxygen, and sulfur independently selected from 1 to 4 heteroatoms having 5 to 12 membered heteroaryl, and said cycloalkyl, aryl, heterocyclyl, or heteroaryl is cyano, C １～４ alkyl, C １～４ alkoxy, C ６～１０ aryl, and halogen independently selected from the same or different 1 to 3 substituents, each optionally substituted, and said C １～４ alkyl is optionally substituted with the same or different 1 to 3 substituents independently selected from C １～４ alkoxy and halogen, and said C ６～１０ aryl is optionally substituted with the same or different 1 to 3 substituents independently selected from C １～４ alkyl, C １～４ alkoxy, and halogen, Here, when Y1 and Z together with the carbon to which they are attached form a C3-6 cycloalkyl or a 3-12 membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, then Y ２ is hydrogen or deuterium, wherein when Y1 and Z together with the carbon to which they are attached form a C6-12 aryl or a 5-12 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Y2 is absent, a compound, or a pharmaceutically acceptable salt thereof. **Claim 2** The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (Ia): 【Chemical Formula 50】 **Claim 3** R ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen. **Claim 4** Each Y １ and Y ２ is independently optionally substituted with the same or different one to three substituents each independently selected from hydrogen, deuterium, or halogen, cyano, C ２～３ alkynyl, C １～４ alkoxy, and -C(O)NH-(C １～４ H ３－９ ) and is C １～６ alkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof. **Claim 5** Y １ is optionally substituted with the same or different 1 to 3 substituents each independently selected from halogen, cyano, and C １～４ alkoxy, and is C １～４ alkyl, and Y ２ is hydrogen, the compound according to claim 1, or a pharmaceutically acceptable salt thereof. **Claim 6** Y １ is methyl optionally substituted with 1 to 3 identical or different substituents each independently selected from -F, -Cl, -CN, and -O-CH ３ and the compound according to claim 1, or a pharmaceutically acceptable salt thereof. **Claim 7** Y １ is -CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is -CH **Claim 8** Y ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is hydrogen. **Claim 9** Z is a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the heteroaryl is optionally substituted with 1 to 3 identical or different substituents each independently selected from halogen and C １～４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 3 identical or different substituents each independently selected from alkyl. **Claim 10** The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is pyridyl optionally substituted with one or two substituents each independently selected from -F and -Cl. **Claim 11** Z is 【Chemical Formula 51】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof. **Claim 12** Y １ is -CH ３ and Z is 【Chemical 52】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof. **Claim 13** R ５ is C alkyl optionally substituted with 1 to 3 same or different substituents independently selected from halogen, cyano, C １～４ alkoxy, -C(O)N(R ５Ａ１ ), and -N(R ５Ａ１ )(R ５Ａ２ ), and each R １～６ and R ５Ａ１ and R ５Ａ２ is independently H, C １～６ alkyl, or C ３～１０ cycloalkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof. **Claim 14** R ５ is -CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is -CH **Claim 15** The compound of formula (I) is of formula (II): 【Chemical 53】 wherein R6 is hydrogen, halogen, cyano, C1-4 alkyl, C1-4 alkoxy, or C3-6 cycloalkyl, and the C1-4 alkyl is optionally substituted with 1 to 3 substituents, the same or different, selected from C1-4 alkoxy and halogen, wherein R7 is hydrogen, halogen, cyano, C1-4 alkyl, C1-4 alkoxy, or C3-6 cycloalkyl, and the C1-4 alkyl is optionally substituted with 1 to 3 substituents, the same or different, selected from C1-4 alkoxy and halogen, The compound according to claim 1, or a pharmaceutically acceptable salt thereof. **Claim 16** The compound of formula (I), formula (Ia), or formula (II) is of formula (IIa): 【Chemical 54】 wherein R6 is hydrogen, halogen, cyano, C1-4 alkyl, C1-4 alkoxy, or C3-6 cycloalkyl, and the C1-4 alkyl is optionally substituted with 1 to 3 substituents, the same or different, selected from C1-4 alkoxy and halogen, Here, R7 is hydrogen, halogen, cyano, C1-4 alkyl, C1-4 alkoxy, or C3-6 cycloalkyl, and the C1-4 alkyl is optionally substituted with one to three identical or different substituents selected from C1-4 alkoxy and halogen. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

17. R １ is cyclopropyl or cyclobutyl, optionally substituted independently by one or two Rs selected from -F and phenyl, each phenyl optionally substituted by the same or different one to four Rs １Ａ and each R １Ｃ is independently C １Ｃ alkyl, halogen, the compound according to claim 1, or a pharmaceutically acceptable salt thereof. １～４ ​

18. R １ is 【Chemical Formula 55】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is as defined in

17. .

19. Said C ３～１０ wherein the cycloalkyl is C ５～１０ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the cycloalkyl is bicyclic cycloalkyl.

20. Said C ５～１０ wherein the bicyclic cycloalkyl is C ５～８ The compound according to claim 19, or a pharmaceutically acceptable salt thereof, wherein the bicyclic cycloalkyl is a bridged bicyclic cycloalkyl.

21. Said C ５～８ The bridged bicyclic cycloalkyl is independently selected from -F, -Cl, -CN, -CH ３ , -CH ２ -OH, -CHF ２ , -CF ３ , -O-CH ３ , -CO ２ -CH ３ , -SO ２ -CH ３ The compound according to claim 20, or a pharmaceutically acceptable salt thereof, which is bicyclopentanyl optionally substituted with 1 to 3 same or different substituents each independently selected from phenyl.

22. R １ is 【Chemical 56】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is as defined in

18. .

23. R １ is independently selected from each of -F, -Cl, -OH, -CN, -CH ３ , -CH ２ F, -CHF ２ , -CF ３ , and -O-CH ３ , the same or different 1 to 4 Rs optionally substituted with １Ａ tetrahydropyranyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

24. R １ is 【Chemical 57】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is as defined in

19. .

25. R １ is phenyl optionally substituted with 1 to 4 R's which may be the same or different １Ａ each R being １Ａ independently selected from cyano, -CF ３ , -F, -Cl, morpholinyl, phenyl, pyridyl, oxadiazolyl, each morpholinyl, phenyl, pyridyl, and oxadiazolyl being optionally substituted with 1 to 4 R's which may be the same or different １Ｃ each R being １Ｃ independently cyano, halogen, or C １～４ alkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

26. R １ is 【Chemical Formula 58】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is as defined in

20. .

27. R １ is optionally substituted, independently of one another, by the same or different one to four Rs １Ａ with thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, or pyridazinyl, each R １Ａ being independently selected from halogen, cyano, oxo, C １～４ alkyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl having one to four heteroatoms independently selected from nitrogen and oxygen, -N(R １Ｂ１ )(R １Ｂ２ ), -O-R １Ｂ１ and -S(O) ０－２ R １Ｂ１ wherein each R １Ｂ１ and R １Ｂ２ is independently hydrogen or C １～６ alkyl, Each R １Ａ alkyl, cycloalkyl, and heterocyclyl are optionally substituted with 1 to 4 R's which may be the same or different １Ｃ and each R １Ｃ is independently C １～４ alkyl, halogen, or cyano Each R １Ｂ１ and R １Ｂ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the alkyl and cycloalkyl are optionally substituted with 1 to 3 halogens.

28. R １ is -F, -Cl, -CN, -CHF ２ , -CF ３ , -OCH ３ , -OCHF ２ , or 【Chemical Formula 59】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, or pyridazinyl, each independently selected from the group consisting of and each optionally substituted with one to three identical or different substituents.

29. R １ is 【Chemical Formula 60】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is as defined in

21. .

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

31. R ３ is selected from deuterium, halogen, C １～６ alkyl, C ３～６ cycloalkyl, -O-R ３Ａ１ , and -N(R ３Ａ１ )(R ３Ａ２ ), wherein the C １～６ alkyl is optionally substituted with one to three substituents, the same or different, independently selected from C １～４ alkoxy and halogen, and each R ３Ａ１ and R ３Ａ２ is independently hydrogen or C １～４ alkyl optionally substituted with one to three halogens, the same or different, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

32. R ３ is halogen, or C optionally substituted with 1 to 3 halogens １～３ alkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

33. R ３ is -F, -Cl, -CH ３ , or -CF ３ selected from, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

34. Each R ４ is independently selected from deuterium, halogen, C １～６ alkyl, C ３～６ cycloalkyl, -O-R ４Ａ１ , and -N(R ４Ａ１ )(R ４Ａ２ ), and the C １～６ alkyl is optionally substituted with one to three substituents, the same or different, independently selected from C １～４ alkoxy and halogen, and each R ４Ａ１ and R ４Ａ２ is independently hydrogen or C １～４ alkyl optionally substituted with one to three halogens, the same or different, and the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

35. Each R ４ is a halogen, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

36. Each R ４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each R is -F.

37. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.

38. The compound according to claim 37, or a pharmaceutically acceptable salt thereof, wherein n is 0.

39. The compound according to claim 37, or a pharmaceutically acceptable salt thereof, wherein n is 1.

40. The compound according to claim 37, or a pharmaceutically acceptable salt thereof, wherein n is 2.

41. R ６ is hydrogen, halogen, cyano, C １～４ alkyl, C １～４ alkoxy, or C ３～６ cycloalkyl, wherein said C １～４ alkyl is optionally substituted with 1 to 3 same or different substituents selected from C １～４ alkoxy and halogen, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

42. R ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is a halogen.

43. R ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is -F or -Cl.

44. R ７ is hydrogen, halogen, cyano, C １～４ alkyl, C １～４ alkoxy, or C ３～６ cycloalkyl, wherein said C １～４ alkyl is optionally substituted with the same or different one to three substituents selected from C １～４ alkoxy and halogen, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

45. R ７ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or halogen.

46. R ７ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or -F.

47. 【Fig. 61】 【Chemical 62】 【Chemical 63】 【Chemical Formula 64】 【Chemical Formula 65】 A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

48. The compound is 【Chemical Formula 66】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is as defined in

47. .

49. The compound is 【Chemical 67】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is as defined in

48. .

50. The compound is 【Chemical Formula 68】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is as defined in

49. .

51. The compound is 【Chemical 69】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

52. wherein the compound is 【Chemical Formula 70】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

53. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

54. The pharmaceutical composition according to claim 53, further comprising an additional therapeutic agent.

55. In a patient in need of treating or stabilizing an LPAR1-mediated disease or condition, or reducing its severity or progression, a composition comprising a compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, for treating or stabilizing an LPAR1-mediated disease or condition, or reducing its severity or progression, or the pharmaceutical composition according to claim 53 or 54.

56. The composition according to claim 55, wherein the LPAR1-mediated disease or condition is selected from the group consisting of wound healing, cancer, pain, respiratory disorders, allergic disorders, nervous system disorders, cardiovascular disorders, and inflammatory disorders.

57. The composition according to claim 55, wherein the LPAR1-mediated disease or condition is interstitial pneumonia (ILD).

58. The composition according to claim 57, wherein the interstitial pneumonia (ILD) is non-specific interstitial pneumonia (NSIP), sarcoidosis, asbestosis, ILD related to occupational exposure, progressive fibrotic ILD, idiopathic interstitial pneumonia (IIP), connective tissue disease-related interstitial pneumonia (CTD-ILD), rheumatoid arthritis-related ILD, scleroderma-related ILD, or exogenous alveolitis.

59. The composition according to claim 55, wherein the LPAR1-mediated disease or condition is chronic kidney disease (CKD).

60. The composition according to claim 59, wherein the CKD is complement glomerulopathy, membranous glomerulopathy, polycystic kidney disease, IgA nephropathy, focal segmental glomerulosclerosis (FSGS), or Alport syndrome.

61. The composition according to claim 59, wherein the LPAR1-mediated disease or condition includes fibrosis.

62. The composition according to claim 61, wherein the fibrosis is pulmonary fibrosis, renal fibrosis, hepatic fibrosis, ocular fibrosis, cardiac fibrosis, or systemic sclerosis.

63. The composition according to claim 62, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF) or progressive fibrotic interstitial lung disease (PF-ILD).

64. The composition according to claim 62, wherein the pulmonary fibrosis is secondary to a systemic inflammatory disease.

65. The composition according to claim 64, wherein the systemic inflammatory disease is rheumatoid arthritis, scleroderma, lupus, idiopathic pulmonary fibrosis, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, chronic asthma, silicosis, asbestos-induced pulmonary or pleural fibrosis, acute lung injury or acute respiratory distress.

66. The composition according to claim 62, wherein the renal fibrosis is associated with diabetic kidney disease.

67. The composition according to claim 55, wherein the LPAR1-mediated disease or condition is a liver disease.

68. The composition according to claim 67, wherein the liver disease includes liver fibrosis.

69. The composition according to claim 67, wherein the liver disease includes non-alcoholic fatty liver disease (NAFLD).

70. The composition according to claim 67, wherein the liver disease includes steatosis.

71. The composition according to claim 67, wherein the liver disease includes non-alcoholic steatohepatitis (NASH).

72. The composition according to claim 67, wherein the liver disease includes cirrhosis.

73. The composition according to claim 72, wherein the cirrhosis is compensated cirrhosis.

74. The composition according to claim 72, wherein the cirrhosis is decompensated cirrhosis.

75. The composition according to claim 67, wherein the liver disease includes hepatocellular carcinoma (HCC).

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

77. The composition according to claim 67, wherein the liver disease includes portal hypertension.

78. The composition according to claim 55, wherein the composition is administered in combination with an additional therapeutic agent.

79. The pharmaceutical composition according to claim 54, wherein the additional therapeutic agent is one, two, three, or four additional therapeutic agents.

80. The pharmaceutical composition according to claim 54, wherein the additional therapeutic agent includes an acetyl-CoA carboxylase (ACC) inhibitor, an apoptosis signal-regulating kinase (ASK-1) inhibitor, a farnesoid X receptor (FXR) agonist, fish oil, a glucagon-like peptide-1 (GLP-1) receptor agonist, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, or a TGFβ antagonist.

81. The composition according to claim 80, wherein the ACC inhibitor is fiscostat.

82. The composition according to claim 80, wherein the ASK-1 inhibitor is ceronsertib.

83. The composition according to claim 80, wherein the FXR agonist is sirukefexal.

84. The composition according to claim 80, wherein the PPARα agonist is fibrate.

85. The composition according to claim 80, wherein the fish oil is ethyl eicosapentaenoate.

86. The composition according to claim 80, wherein the GLP-1 receptor agonist is liraglutide or semaglutide.

87. The composition according to claim 80, wherein the TGFβ antagonist is an anti-TGFβ1 specific antibody.

88. The composition according to claim 80, wherein the TGFβ antagonist is a TGFβ receptor.

89. The composition according to claim 80, wherein the additional therapeutic agent comprises fiscostat and sirukefexal.

90. The composition according to claim 80, wherein the additional therapeutic agent comprises fiscostat and liraglutide or semaglutide.

91. The composition according to claim 80, wherein the additional therapeutic agent comprises fibrate or ethyl eicosapentaenoate.

92. The composition according to claim 80, wherein the additional therapeutic agent comprises sirukefexal and liraglutide or semaglutide.

93. The additional therapeutic agent is a VEGFR inhibitor, FGFR inhibitor, PDGFR inhibitor, autotaxin inhibitor, GPR84 agonist, PASK inhibitor, CFTR agonist, JAK1 inhibitor, ADAMTS5 inhibitor, TOL2 / 3 inhibitor, CTGF inhibitor, soluble PTX2, anti-galectin-3 antibody, integrin-α Ｖ -β ６ / α Ｖ -β １ antagonist, JNK1 inhibitor, mineralocorticoid receptor antagonist, Nrf2 activator, chemase inhibitor, PDE inhibitor, NOX1 / 4 inhibitor, leukotriene / thromboxane receptor antagonist, SLC22A12 inhibitor, sGC inhibitor, or xanthine oxidase inhibitor, the pharmaceutical composition according to claim 54.

94. The pharmaceutical composition according to claim 54, wherein the additional therapeutic agent is selected from the group consisting of nintedanib, pirfenidone, pembrolizumab, PRM-151, GB-0139, PLN-74809, CC-90001, finerenone, BAY1142524, PCS-499, cetanaxib, SER150, RDEA3170, praliciguat, TMX-049, GLPG1690, GLPG1205, GLPG1972, GLPG4059, GLPG2737, GLPG3970, and filgotinib.

95. Use for the manufacture of a medicament for the treatment of an LPAR1-mediated disease or condition, comprising the use of a compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof.

96. A composition for the treatment of an LPAR1-mediated disease or condition, wherein the composition comprises a compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof.

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