LPA receptor antagonists and their use

Abstract

The present disclosure generally relates to compounds that bind to lysophosphatidic acid receptor 1 (LPAR1) and act as antagonists of LPAR1. The present disclosure further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and / or conditions mediated by LPAR1 binding, including fibrosis and liver disease, such as nonalcoholic steatohepatitis (NASH), interstitial lung disease (ILD), or chronic kidney disease (CKD).

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 287,252, filed on December 8, 2021, the entire disclosure of which is incorporated herein by reference for all purposes.

[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 binding of LPAR1 by the compounds.

[0007] Provided herein is, hereinafter,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0008] In some embodiments, a pharmaceutical composition comprising the 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 the 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 inhibiting LPAR1 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of Compounds 1-13), 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 Compounds 1-13), 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 LPAR1 antagonists 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 defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Note 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 their equivalents.

[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] “Compounds disclosed herein” or “compounds of the present disclosure” or “compounds provided herein” or “compounds described herein” refer to Compounds 1-13.

[0018] References to values or parameters herein as "about" include (and describe) embodiments that relate to the value or parameter itself. In certain embodiments, the term "about" includes the indicated amount plus or minus 10%. In other embodiments, the term "about" includes the indicated amount plus or minus 5%. In certain other embodiments, the term "about" includes the indicated amount plus or minus 1%. Also, with respect to that term, "about X" includes the description of "X". Also, the singular forms "a" and "the" include plural references unless the context clearly indicates 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 their equivalents.

[0019] 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. Additionally, 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, or portions thereof, of the features shown and described, although it is recognized that various modifications are possible within the scope of the claimed disclosure.

[0020] 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 can be used, according to the present disclosure, 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 addition salts containing inorganic or organic acids, according to 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.

[0021] 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, 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, by conventional methods known to those skilled in the art.

[0022] The present disclosure also includes all salts of the compounds of the present disclosure that, while not directly suitable for use in pharmaceuticals due to low physiological compatibility, 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.

[0023] Furthermore, the compounds disclosed herein may be subject to the effects of tautomerism. When tautomerism, such as 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 are mixtures thereof in any ratio. The same applies to stereoisomers, such as enantiomers, cis / trans isomers, diastereomers, conformational isomers, and the like.

[0024] 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 deliberately form and cleave chemical bonds. The term "deprotection" refers to the removal of a protecting group.

[0025] 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 with the knowledge of one of ordinary skill in the art to include only those members of the list that are suitable for replacing the particular group.

[0026] 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, especially ethanol. A "solvate" is formed by the interaction of a solvent with a compound.

[0027] In certain embodiments, provided are the optical isomers, racemic compounds, or other mixtures of these or mixtures thereof 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, for example, a chiral high-pressure liquid chromatography (HPLC) column.

[0028] "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.

[0029] The compounds disclosed herein and their pharmaceutically acceptable salts may, in some embodiments, contain chiral centers and, thus, may give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- with respect to absolute stereochemistry or, for amino acids, as (D)- or (L)-. 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 may be prepared using a chiral synthon or chiral reagent or resolved using prior art, e.g., chromatography and fractional crystallization. Prior art for the preparation / isolation of individual enantiomers includes chiral synthesis from suitable optically pure precursors or resolution of a racemic compound (or a racemic compound of a salt or derivative) using, e.g., chiral high performance liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometrically chiral centers and are not otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0030] The compositions provided herein that contain a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, may contain 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.

[0031] Any 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 the 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.

[0032] The present disclosure also includes "deuterated analogs" of the compounds disclosed herein, in which 1 to n hydrogens bonded to carbon atoms 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, such as 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 for deuterium.

[0033] 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 heavier isotopes such as deuterium can result in certain therapeutic advantages due to greater metabolic stability, such as an extended half-life in vivo, a reduction in dosing requirements, and / or an improvement in the therapeutic index. 18 F-labeled compounds may be useful in PET or SPECT studies.

[0034] 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 of hydrogen. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) means deuterium.

[0035] 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.

[0036] “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 dissociation of one or more of the ingredients, or from another type 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.

[0037] 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. that 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. (see G.S. Banker & C.T. Rhodes, Eds.)).

[0038] "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 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.

[0039] "Treatment" or "treating" is an approach to obtain 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 diminishing 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 a 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 prolonging survival). In some embodiments, the term "treatment" or "treating" means administering a compound of Compounds 1-13, 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.

[0040] "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.

[0041] "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 applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0042] The term "therapeutically effective amount" or "effective amount" of a compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, means an amount sufficient to provide a therapeutic benefit upon administration to a subject, such as improvement of symptoms or retardation of the progression of a disease. 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 2]

[0043] As used herein, "LPAR1 inhibitor" refers to any agent that can bind to and inhibit LPAR1. LPAR1, also known as LPA1, is a GPCR that binds to the lipid signaling molecule lysophosphatidic acid (LPA). Exemplary reference sequences for LPAR1 include NCBI reference sequences NP_001392 (human protein), NP_001277415 (mouse protein), NM_001401 (human mRNA), and NM_001290486 (mouse mRNA). LPAR1 antagonists can act as competitive inhibitors of full or partial LPAR1 agonists or as inverse agonists. The activity of LPAR antagonists can be measured by methods known in the art, such as those described 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.

[0044] 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.

[0045] As used herein, an "ASK1 inhibitor" can be any agent that is capable of inactivating 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.

[0046] 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 by several different methods in in vitro assays using, for example, 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.

[0047] Compound Provided herein are, hereinafter,

Chem.

Chem.

Chem.

Chem.

Chem.

[0048] In some embodiments, the compound is Compound 1 having the following structure

Chem.

[0049] In some embodiments, the compound is Compound 2 having the following structure,

Chemical formula

[0050] In some embodiments, the compound is Compound 3 having the following structure,

Chemical formula

[0051] In some embodiments, the compound is Compound 4 having the following structure,

Chemical formula

[0052] In some embodiments, the compound is Compound 5 having the following structure,

Chemical formula

[0053] In some embodiments, the compound is Compound 6 having the following structure,

Chemical formula

[0054] In some embodiments, the compound is Compound 7 having the following structure,

Chemical formula

[0055] In some embodiments, the compound is Compound 8 having the following structure, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the compound is Compound 9 having the following structure, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, the compound is Compound 10 having the following structure, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, the compound is Compound 11 having the following structure, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the compound is Compound 12 having the following structure, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, the compound is Compound 13 having the following structure, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0061] Pharmaceutical Compositions and Modes of Administration 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] The pharmaceutical composition of the present disclosure may additionally contain one or more other compounds as active ingredients, such as prodrug compounds or other enzyme inhibitors.

[0063] 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.

[0064] 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 wide variety of forms depending on the form of 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, in the case of oral solid preparations such as powders, hard capsules and 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.

[0065] Because of the ease of their administration, tablets and capsules represent the most advantageous oral unit dosage forms, in which case solid pharmaceutical carriers are used. If desired, the tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent active compound. The proportion of the active compound in these compositions can, of course, vary widely and conveniently can 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 intranasally, for example, as droplets or a spray.

[0066] 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 sweetening agents such as sucrose, lactose, or saccharin. When the unit dosage form is a capsule, it may contain a liquid carrier such as a fatty oil in addition to the materials of the above types.

[0067] 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 sweetening agent, methylparaben and propylparaben as preservatives, dyes, and flavoring agents such as cherry or orange flavor.

[0068] In some embodiments, the compounds of the present disclosure are also used as salts having various counter cations to obtain orally available formulations.

[0069] The compounds of the present disclosure can 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, liquid polyethylene glycols, and mixtures thereof in oil. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0070] Pharmaceutical forms suitable for use in injection include sterile aqueous solutions or dispersions, and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and fluid to the extent that it is easy to place 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.

[0071] 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.

[0072] 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.

[0073] Also provided herein are manufactured articles containing in a suitable container a compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof. The container can be a vial, bottle, ampule, prefilled syringe, and infusion bag.

[0074] Therapeutic Methods and Uses The present disclosure further relates to the use of a compound disclosed herein for the treatment and / or prevention of a disease and / or condition through binding of LPAR1 by the compound. Further, the present disclosure relates to the use of the compound for the preparation of a medicament for the treatment and / or prevention of a disease and / or condition through binding of LPAR1 by the compound.

[0075] 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.

[0076] 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 Compounds 1-13, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Compounds 1-13, or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, LPAR1-mediated diseases or conditions include those in which there is and / or is observed an absolute or relative excess amount of LPA.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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).

[0083] 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, for example, glomerulonephritis secondary to systemic inflammatory diseases such as lupus and scleroderma, diabetes, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allografts, and Alport; intestinal fibrosis, for example, scleroderma, and radiation-induced intestinal fibrosis.

[0084] 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.

[0085] In some embodiments, the LPAR1-mediated disease or condition includes, for example, radiation-induced head and neck fibrosis.

[0086] In some embodiments, LPAR1-mediated diseases or conditions include, for example, LASIK (laser-assisted in situ keratomileusis), corneal transplantation, or trabeculectomy. In some embodiments, the compounds of Compounds 1-13, or pharmaceutically acceptable salts thereof, are used to improve corneal hypoesthesia caused by corneal surgery such as LASIK, or cataract surgery, corneal hypoesthesia caused by corneal degeneration, and dry eye symptoms caused thereby. In some embodiments, the compounds of Compounds 1-13, or pharmaceutically acceptable salts thereof, are used in the treatment or prevention of ocular inflammation and allergic conjunctivitis, vernal catarrh, and papillary conjunctivitis. In some embodiments, the compounds of Compounds 1-13, or pharmaceutically acceptable salts thereof, are used in the treatment or prevention of Sjogren's disease or inflammatory diseases associated with dry eye.

[0087] In some embodiments, LPAR1-mediated diseases or conditions include, 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.

[0088] In some embodiments, LPAR1-mediated diseases or conditions include pain. In some embodiments, pain includes neuropathic pain. In some embodiments, pain includes acute pain. In some embodiments, pain includes chronic pain.

[0089] 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) (at any stage of the disease, regardless of the presence or absence of metastasis) such as 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 myelogenous 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, plasmacytoma / 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.

[0090] 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, isocapnic hyperventilation, childhood-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, and hypoxia.

[0091] 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.

[0092] 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.

[0093] 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 pulmonary fibrosis, arthritis, allergy, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, pain, proliferative disorders, and inflammatory conditions.

[0094] 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.

[0095] In some embodiments, provided herein is a method of doing so in a patient in need of treatment and / or prevention of NAFLD or NASH, the method comprising administering to the patient a therapeutically effective amount of a compound of Compounds 1-13, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Compounds 1-13, or a pharmaceutically acceptable salt thereof. In some embodiments, NAFLD or NASH includes hepatic fibrosis. In some embodiments, NAFLD or NASH includes cirrhosis. In some embodiments, the cirrhosis is compensated cirrhosis. In some embodiments, the cirrhosis is decompensated cirrhosis. In some embodiments, NAFLD or NASH includes HCC.

[0096] In some embodiments, provided herein is a method of doing so in a patient in need of prevention of a liver disease or condition, the method comprising administering to the patient a therapeutically effective amount of a compound of Compounds 1-13, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Compounds 1-13, or a pharmaceutically acceptable salt thereof. In some embodiments, the liver disease or condition is hepatic 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.

[0097] In some embodiments, the present disclosure relates to the use of Compounds 1-13, 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.

[0098] 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.

[0099] When treating or preventing an LPAR1-mediated disease or condition for which the compounds of the present disclosure are needed, generally satisfactory results are obtained when the compounds of the present disclosure are 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 compounds of the present disclosure are administered as a single daily dose or as divided doses two to six 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.

[0100] The compounds or compositions 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, administration or treatment with the compounds can be continued for several days. For example, typically, treatment will continue for at least 7 days, 14 days, or 28 days for one treatment cycle. Treatment cycles alternate periodically with a rest period of about 1 to 28 days, usually about 7 days or about 14 days, between cycles. Treatment cycles can also be continuous in other embodiments.

[0101] In some embodiments, the methods provided herein involve administering an initial daily dose of about 1 to 800 mg of the compounds 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.

[0102] Combination In some embodiments, the compounds of Compounds 1-13 provided herein, or pharmaceutically acceptable salts thereof, are administered in combination with one or more additional therapeutic agents for treating or preventing the diseases or conditions 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.

[0103] In some embodiments, the pharmaceutical compositions provided herein comprise the compounds of Compounds 1-13 provided herein, or pharmaceutically acceptable salts 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.

[0104] 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 stimulants, bioactive lipids, calcitonin agonists, cannabinoid receptor modulators, caspase inhibitors, caspase-3 stimulants, cathepsin inhibitors (e.g., cathepsin B inhibitors), caveolin 1 inhibitors, CCR2 chemokine antagonists, CCR3 chemokine antagonists, CCR5 chemokine antagonists, CD3 antagonists, chloride channel stimulants, cholesterol solubilizers, CNR1 inhibitors, cyclin D1 inhibitors, cytochrome P450 7A1 inhibitors, cytochrome P450 2E1 (CYP2E1) inhibitors, diacylglycerol O acyltransferase 1 (DGAT1) inhibitors, diacylglycerol O acyltransferase 1 (DGAT2) inhibitors, CXCR4 chemokine antagonists, dipeptidyl peptidase IV inhibitors, endothelin modulators, endothelial nitric oxide synthase stimulants, 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, peptidylprolyl 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, 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 (SnitrosoglutathioneSelected from reductase, GSNOR enzyme inhibitors, suppressors of cytokine signaling-1 stimulators, suppressors of cytokine signaling-3 stimulators, spleen tyrosine kinase (SYK) inhibitors, transforming growth factor β (TGF-β), TGF-β antagonists (e.g., TGF-β1 antagonist, TGF-β2 antagonist, TGF-β3 antagonist, latent TGF-β complex modulator), TGF-β receptor antagonists, transforming growth factor β activated kinase 1 (TAK1), thyroid hormone receptor β agonists, Toll-like receptor (TLR)-4 antagonists, transglutaminase inhibitors, tumor necrosis factor alpha (TNFα) ligand inhibitors, tumor progression locus 2 (Tpl2) kinase inhibitors, tyrosine kinase receptor modulators, GPCR modulators, nuclear hormone receptor modulators, WNT modulators, YAP / TAZ modulators, and zonulin inhibitors.

[0105] 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 (filsocostat), 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 stimulants 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 stimulants 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 stimulants 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; Cathepsin B inhibitors such as VBY-376; Cathepsin inhibitors such as VBY-825; CCR2 / CCR5 chemokine antagonists such as cenicriviroc, maraviroc, CCX-872, or WXSH-0213; CCR2 chemokine antagonists such as propargermanium; CCR2 chemokine / angiotensin II AT-1 receptor antagonists such as DMX-200 or DMX-250; CCR2 / CCR5 chemokine antagonists and FXR agonists such as LJC-242 (tropifexor + cenicriviroc); CCR3 chemokine antagonists such as belimumab; 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 belimumab 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 stimulators 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 odesivabat (A-4250), volixibat 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; MEKK-5 protein kinase (ASK-1) inhibitors 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 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); clofibrate aluminum, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, pemafibrate, ronifibrate, simfibrate, omega-3 fatty acids (fish oil, e.g., eicosapentaenoic acid ethyl (Vascepa (registered trademark)), or docosahexaenoic acid), pyrinixic 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 ceradelpar; 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 alamethicol; 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).

[0106] Additional non-limiting examples of one or more additional therapeutic agents include the following. ACE inhibitors such as benazepril, imidapril, 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 (trademark), AMP-activated protein kinase stimulant / precursor protein convertase PC9 inhibitor such as O-304, AMP-activated protein kinase stimulant such as DZCY-01, MK-8722, PXL-770, Angiotensin II AT-1 receptor / CCR2 chemokine antagonist such as DMX-200, Angiotensin II AT-2 receptor antagonist such as MOR-107, irbesartan, Angiotensin II receptor antagonist such as losartan, Angiotensinogen ligand inhibitor such as ALN-AGT, Anti-C1 antibody such as BIVV-009 (stimlimab), Anti-CB1 antibody, for example, GFB-024, Anti-CX3CR1 nanobody such as BI-655088, Anti-IL-6 antibody, for example, COR-001, Anti-VEGF-B antibody such as CSL-346, APOA1 gene stimulant / bromodomain-containing protein 2 / bromodomain-containing protein 4 inhibitor such as apabetalone, Bone morphogenetic protein-7 ligand modulator such as BMP-7, Calcium channel inhibitor such as TBN (xiaotongqin), Cannabinoid CB1 receptor antagonist such as JNJ-2463, CB1 inverse agonist such as CRB-4001, Kinase inhibitor such as flasimirstat (BAY-1142524), Cyclooxygenase 1 inhibitor such as GLY-230, Cyclooxygenase 2 / epoxide hydrolase inhibitor such as COX-2 / soluble epoxide hydrolase, Cytochrome P450 11B2 inhibitor such as aldosterone synthase inhibitor, Ectonucleotide pyrophosphatase-PDE-2 inhibitor such as BLD-0409, Endothelin ET-A / Endothelin ET-B receptor antagonists such as aprositentan, 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 ligand / growth hormone receptor agonists such as Jintropin AQ (trademark), Growth hormone receptor agonists such as LAT-8881, Guanylate cyclase receptor agonists / guanylate cyclase stimulators such as praliciguat, Guanylate cyclase stimulators such as MRL-001, 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 stimulators such as SFX-01, LDHA gene inhibitors such as nedocilan, 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 selonsertib, 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, and KBP-5074, 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 and bardoxolone methyl (NSC-713200), PDE 4 inhibitors such as ART-648 and PCS-499, 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 and PF-06685249, Prostacyclin (PGI2) agonists such as YS-1402, Protein C activator / glycoprotein Ib (GPIb) antagonist such as AB-002, Protein NOV homolog modulator such as BLR-200, Protein tyrosine phosphatase-1B inhibitor such as MSI-1436, Reactive oxygen species modulator inhibitor such as SUL-121, Renin inhibitor such as imalixiren hydrochloride, Rho-associated protein kinase 2 inhibitor such as ANG-4201, RXC-007, Sodium glucose transporter-2 inhibitor such as canagliflozin, dapagliflozin propanediol, empagliflozin, Thromboxane A2 receptor antagonist / thromboxane synthesis inhibitor such as SER-150, Tissue transglutaminase inhibitor such as ZED-1227, TRP cation channel C5 inhibitor such as GFB-887, TRP cation channel C6 inhibitor such as ALGX-2224, Cell adhesion molecule inhibitor such as glycoside bacterial adhesin antagonist, Urate anion exchanger 1 (URAT1) / SLC22A12 inhibitor such as berinurad (RDEA3170), VIP1 / VIP2 receptor agonist such as LBT-3627, and Xanthine oxidase inhibitor such as TMX-049, TMX-049DN.

[0107] In some embodiments, one or more additional therapeutic agents are A-4250, AC-3174, acetylsalicylic acid, AK-20, alipogene tiparvovec, AMX-342, AN-3015, alamchol, ARI-3037MO, ASP-8232, AZD-2693, belimumab, anhydrous betaine, 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, colecalciferol, 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, fludroxycortide (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,icosapentate (PRC-4016), ethyl icosapentate, IMM-124-E, INT-767, INV-240, IONIS-DGAT2Rx, ipragliflozin, ilbesartan, propyl gallium, 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.

[0108] In some embodiments, the methods and pharmaceutical compositions provided herein comprise 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 Compounds 1-13 provided herein, or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the ASK1 inhibitor is GS-4997 (selonsertib, SEL).

[0110] 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.

[0111] 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 Compounds 1-13 provided herein, or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the ACC inhibitor is GS-0976 (filsoctostat, FIR).

[0113] 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.

[0114] 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 Compounds 1-13 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 (registered trademark)).

[0115] In some embodiments, the methods and compositions provided herein include 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 Compounds 1-13 provided herein, or a pharmaceutically acceptable salt thereof.

[0116] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the FXR agonist is GS-9674 (cilofexor, CILO).

[0117] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the FXR agonist is a compound having the following structure,

Chemical formula

[0118] In some embodiments, the methods and compositions provided herein include 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 Compounds 1-13 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.

[0119] In some embodiments, the methods and compositions provided herein include 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 Compounds 1-13 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, for example, the liver. In some embodiments, the anti-LAP antibody specifically binds to the LAP-TGFβ complex on the surface of certain immunosuppressive cell types, such as regulatory T cells (Tregs), tumor-associated macrophages, or myeloid-derived suppressor cells, in, for example, the tumor microenvironment. 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 that comprises 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).

[0120] In some embodiments, the methods and compositions provided herein include 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 MAP kinase inhibitor, PDE4 inhibitor, PDGF receptor antagonist, PDGF receptor beta modulator, phosphatonin receptor agonist, PRKAA2 gene stimulator, proprotein convertase PC9 inhibitor, prostacyclin (PGI2) agonist, protein C activator, protein NOV homolog modulator, protein tyrosine phosphatase-1B inhibitor, reactive oxygen species modulator inhibitor, renin inhibitor, Rho-associated protein kinase 2 inhibitor, SLC22A12 inhibitor, sodium glucose transporter-2 inhibitor, solute carrier family inhibitor, TGF beta ligand inhibitor, TGF beta receptor antagonist, thromboxane A2 receptor antagonist, thromboxane synthase inhibitor, tissue transglutaminase inhibitor, TRP cation channel C5 inhibitor, TRP cation channel C6 inhibitor, tryptophanase inhibitor, unspecified cell adhesion molecule inhibitor, urate anion exchanger 1 inhibitor, vasopressin V1a receptor antagonist, VEGF receptor antagonist, VIP1 receptor agonist, VIP2 receptor agonist, and xanthine oxidase inhibitor.

[0121] 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 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 -β6 / α V -β1 antagonist, JNK1 inhibitor, mineralocorticoid receptor antagonist, Nrf2 activator, kinase inhibitor, PDE inhibitor, NOX1 / 4 inhibitor, leukotriene / thromboxane receptor antagonist, SLC22A12 inhibitor, sGC inhibitor, and xanthine oxidase inhibitor.

[0122] 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, cetanixib, SER150, RDEA3170, praliciguat, TMX-049, GLPG1690, GLPG1205, GLPG1972, GLPG4059, GLPG2737, GLPG3970, and filgotinib.

[0123] 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, bevelimer, VS-105, and XRx-221.

Example

[0124] 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 practice of the present disclosure and can, therefore, be considered to constitute specific modes for its practice. 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 changes can be made in the specific embodiments disclosed and still obtain similar or like results.

[0125] The compounds disclosed herein can be prepared using suitable materials according to the procedures of the following examples and are further illustrated by the following specific examples. 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 for the identity of the required starting materials, taking into account 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.

[0126] 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.

[0127] Example 1: Preparation of (R)-1-(3-fluorophenyl)ethyl (1-methyl-4-(5-(2,2,2-trifluoroacetamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 1) [Chemical formula] Step 1: 4-(5-((tert-butoxycarbonyl)amino)pyrimidin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1) 4-Bromo-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (50 mmol) was dissolved in 500 mL of tetrahydrofuran and immersed in a -78 °C bath for 15 minutes. A 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (54 mmol) was added dropwise over 15 minutes. A 2.5 M solution of n-butyllithium (105 mmol) in hexane was added dropwise over 20 minutes and stirred for an additional 1 hour. A 1.9 M solution of zinc chloride (105 mmol) in 2-methyltetrahydrofuran was added dropwise over 15 minutes. The reaction mixture was warmed to ambient temperature by immersion in a water bath and stirred for 30 minutes. The resulting mixture was sparged with argon gas for 10 minutes, after which tert-butyl (6-bromopyridin-3-yl)carbamate (50 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex (5 mmol) complexed with dichloromethane were added. The reaction was heated at 75 °C for 3 hours and then cooled to ambient temperature. The reaction was diluted with 350 mL of 2 M aqueous sodium hydroxide and 300 mL of diethyl ether. The aqueous layer was separated and the organic layer was diluted with 1 M aqueous sodium hydroxide (100 mL). The combined aqueous layers were washed with a 1:1 mixture of ethyl acetate and diethyl ether (150 mL × 2). 80 mL of concentrated hydrochloric acid was added dropwise over 10 minutes with vigorous stirring to adjust the pH to 4. The mixture was filtered and the filter cake was washed with water (100 mL) and a 1:1 mixture of ethyl acetate and diethyl ether (100 mL × 2). The precipitate was dried under reduced pressure to obtain 4-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1).

[0128] Step 2: 5-(5-Amino-2-pyridyl)-3-methyl-triazole-4-carboxylic acid, trifluoroacetate (Intermediate 2) A mixture of 4-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (0.27 mmol) in dichloromethane (3 mL) was treated with trifluoroacetic acid (1.0 mL, 13 mmol), and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated in vacuo to give 5-(5-amino-2-pyridyl)-3-methyl-triazole-4-carboxylic acid, trifluoroacetate salt (Intermediate 2).

[0129] Step 3: (R)-1-(3-Fluorophenyl)ethyl (1-methyl-4-(5-(2,2,2-trifluoroacetamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 1) To a mixture of 5-(5-amino-2-pyridyl)-3-methyl-triazole-4-carboxylic acid, trifluoroacetate salt (Intermediate 2, 96 μmol), 1-propanephosphonic acid cyclic anhydride (50% in THF, 0.24 mmol), and azidotrimethylsilane (0.24 mmol) in THF (1 mL) was added dropwise triethylamine (0.38 mmol), followed by dropwise addition of (1R)-1-(3-fluorophenyl)ethanol (0.13 mmol). The reaction mixture was heated at 80 °C for 2 hours, cooled to room temperature, concentrated, and purified by silica gel chromatography to give (R)-1-(3-fluorophenyl)ethyl (1-methyl-4-(5-(2,2,2-trifluoroacetamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 1). (MS (m / z) 453.1 [M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 8.88 (s, 1H), 8.18 (dd, J = 8.7, 2.6 Hz, 1H), 8.01 - 7.91 (m, 1H), 7.36 (m, 1H), 7.31 - 7.08 (m, 2H), 7.03 (t, J = 8.6 Hz, 1H), 5.82 (m, 1H), 3.98 (s, 3H), 1.51 (m, 3H).

[0130] Example 2: Preparation of (S)-2-fluoro-1-(3-fluorophenyl)ethyl (4-(5-acetamido-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 2) [Chemical formula] Step 1: 4-(5-((tert-Butoxycarbonyl)amino)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 3) Following the procedure described in the above example for the synthesis of 4-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1), 4-(5-((tert-butoxycarbonyl)amino)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 3) was prepared by replacing tert-butyl (6-bromopyridin-3-yl)carbamate with tert-butyl (6-bromo-2-methylpyridin-3-yl)carbamate. Step 2: tert-Butyl (S)-(6-(5-(((2-fluoro-1-(3-fluorophenyl)ethoxy)carbonyl)carbamoyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)carbamate (Intermediate 4)

[0131] 4-(5-((tert-Butoxycarbonyl)amino)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 3, 1.6 mmol), azidotrimethylsilane (2.3 mmol), and T3P (50% in THF) (2.3 mmol) were dissolved in THF (6 mL). Triethylamine (4.7 mmol) was added dropwise at room temperature, and a clear solution formed after 5 - 30 minutes. (S)-2-Fluoro-1-(3-fluorophenyl)ethan-1-ol (3.2 mmol) was added, and the reaction mixture was heated at 70 °C for 1 - 2 hours. After cooling, water and ethyl acetate were added, and the layers were separated. The organic phase was concentrated under reduced pressure, and the residue was then purified by column chromatography to obtain tert-butyl (S)-(6-(5-(((2-fluoro-1-(3-fluorophenyl)ethoxy)carbonyl)carbamoyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)carbamate (Intermediate 4).

[0132] Step 3: (S)-2-Fluoro-1-(3-fluorophenyl)ethyl (4-(5-amino-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carbonyl)carbamate hydrochloride (Compound 5) tert-Butyl (S)-(6-(5-(((2-fluoro-1-(3-fluorophenyl)ethoxy)carbonyl)carbamoyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)carbamate (Intermediate 4) was suspended in a hydrogen chloride solution (10 mL, 4 M in dioxane) for 1 hour. The mixture was then concentrated in vacuo to obtain (S)-2-fluoro-1-(3-fluorophenyl)ethyl (4-(5-amino-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carbonyl)carbamate hydrochloride (Intermediate 5), which was used without further purification.

[0133] Step 4: (S)-2-Fluoro-1-(3-fluorophenyl)ethyl (4-(5-acetamido-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 2) A solution of (S)-2-fluoro-1-(3-fluorophenyl)ethyl (4-(5-amino-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carbonyl)carbamate hydrochloride (Intermediate 5, 67 μmol) in 1 mL of DCM was treated with pyridine (0.2 mL). Acetyl chloride (0.14 mmol) was added and the mixture was stirred at room temperature. After 30 minutes, the reaction was concentrated and dissolved in tetrahydrofuran (2 mL) and 1 M aqueous sodium hydroxide solution (2 mL), and stirred vigorously for 10 minutes. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (2 × 10 mL). The combined organics were dried over sodium sulfate, concentrated, and purified by RP HPLC to give (S)-2-fluoro-1-(3-fluorophenyl)ethyl (4-(5-acetamido-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 2). (MS (m / z) 431.4 [M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 8.07 - 7.75 (m, 2H), 7.61 - 7.45 (m, 1H), 7.34 (dd, J = 17.3, 8.8 Hz, 2H), 7.17 (td, J = 8.4, 2.5 Hz, 1H), 6.01 (t, J = 8.2 Hz, 1H), 4.48 (t, J = 8.5 Hz, 1H), 4.19 (t, J = 8.0 Hz, 1H), 4.06 (s, 3H), 2.37 (s, 3H), 2.18 (s, 3H).

[0134] Example 3: (R)-1-(2-Chloropyridin-3-yl)ethyl (4-(5-(1-hydroxycyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 3)

Chemical Structure

[0135] Process 2: Preparation of (R)-1-(2-Chloropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 7) 4M HCl in 1,4-dioxane (20 mL) was added to (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 6, 6.9 mmol). The resulting suspension was stirred at room temperature for 18 h. The reaction mixture was concentrated to give (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 7) as the hydrochloride salt.

[0136] Step 3: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-(1-hydroxycyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 3) To a mixture of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 7) (0.060 mmol) in pyridine (0.5 mL) were added 1-hydroxycyclopropanecarboxylic acid (0.064 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.091 mmol). The reaction mixture was left for 2 h with magnetic stirring, at which point water (1 mL) was added and the mixture was concentrated under reduced pressure. The residue was subjected to purification by RP-HPLC to give (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-(1-hydroxycyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 3). (MS (m / z) 458.2 [M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 8.92 (s, 1H), 8.55 - 7.75 (m, 4H), 7.47 (s, 1H), 6.08 (q, J = 6.4 Hz, 1H), 3.99 (s, 3H), 1.61 (s, 3H), 1.42 - 1.25 (m, 2H), 1.20 - 1.03 (m, 2H).

[0137] Example 4: (R)-1-(2-Chloropyridin-3-yl)ethyl (4-(5-(1-methoxycyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 4)

Chem.

[0138] Example 5: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(6-chloro-5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 5)

Chem.

[0139] Step 2: Preparation of 5-[5-(tert-butoxycarbonylamino)-6-chloro-2-pyridyl]-3-methyl-1,2,3-triazole-4-carboxylic acid (Intermediate 9) The title intermediate was prepared according to the procedure that provided 4-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1), replacing tert-butyl (6-bromopyridin-3-yl)carbamate with tert-butyl N-(6-bromo-2-chloro-3-pyridyl)carbamate and replacing [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II] complexed with dichloromethane with chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II).

[0140] Step 3: Preparation of (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-((tert-butoxycarbonyl)amino)-6-chloropyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carbonyl)carbamate (Compound 10) 5-[5-(tert-Butoxycarbonylamino)-6-chloro-2-pyridyl]-3-methyl-1,2,3-triazole-4-carboxylic acid (Intermediate 9) was replaced with 4-(5-((tert-butoxycarbonyl)amino)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 3), and (1R)-1-(2,5-difluoro-3-pyridyl)ethanol was replaced with (S)-2-fluoro-1-(3-fluorophenyl)ethan-1-ol. The title intermediate was prepared via a procedure similar to the procedure that provided tert-butyl (S)-(6-(5-(((2-fluoro-1-(3-fluorophenyl)ethoxy)carbonyl)carbamoyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)carbamate (Intermediate 4, Example 2, Step 2).

[0141] Step 4: [(1R)-1-(2,5-Difluoro-3-pyridyl)ethyl] N-[5-(5-Acetamido-6-chloro-2-pyridyl)-3-methyl-1,2,3-triazol-4-yl]carbamate hydrochloride (Compound 11) The title intermediate was obtained by the same procedure (HCl / dioxane) used to obtain (S-2-fluoro-1-(3-fluorophenyl)ethyl (4-(5-amino-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carbonyl)carbamate hydrochloride (Intermediate 5, Example 2, Step 3).

[0142] Step 5: Preparation of (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(6-chloro-5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 5) Replace [(1R)-1-(2,5-difluoro-3-pyridyl)ethyl] N-[5-(5-amino-6-chloro-2-pyridyl)-3-methyl-triazol-4-yl] carbamate hydrochloride (Intermediate 11) instead of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl) carbamate hydrochloride (Intermediate 7), and replace 1-hydroxycyclopropanecarboxylic acid with 1-cyanocyclopropanecarboxylic acid. In the same manner as (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-(1-hydroxycyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl) carbamate (Compound 3), the title example was prepared. (MS(m / z) 502.9 [M+H] + ). 1 H NMR(400 MHz, methanol-d4) δ 8.37 (d, J = 8.3 Hz, 1H), 8.01 (d, J = 8.4 Hz, 3H), 6.00 (d, J = 7.6 Hz, 1H), 4.00 (s, 3H), 1.87 - 1.37 (m, 7H).

[0143] Example 6: (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-(6-cyclopropylnicotinamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl) carbamate (Compound 6)

Chemical Structure

[0144] Step 2: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 13) 4M HCl in 1,4-dioxane (15 mL) was added to tert-butyl (R)-(6-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamate (4.2 mmol). The resulting suspension was stirred at room temperature for 18 h. The reaction was concentrated to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 13).

[0145] Step 3: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(5-(6-cyclopropylnicotinamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 6) Replace (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 7) with (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 13), and replace 1-hydroxycyclopropanecarboxylic acid with 6-cyclopropylpyridine-3-carboxylic acid. Thus, the title example was prepared in the same manner as (R-1-(2-chloropyridin-3-yl)ethyl (4-(5-(1-hydroxycyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 3). (MS (m / z) 521.0 [M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 9.09 - 8.83 (m, 2H), 8.23 (ddd, J = 8.3, 6.1, 2.5 Hz, 2H), 8.16 - 7.61 (m, 3H), 7.41 (dd, J = 8.3, 0.8 Hz, 1H), 5.96 (d, J = 6.7 Hz, 1H), 4.00 (s, 3H), 2.22 (tt, J = 8.0, 5.1 Hz, 1H), 1.62 (s, 3H), 1.12 (ddt, J = 12.2, 7.5, 2.6 Hz, 4H).

[0146] Example 7: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(5-(2-cyclopropyloxazole-5-carboxamido)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 7)

Chemical Structure

[0147] Step 2: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(5-amino-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 15) (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(5-((tert-butoxycarbonyl)amino)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 14) was suspended in a hydrogen chloride solution for 1 hour. The mixture was then concentrated in vacuo to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-amino-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 15), which was used without further purification.

[0148] Step 3: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(5-(2-cyclopropyloxazole-5-carboxamido)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 7) (R)-1-(2-Cyclopyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 7) was replaced with (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-amino-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (Intermediate 15), and 1-hydroxycyclopropanecarboxylic acid was replaced with 2-cyclopropyloxazole-5-carboxylic acid. Thus, the title example was prepared in the same manner as (R-1-(2-chloropyridin-3-yl)ethyl (4-(5-(1-hydroxycyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H(1,2,3-triazol-5-yl)carbamate (Example 3, Step 3)). (MS (m / z) 521.0 [M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 8.04 (bs, 1H), 7.92 - 7.82 (m, 2H), 7.75 (s, 1H), 5.98 (m, 1H), 4.02 (s, 3H), 2.50 (s, 3H), 2.25 (p, J = 6.7 Hz, 1H), 1.61 (bs, 3H), 1.23 (m, 4H).

[0149] Example 8: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(5-(2-(3-chlorophenyl)pyrimidine-5-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 8)

Chemical Structure

[0150] Step 2: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(5-(2-(3-chlorophenyl)pyrimidine-5-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 8) Into a vial equipped with a stir bar, (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-(2-chloropyrimidine-5-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 16, 97 μmol), (3-chlorophenyl)boronic acid (145 μmol, 1.5 equiv), tetrakis(triphenylphosphine)palladium(0) (9.7 μmol, 10 mol%), and potassium carbonate (290 μmol, 3.0 equiv) were charged. 1,4-Dioxane (2 mL) and distilled water (0.2 mL) were added by syringe, and the mixture was degassed by bubbling argon through it for 5 minutes with stirring. The vial was sealed with a septum cap and the mixture was heated to 90 °C. When the starting materials were completely consumed, saturated aqueous sodium chloride was added to the reaction mixture in a volume equal to the initial reaction volume. The resulting mixture was extracted three times with ethyl acetate, the organic layers were collected, the volatile substances were removed in vacuo, and the residue was purified by silica gel column chromatography to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-(2-(3-chlorophenyl)pyrimidine-5-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 8). (MS (m / z) 592.0 [M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 9.39 (s, 2H), 8.98 (s, 1H), 8.63 - 8.40 (m, 2H), 8.28 (dd, J = 8.6, 2.6 Hz, 1H), 8.21 - 7.64 (m, 3H), 7.64 - 7.47 (m, 2H), 5.97 (d, J = 7.0 Hz, 1H), 4.01 (s, 3H), 1.63 (s, 3H).

[0151] Example 9: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(5-(1-(aminomethyl)-3,3-difluorocyclobutane-1-carboxamido)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 9)

Chemical Structure

[0152] Example 10: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (1-methyl-4-(5-(3-phenylbicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)carbamate (Compound 10)

Chemical formula

[0153] Example 11: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(5-(4-(bicyclo[1.1.1]pentan-1-yl)benzamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 11)

Chemical formula

[0154] Example 12: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Compound 12)

Chemical Structure

[0155] Compound 13: (R)-3-((6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamoyl)bicyclo[1.1.1]pentan-1-ylmethanesulfonate (Compound 13)

Chem.

[0156] Step 2: (R)-Methyl 3-((6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamoyl)bicyclo[1.1.1]pentan-1-ylmethanesulfonate (Compound 13) A solution of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-(3-hydroxybicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate dihydrochloride (Intermediate 18, 68 μmol) in dichloromethane (2 mL) was treated with triethylamine (0.34 mmol) at room temperature. Methanesulfonyl chloride (0.40 mmol) was added to the stirred mixture. When the reaction was judged to be complete by LC / MS analysis, the mixture was quenched with isopropanol and concentrated under reduced pressure. The residue was subjected to reverse-phase HPLC to give (R)-3-((6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)carbamoyl)bicyclo[1.1.1]pentan-1-yl methanesulfonate (Compound 13). (MS (m / z) 562.1 [M+H] + ). 1 H NMR (400 MHz, acetonitrile-d3) δ 8.91 (s, 1H), 8.55 (s, 1H), 8.31 (d, J = 3.2 Hz, 1H), 8.15 (dd, J = 8.7, 2.4 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.90 (bs, 1H), 7.38 (bs, 1H), 6.01 (q, J = 6.5 Hz, 1H), 3.93 (s, 3H), 3.10 (s, 3H), 2.59 (s, 6H), 1.55 (s, 3H).

[0157] Example 14: Calcium Assay In vitro LPAR1 activity was measured in an intracellular calcium mobilization assay.

[0158] CHO-K1 EDG2 cells (DiscoverX catalog number 93 - 0644C2) expressing human LPAR1 (NM_001401.3) were seeded at 15,000 cells / well in a 384-well tissue culture plate (Grenier number 781091) in a total volume of 25 μL of Dulbecco's Modified Eagle's Medium (DMEM) containing 10% fetal bovine serum, 1×PenStrepGlutamine, 300 μg / ml of hygromycin, and 800 μg / ml of G418, and incubated overnight at 37°C. Prior to the test, 25 μL of calcium-loading dye component A (FLIPR Calcium 6 assay kit molecular device number R8190), 2.5 mM probenecid (Invitrogen number P36400, freshly prepared), 20 mM HEPES (Corning number 25 - 060 - CI), and 0.1% bovine serum albumin (Sigma-Aldrich number A7906 - 500G) in Hank's Balanced Salt Solution (Corning number 21 - 023 - CV) were added to the cells at 37°C for 60 minutes.

[0159] 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 of LPA 18:2 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.

[0160] 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 80Pre-incubated with LPA at a concentration (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 with 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 .

[0161] To evaluate the antagonist potential of the exemplified compounds, the EC 50 values were determined for Compounds 1 - 13 in the LPAR1 calcium mobilization assay. The results are shown in Table 1 (LPAR1 EC 50 ). The compound numbers correspond to the compound numbers of Examples 1 - 13.

Table 1

[0162] 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.

[0163] Accordingly, although the present disclosure has been specifically disclosed by preferred embodiments, any features, modifications, improvements, and variations of the disclosure embodied herein disclosed in this specification can 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 exemplary, and are not intended as limitations on the scope of the present disclosure.

[0164] The present disclosure has been described herein in a wide and comprehensive manner. Each of the more narrow species and subgeneric groups that fall within the comprehensive disclosure also forms part of the present disclosure. This includes the general description of the present disclosure with conditional or negative limitations that remove any subject from the genus, regardless of whether the deleted material is specifically recited herein.

[0165] 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 limiting of 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)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Claims

1. 【Fig. 38】 【Chemical Formula 39】 【Chemical 40】 【Chemical Formula 41】 【Chemical Formula 42】 A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

2. The compound is 【Chemical Formula 43】 the compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

3. The compound is 【Chemical 44】 the compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

4. The compound is 【Chemical 45】 the compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

5. The compound is 【Chemical 46】 the compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

6. The compound is 【Chemical 47】 the compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

7. The compound is 【Chemical 48】 the compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

8. The compound is 【Chemical Formula 49】 the compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

9. The compound is 【Chemical Formula 50】 the compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

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

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

12. The compound is 【Chemical Formula 53】 the compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

13. The compound is 【Chemical 54】 the compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

14. The compound is 【Chemical Formula 55】 the compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

15. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

16. The pharmaceutical composition according to claim 15, further comprising an additional therapeutic agent.

17. A composition for treating, stabilizing, or reducing the severity or progression of an LPA1-mediated disease or condition, comprising the compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein the LPA1-mediated disease or condition is interstitial lung disease (ILD) or non-alcoholic steatohepatitis (NASH).

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