LPA receptor antagonists and their uses

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 priority to U.S. Provisional Patent Application No. 63 / 287,252, filed December 8, 2021, which is incorporated herein in its entirety for all purposes.

[0002] The present disclosure relates to compounds that bind to and act as antagonists of lysophosphatidic acid (LPA) receptors, such as LPAR1. 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-associated diseases or conditions. [Background technology]

[0003] Lysophosphatidic acid (mono-acyl-glycerol-3-phosphate, LPA) is a class of biologically active phospholipids that can be generated from lysophosphatidyl choline (LPC), for example, 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 interchangeably referred to 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 involving LPA receptor-deficient mice or certain tool compounds have suggested the possibility of LPA receptors as potential drug targets in a variety of diseases, including cancer, fibrosis, inflammation, pain, and cardiovascular disease. More recently, LPAR1 antagonists have been clinically investigated in association with fibrotic disease states such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis.

[0005] There remains a need for LPA antagonists that have desirable selectivity, potency, metabolic stability, or reduced adverse effects. Summary of the Invention

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

[0007] Provided herein are: [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0008] In some embodiments, provided herein is a pharmaceutical composition comprising a compound provided herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound provided herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient or carrier.

[0009] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents, or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions further comprise 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 a pharma- ceutically acceptable salt thereof.

[0010] In some embodiments, the disclosure provides a method of inhibiting LPAR1 activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of compounds 1-13), or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition provided herein.

[0011] In some embodiments, the disclosure provides a method of treating a patient having an LPAR1-mediated condition, comprising administering to the patient a therapeutically effective amount of a compound provided herein (e.g., any of compounds 1-13), or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition provided herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

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

[0014] Definitions and general parameters The following description is made with the understanding that the present disclosure should be considered as an example of the claimed subject matter and is not intended to limit the scope of the appended claims to the specific embodiments illustrated. Headings used throughout this disclosure are for convenience only and should not be construed as limiting the scope of the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Please 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 indicates otherwise. Thus, for example, a reference to a "compound" includes a plurality of such compounds, and a reference to an "assay" includes a reference to one or more assays and equivalents thereof known to those skilled in the art, etc.

[0016] As used herein, the following words and phrases are intended to have the meanings generally set forth below, unless a different meaning is suggested by the context in which they are used.

[0017] "Compounds disclosed herein" or "compounds of the disclosure" or "compounds provided herein" or "compounds described herein" refers to Compounds 1-13.

[0018] Reference herein to "about" a value or parameter includes (and describes) embodiments relating to the value or parameter itself. In certain embodiments, the term "about" includes the indicated amount ±10%. In other embodiments, the term "about" includes the indicated amount ±5%. In certain other embodiments, the term "about" includes the indicated amount ±1%. Also, for those terms, "about X" includes the description of "X." Additionally, 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 and equivalents thereof known to those of skill in the art.

[0019] The disclosure illustratively described herein may suitably be 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., should be read broadly and without limitation. Additionally, the terms and expressions used herein are used as terms of description and not of limitation, and there is no intention to use such terms and expressions to exclude any equivalents of the features shown and described, or portions thereof, but it is recognized that various modifications are possible within the scope of the disclosure as claimed.

[0020] The compounds of the present disclosure may 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 may 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, in particular the pharmaceutically available salts of the compounds. Thus, the compounds of the present disclosure that contain acidic groups may be present in these groups and may be used in accordance with the present disclosure, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts 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 may contain one or more basic groups, i.e., groups that can be protonated, and may be used in the form of their addition salts with inorganic or organic acids according to the present disclosure. Examples of suitable acids include hydrochloric acid, hydrobromic acid, 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] In the case where the compounds of the present disclosure simultaneously contain acidic and basic groups in the molecule, the present disclosure also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The respective salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting these salts with organic or inorganic acids or bases in a solvent or dispersant, or by anion or cation exchange with other salts.

[0022] The present disclosure also includes all salts of the compounds of the present disclosure that are not directly suitable for use in pharmaceuticals due to poor physiological compatibility, but can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts. Acids and bases useful for reacting with the base compound to form pharmaceutically acceptable salts (acid addition salts or base addition salts, respectively) are known to those skilled in the art. Similarly, methods for preparing pharmaceutically acceptable salts from the base compound (as disclosed) are known to those skilled 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 tautomerism. Where tautomerism, e.g., keto-enol tautomerism, of the compounds or their prodrugs may occur, each of the individual forms, e.g., keto and enol forms, are within the scope of the present disclosure, as are mixtures thereof in any ratio. The same applies to stereoisomers, e.g., enantiomers, cis / trans isomers, diastereomers, conformers, etc.

[0024] The term "protecting group" refers to a moiety of a compound that masks or changes 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 utilized to mask the reactivity of certain functional groups to aid in the effectiveness of desired chemical reactions, e.g., to create and break chemical bonds in an orderly and planned manner. The term "deprotection" refers to the removal of a protecting group.

[0025] Those of skill in the art will understand that if the list of alternative substituents includes members that cannot be used to replace a particular group due to the members' valence requirements or for other reasons, the list is intended to be read with the knowledge of those of skill in the art to include only those members of the list that are suitable to replace the particular group.

[0026] Additionally, the compounds of the present disclosure may exist in the form of solvates, such as solvates that include pharma- ceutically acceptable solvates such as water of solvation or alcohols, particularly ethanol. A "solvate" is formed by the interaction of a solvent with a compound.

[0027] In certain embodiments, the optical isomers, racemates, or other mixtures thereof or mixtures thereof of the compounds described herein or their pharma- ceutically acceptable salts are provided. If desired, isomers can be separated by methods well known in the art, for example, liquid chromatography. In these situations, single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution. Resolution can be achieved by conventional methods, such as, for example, crystallization in the presence of a resolving agent, or chromatography, for example, using 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 pharma- ceutically acceptable salts may, in some embodiments, contain asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined in terms of absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. Some embodiments include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using prior art techniques, such as chromatography and fractional crystallization. Prior art techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0030] Compositions provided herein that contain the compounds described herein, or pharma- ceutically acceptable salts, isomers, or mixtures thereof, may include racemic mixtures, or mixtures containing an enantiomeric excess of one enantiomer or a single diastereomer, or diastereomeric mixtures. All such isomeric forms of these compounds are expressly included herein as if each and every isomeric form were specifically and individually listed.

[0031] Any structure given herein is also intended to represent unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have 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 Included among the isotopes are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as I. Various isotopically labeled compounds of the present disclosure include, for example, 3 H, 13 C and 14 A radioisotope such as C is incorporated. Such isotopically labeled compounds may be useful in detection or imaging techniques such as metabolism studies, reaction kinetic studies, positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radiotherapy of patients. The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting readily available isotopically labeled reagents with non-isotopically labeled reagents.

[0032] The present disclosure also includes "deuterated analogs" of the compounds disclosed herein in which 1 to n hydrogens attached to a carbon atom have been replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and thus may be useful for increasing the half-life of any compound of formula (I) when administered to a mammal, e.g., a human. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol.Sci.5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, e.g., by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0033] 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 may confer certain therapeutic advantages due to greater metabolic stability, e.g., extended in vivo half-life, reduced dosage requirements and / or improved 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 isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", the position is understood to have hydrogen with the natural abundance isotopic composition of hydrogen. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0035] Further, 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 pharma- ceutically acceptable salt or solvate thereof, together with a pharma- ceutically acceptable carrier.

[0036] "Pharmaceutical composition" refers to one or more active ingredients and one or more inactive ingredients that make up the carrier, as well as any product that results directly or indirectly from the combination, complexation or aggregation of any two or more of the ingredients, or from the dissociation of one or more of the ingredients, or from any other type of reaction or interaction of one or more of the ingredients. Thus, the pharmaceutical composition of the present disclosure can include any composition made by mixing at least one compound of the present disclosure with a pharma- ceutical acceptable carrier.

[0037] As used herein, "pharmaceutical acceptable carriers" include excipients or agents, such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, that are not deleterious to the disclosed compounds or their use. The use of such carriers and agents to prepare compositions of pharma- ceutically active substances is well known in the art (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0038] "I C 50 " or "EC 50 " refers to the inhibitory concentration required to achieve 50% of the maximum desired effect. In many cases herein, the maximum desired effect is the inhibition of LPA-induced LPAR1 activation. This term is obtained using an in vitro assay, such as a calcium mobilization assay, that evaluates the concentration-dependent inhibition of LPA-induced LPAR1 activity.

[0039] "Treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition and / or lessening the severity of the disease or condition); b) delaying or arresting the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition); and / or c) palliating the disease, i.e., causing regression of clinical symptoms (e.g., ameliorating the disease state, reducing the severity of the disease or condition). providing partial or complete remission, enhancing the effect of another drug, delaying disease progression, improving quality of life, and / or prolonging survival. In some embodiments, the term "treatment" or "treating" refers to administering a compound of Compounds 1-13, or a pharma- ceutical acceptable salt thereof, for the purpose of (i) delaying the onset of the disease, i.e. preventing or delaying the onset of clinical symptoms of the disease, (ii) inhibiting the disease, i.e. preventing the onset of clinical symptoms, and / or (iii) relieving the disease, i.e. causing regression of clinical symptoms or their severity.

[0040] "Prevention" or "preventing" refers to any treatment of a disease or condition that does not result in the development of clinical symptoms of the disease or condition. In some embodiments, the compounds may be administered to subjects (including humans) who are at risk or have a family history of the disease or condition.

[0041] "Subject" refers to an animal, such as a mammal (including a human), that has been or is the object 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 pharma- ceutical acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogue thereof, refers to an amount sufficient to effect treatment and provide a therapeutic benefit, such as amelioration of symptoms or delay of disease progression, when administered to a subject. For example, a therapeutically effective amount may be an amount sufficient to reduce symptoms of a disease or condition in response to an LPAR1 antagonist. A therapeutically effective amount may vary depending on the subject, the disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the mode of administration, and can be easily determined by one skilled 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 capable of binding to and inhibiting Acetyl-CoA carboxylase (ACC). ACC inhibitors can act as inhibitors or partial inhibitors of ACC. The agent can be a chemical compound or a biological molecule (e.g., a protein or an antibody). The activity of ACC inhibitors can be measured by methods known in the art, such as those described and cited in U.S. Pat. No. 8,969,557 and / or U.S. Pat. No. 10,208,063, the entireties of which are incorporated herein by reference.

[0045] As referred to herein, an "ASK1 inhibitor" can be any agent capable of inactivating apoptosis signal regulating kinase 1 (ASK1) protein. The agent can be a chemical compound or a biological molecule (e.g., a protein or an antibody). ASK1 protein activity can be measured by several different methods. For example, the activity of ASK1 protein can be determined based on the ability of ASK1 protein to phosphorylate a substrate protein. Methods for identifying ASK1 inhibitors are known (see, for example, US 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 ASK1 protein, for example, the phosphorylation level of the threonine residue in ASK1 protein corresponding to threonine 838 (T838) of human full-length ASK1 protein or threonine 845 (T845) of mouse full-length ASK1 protein.For example, when ASK1 protein comprises full-length human ASK1 protein sequence, ASK1 inhibitor can attenuate the phosphorylation of T838 in full-length human ASK1 protein sequence.The phosphorylation level can be detected using a site-specific antibody against human ASK1 T838 or mouse ASK1 T845.

[0046] As used herein, "FXR agonist" refers to any agent capable of binding to and activating the farnesoid X receptor (FXR), which may be referred to as the bile acid receptor (BAR) or NR1H4 (nuclear receptor subfamily 1, group H, member 4). FXR agonists may act as agonists or partial agonists of FXR. The agent may be a chemical compound or a biological molecule (e.g., a protein or an antibody). The activity of FXR agonists may be measured by several different methods, for example, in an in vitro assay using a fluorescence resonance energy transfer (FRET) cell-free assay as described in Pellicciari, et al. Journal of Medicinal Chemistry, 2002 vol.15, No.45:3569-72.

[0047] compound Provided herein are: [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0048] In some embodiments, the compound is Compound 1, having the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0049] In some embodiments, the compound is Compound 2, having the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0050] In some embodiments, the compound is Compound 3, having the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0051] In some embodiments, the compound is Compound 4, having the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0052] In some embodiments, the compound is Compound 5, having the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0053] In some embodiments, the compound is compound 6, having the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0054] In some embodiments, the compound is Compound 7, having the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0055] In some embodiments, the compound is compound 8, having the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0056] In some embodiments, the compound is compound 9, having the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0057] In some embodiments, the compound is compound 10, having the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0058] In some embodiments, the compound is compound 11, having the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0059] In some embodiments, the compound is compound 12, having the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0060] In some embodiments, the compound is compound 13, having the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0061] Pharmaceutical Compositions and Modes of Administration Further, the present disclosure provides a pharmaceutical composition comprising at least a compound of the present disclosure, or a prodrug compound thereof, or a pharma- ceutically acceptable salt or solvate thereof, as an active ingredient, together with a pharma- ceutically acceptable carrier.

[0062] The pharmaceutical compositions 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 compositions are suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (intranasal or buccal inhalation) or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the active ingredient. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art.

[0064] In practical use, the compounds of the present disclosure can be combined as active ingredients in homogeneous admixture with pharmaceutical carriers according to conventional pharmaceutical compounding techniques. Carriers 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 compositions for oral dosage forms, any of the usual pharmaceutical media can be used, such as water, glycols, oils, alcohol, flavoring agents, preservatives, coloring agents, etc., for oral liquid preparations, such as suspensions, elixirs, and solutions, or carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc., for oral solid preparations, such as powders, hard capsules and soft capsules, and tablets, and solid oral preparations are preferred over liquid preparations.

[0065] Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are used. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of the active compound. The percentage of the active compound in these compositions can, of course, vary and can conveniently be about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage is obtained. The active compound can also be administered intranasally, for example, as drops or spray.

[0066] Tablets, pills, capsules and the like may also contain binders such as gum tragacanth, acacia, corn starch, or gelatin, excipients such as dicalcium phosphate, disintegrating agents such as corn starch, potato starch, alginic acid, lubricants such as magnesium stearate, and sweeteners such as sucrose, lactose, or saccharin. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

[0067] Various other materials may be present as coatings or to modify the physical form of the unit dosage form. For example, tablets may be coated with shellac, sugar, or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and a flavoring such as cherry or orange flavor.

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

[0069] The compounds of the present disclosure may also be administered parenterally.These active compounds solutions or suspensions may be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose.Dispersions may be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils.Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0070] Suitable pharmaceutical forms for injection use include sterile aqueous solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. 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, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0071] Any suitable route of administration can be used to provide an effective dose of the disclosed compound to a mammal, particularly a human. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, etc. can be used. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc. In some embodiments, the disclosed compound is administered orally.

[0072] kit Also provided herein is a kit comprising a compound of the present disclosure, or a pharma- ceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and suitable packaging. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit comprises a compound of the present disclosure, or a pharma- ceutically 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, including a disease or condition described herein.

[0073] Also provided herein is an article of manufacture comprising a compound described herein, or a pharma- ceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogue thereof, in a suitable container, which may be a vial, bottle, ampoule, pre-filled syringe, and infusion bag.

[0074] Treatment Methods and Uses The present disclosure further relates to the use of the compounds disclosed herein for the treatment and / or prevention of diseases and / or conditions through the binding of LPAR1 by the compounds.The present disclosure further relates to the use of the compounds for the preparation of a medicament for the treatment and / or prevention of diseases and / or conditions through the binding of LPAR1 by the compounds.

[0075] The pharmaceutical agents referred to herein can be prepared by conventional processes involving combining a compound according to the present disclosure with a pharma- ceutically acceptable carrier.

[0076] In some embodiments, provided herein is a method of treating and / or preventing an LPAR1-mediated disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Compound 1-13, or a pharma- ceutical acceptable salt thereof, or a composition comprising a compound of Compound 1-13, or a pharma-ceutical acceptable salt thereof.

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

[0078] In some embodiments, the LPAR1 mediated disease or condition comprises fibrosis, wound healing, cancer, pain, a respiratory disorder, an allergic disorder, a nervous system disorder, a cardiovascular disorder, or an inflammatory disorder.

[0079] In some embodiments, the LPAR1-mediated disease or condition is an 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 fibrosing ILD, idiopathic interstitial pneumonia (IIP), connective tissue disease-associated interstitial lung disease (CTD-ILD), rheumatoid arthritis-associated ILD, scleroderma-associated ILD, or extrinsic 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 comprises fibrosis. In some embodiments, the fibrosis comprises pulmonary fibrosis, renal fibrosis, hepatic fibrosis, ocular fibrosis, or cardiac fibrosis.

[0082] In some embodiments, the LPAR1-mediated disease or condition comprises pulmonary fibrosis. In some embodiments, the pulmonary fibrosis comprises idiopathic pulmonary fibrosis (IPF). In some embodiments, the pulmonary fibrosis comprises progressive fibrotic interstitial lung disease (PF-ILD). In some embodiments, the pulmonary fibrosis comprises pulmonary fibrosis secondary to systemic inflammatory diseases such as rheumatoid arthritis, scleroderma, lupus, fibrosing alveolitis of unknown etiology, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, chronic asthma, silicosis, asbestos-induced pulmonary or pleural fibrosis, acute lung injury and acute respiratory distress (including bacterial pneumonia-induced, trauma-induced, viral pneumonia-induced, ventilator-induced, non-pulmonary sepsis-induced, and aspiration-induced).

[0083] In some embodiments, the LPAR1-mediated disease or condition comprises renal fibrosis. In some embodiments, renal fibrosis comprises chronic nephropathy (renal fibrosis) associated with injury / ibrosis, e.g., lupus and scleroderma, glomerulonephritis secondary to systemic inflammatory diseases, such as diabetes, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allografts, and Alport; intestinal fibrosis, e.g., scleroderma, and radiation-induced intestinal fibrosis.

[0084] In some embodiments, the LPAR1-mediated disease or condition comprises liver fibrosis. In some embodiments, liver fibrosis comprises liver cirrhosis, alcohol-induced liver fibrosis, non-alcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis, infection or virus-induced liver fibrosis (e.g., chronic HCV infection), and autoimmune hepatitis.

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

[0086] In some embodiments, the LPAR1-mediated disease or condition includes, for example, LASIK (laser-assisted in situ keratomileusis), corneal transplant, or trabeculectomy. In some embodiments, the compounds of compounds 1-13, or pharma- ceutical acceptable salts thereof, are used to improve corneal sensitivity loss caused by corneal surgery such as LASIK, or cataract surgery, corneal sensitivity loss caused by corneal degeneration, and dry eye symptoms caused by them. In some embodiments, the compounds of compounds 1-13, or pharma-ceutical acceptable salts thereof, are used in the treatment or prevention of ocular inflammation and allergic conjunctivitis, vernal conjunctivitis, and papillary conjunctivitis. In some embodiments, the compounds of compounds 1-13, or pharma-ceutical 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, the LPAR1-mediated disease or condition includes, for example, hypertrophic scars and keloids from 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, the LPAR1 mediated disease or condition comprises pain. In some embodiments, the pain comprises neuropathic pain. In some embodiments, the pain comprises acute pain. In some embodiments, the pain comprises chronic pain.

[0089] In some embodiments, the LPAR1 mediated disease or condition comprises cancer. In some embodiments, the cancer comprises 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 comprises solid tumors such as bladder, intestine, brain, breast, endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas, or other endocrine organs (thyroid), prostate, skin (melanoma or basal cell carcinoma) at any stage of the disease with or without metastasis, or hematological tumors (such as leukemia). In some embodiments, the cancer is selected from the group consisting of 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), brain stem glioma, brain tumor, brain and spinal cord tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing's sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor,tumor, GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor (endocrine pancreas), Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hair cell leukemia, liver pancreatic cancer, non-small cell lung cancer, small cell lung cancer, Burkitt's lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoma, Waldenstrom's macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, oral cancer, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant bone Fibrous histiocytoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, moderately differentiated pineal parenchymal tumor, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, meat tumors, Ewing family of tumors, sarcoma, Kaposi-Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric (stomach) cancer, supratentorial primitive, neuroectodermal tumors, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, and Wilms' tumor.

[0090] In some embodiments, the LPAR1-mediated disease or condition comprises a respiratory or allergic disorder. In some embodiments, the respiratory or allergic disorder comprises asthma, peribronchiolar fibrosis, bronchiolitis obliterans, and chronic obstructive pulmonary disease (COPD). In some embodiments, COPD comprises chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or airway inflammation, and cystic fibrosis. In some embodiments, the respiratory disease comprises 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 comprises a nervous system disorder. In some embodiments, the nervous system disorder comprises the neurological aspects of disorders such as Alzheimer's disease, cerebral edema, cerebral ischemia, stroke, multiple sclerosis, neuropathy, Parkinson's disease, neurological conditions found after paralysis or surgical trauma (including postoperative cognitive dysfunction and spinal cord or brainstem injury), as well as degenerative disc disease and sciatica.

[0092] In some embodiments, the LPAR1-mediated disease or condition comprises cardiovascular disorder. In some embodiments, the cardiovascular disorder comprises arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina pectoris; heart rate dysfunction; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis; stroke; peripheral occlusive arteriopathy of limbs, organs or tissues; reperfusion injury after ischemia of brain, heart or other organs or tissues; endotoxin, surgical or traumatic shock; hypertension; valvular heart disease; heart failure; abnormal blood pressure; shock; vasoconstriction (including those associated with migraine); vascular abnormalities, and cardiovascular insufficiency limited to a single organ or tissue.

[0093] In some embodiments, the LPAR1 mediated disease or condition comprises pulmonary fibrosis, kidney fibrosis, liver fibrosis, scarring, asthma, rhinitis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, interstitial lung fibrosis, arthritis, allergies, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, pain, proliferative disorders and inflammatory conditions.

[0094] In some embodiments, the LPAR1-mediated disease or condition is a metabolic disorder or liver disease. In some embodiments, the liver disease is Hepatitis C, liver cancer, familial combined hyperlipidemia, nonalcoholic 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 comprises portal hypertension. In some embodiments, the liver cancer comprises hepatocellular carcinoma (HCC), cholangiocarcinoma, angiosarcoma, or angiosarcoma. In some embodiments, the liver cancer comprises HCC. In some embodiments, the NAFLD comprises steatosis. In some embodiments, the NAFLD comprises NASH. In some embodiments, the NAFLD or NASH comprises liver fibrosis. In some embodiments, NAFLD or NASH comprises cirrhosis. In some embodiments, NAFLD or NASH comprises compensated cirrhosis. In some embodiments, NAFLD or NASH comprises decompensated liver fibrosis. In some embodiments, NAFLD comprises HCC. In some embodiments, liver disease is NASH.

[0095] In some embodiments, provided herein is a method of treating and / or preventing NAFLD or NASH in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Compounds 1-13, or a pharma- ceutically acceptable salt thereof, or a composition comprising a compound of Compounds 1-13, or a pharma- ceutically acceptable salt thereof. In some embodiments, the NAFLD or NASH comprises liver fibrosis. In some embodiments, the NAFLD or NASH comprises cirrhosis. In some embodiments, the cirrhosis is compensated cirrhosis. In some embodiments, the cirrhosis is decompensated cirrhosis. In some embodiments, the NAFLD or NASH comprises HCC.

[0096] In some embodiments, provided herein is a method of preventing a liver disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Compounds 1-13, or a pharma- ceutically acceptable salt thereof, or a composition comprising a compound of Compounds 1-13, or a pharma- ceutically acceptable salt thereof. In some embodiments, the liver disease or condition is liver fibrosis. In some embodiments, the liver disease or condition is cirrhosis. In some embodiments, the liver cirrhosis is compensated cirrhosis. In some embodiments, the liver 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 pharma- ceutically 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 may be readily ascertained by one skilled in the art.

[0099] When treating or preventing LPAR1-mediated diseases or conditions for which the compounds of the present disclosure are required, generally satisfactory results are obtained when the compounds of the present disclosure are administered in a daily dosage of about 0.1 milligrams to about 300 milligrams per kilogram of animal body weight. In some embodiments, the compounds of the present disclosure are given as a single daily dose or divided doses 2 to 6 times a day, or in sustained release form. For most large mammals, the total daily dosage is about 1 milligram to about 1000 milligrams, or about 1 milligram to about 50 milligrams. For a 70 kg adult human, the total daily dosage will generally be about 0.1 milligrams to about 200 milligrams. This dosage regimen can be adjusted to provide the 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 of the present application or compositions thereof can be administered once, twice, three times, or four times a day using any suitable mode as described above. Also, administration or treatment with the compounds can continue for several days, for example, treatment will usually continue for at least 7 days, 14 days, or 28 days for one treatment cycle. Treatment cycles alternate periodically with rest periods 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 include administering to a subject an initial daily dose of about 1-800 mg of a compound described herein, and increasing the dose in increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice weekly, or once weekly.

[0102] combination In some embodiments, a compound of Compounds 1-13 provided herein, or a pharma- ceutically acceptable salt thereof, is administered in combination with one or more additional therapeutic agents to treat or prevent a disease or condition disclosed herein. In some embodiments, the one or more additional therapeutic agents are one, two, three, or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are two additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are three additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are four additional therapeutic agents.

[0103] In some embodiments, the pharmaceutical compositions provided herein comprise a compound of Compounds 1-13 provided herein, or a pharma- ceutically acceptable salt thereof, and one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one, two, three, or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are two additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are three additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are four additional therapeutic agents.

[0104] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of 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 (APO4) inhibitors, androgen receptor agonists, androgen receptor agonists. C3, APOC3 antagonists, autophagy protein modulators, autotaxin inhibitors, Axl tyrosine kinase receptor inhibitors, Bax protein stimulators, bioactive lipids, calcitonin agonists, cannabinoid receptor modulators, caspase inhibitors, caspase-3 stimulators, cathepsin inhibitors (e.g., cathepsin B inhibitors), caveolin 1 inhibitors, CCR2 chemokine antagonists, CCR3 chemokine antagonists, CCR5 chemokine antagonists, CD3 antagonists, chloride channel stimulators, cholesterol solubilizers, CNR1 inhibitors, cyclin D1 inhibitors, cytochrome P450 7A1 inhibitors, cytochrome P450 2E1 (CYP2E1) inhibitors, diacylglycerol O acyltransferase 1 inhibitors 1, DGAT1 inhibitors, diacylglycerol O-acyltransferase 1 inhibitors (DGAT2) inhibitors, CXCR4 chemokine antagonists, dipeptidyl peptidase IV inhibitors, endosialin modulators, endothelial nitric oxide synthase stimulators, eotaxin ligand inhibitors, extracellular matrix protein modulators, farnesoid X receptor agonists, fatty acid synthase inhibitors, FGF1 receptor agonists, fibroblast activation protein (Fibroblast activation protein)protein (FAP) inhibitors, fibroblast growth factor receptor ligands (e.g., FGF-15, FGF-19, FGF-21), fish oil, galectin-3 inhibitors, glucagon receptor agonists, glucagon-like peptide 1 receptor agonists, glucocorticoid receptor antagonists, glucose 6-phosphate 1-dehydrogenase inhibitors, glutaminase inhibitors, glutathione precursors, G protein-coupled bile acid receptor 1 agonists, G protein-coupled receptor 84 antagonists, hedgehog (Hh) modulators, hepatitis C virus NS3 protease inhibitors, hepatocyte nuclear factor 4 alpha modulators (HNF4A), hepatocyte growth factor modulators, histone deacetylase inhibitors, HMG CoA reductase inhibitors, 11β-hydroxysteroid dehydrogenase (11β-Hydroxysteroid dehydrogenase, 11β-HSD1 inhibitors, hypoxia inducible factor-2 alpha inhibitors, IL-1β antagonists, IL-6 receptor agonists, IL-10 agonists, IL-11 antagonists, IL-17 antagonists, ileal sodium-bile acid cotransporter inhibitors, insulin sensitizers, insulin ligand agonists, insulin receptor agonists, integrin modulators, integrin antagonists intereukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, Jak2 tyrosine kinase inhibitors, ketohexokinase (KHK) inhibitors, Klotho beta stimulators, leptin, leptin analogs, 5-lipoxygenase inhibitors, lipoprotein lipase inhibitors, liver X receptor, LPL gene stimulators, lysophosphatidate-1 receptor receptor (LPAR-1) antagonist, Lysyl oxidase homolog 2 (LOXL2) inhibitor, LXR inverse agonist, Macrophage mannose receptor 1 modulator, Matrix metalloproteinase (MMP) inhibitormetalloproteinase (MMP) inhibitors, MCH receptor-1 antagonists, MEKK-5 protein kinase inhibitors, membrane copper amine oxidase (VAP-1) inhibitors, methionine aminopeptidase-2 inhibitors, methyl-CpG binding protein 2 modulators, microRNA-132 (miR-132) antagonists, microRNA-21 (miR-21) inhibitors, mitochondrial uncouplers, mixed lineage kinase-3 inhibitors, myelin basic protein stimulators, NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, NAD-dependent deacetylase sirtuin-1 stimulators, NADPH oxidase inhibitors (NOX), nicotinic acid receptor 1 agonists, P2X7 purinergic receptor modulators, P2Y13 purinergic receptor stimulators, PDE 3 inhibitors, PDE 4 inhibitors, PDE 5 inhibitors, PDGF receptor beta modulators, peptidyl prolyl cis-trans isomerase A inhibitors, phenylalanine hydroxylase stimulators, phospholipase C inhibitors, PPAR alpha agonists, PPAR gamma agonists, PPAR delta agonists, PPAR gamma modulators, PPAR alpha / delta agonists, PPAR alpha / gamma / delta agonists, PPAR alpha / gamma / delta agonists, protease-activated receptor 2 antagonists, protein kinase modulators, Rho associated protein kinase 2 (ROCK2) inhibitors, S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, sodium glucose transporter-2 (Sodium glucose transporter-2, SGLT2 inhibitors, SREBP transcription factor inhibitors, STAT-1 inhibitors, STAT-3 modulators, stearoyl-CoA desaturase-1 inhibitors, S-nitrosoglutathione reductase (Snitrosoglutathionereductase (GSNOR) enzyme inhibitors, suppressors of stimulators of cytokine signaling-1, suppressors of stimulators of cytokine signaling-3, spleen tyrosine kinase (SYK) inhibitors, transforming growth factor β (TGF-β), TGF-β antagonists (e.g., TGF-β1 antagonists, TGF-β2 antagonists, TGF-β3 antagonists, latent TGF-β complex modulators), TGF-β receptor antagonists, transforming growth factor β activated Kinase 1 (TAK1), thyroid hormone receptor β agonists, Toll-like receptor (TLR)-4 antagonists, transglutaminase inhibitors, tumor necrosis factor alpha (TNFα) ligand inhibitors, tumor progression locus 2 (TMR2) inhibitors, tumor progression locus 2 (TLR ... The inhibitor is selected from a group consisting of a Tpl2 (Tpl1, Tpl2 Locus 2) kinase inhibitor, a tyrosine kinase receptor modulator, a GPCR modulator, a nuclear hormone receptor modulator, a WNT modulator, a YAP / TAZ modulator, and a zonulin inhibitor.

[0105] Non-limiting examples of the one or more additional therapeutic agents include: 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; acetaldehyde dehydrogenase inhibitors such as ADX-629; Adenosine receptor agonists such as CF-102 (namodenoson), CF-101, CF-502, or CGS21680; adiponectin receptor agonists such as ADP-355 or ADP-399; Amylin / calcitonin receptor agonists such as KBP-042 or KBP-089; AMP-activated protein kinase stimulators, such as PXL-770 or O-304; AMP kinase activators / ATP citrate lyase inhibitors such as bempedoic acid (ETC-1002, ESP-55016); AMP-activated protein kinase / endothelial nitric oxide synthase / NAD-dependent deacetylase sirtuin-1 stimulators such as NS-0200 (leucine + metformin + sildenafil); androgen receptor agonists, such as LPCN-1144; angiotensin II AT-1 receptor antagonists such as irbesartan; angiopoietin-related protein-3 inhibitors, such as IONIS-ANGPTL3-LRx; Autotaxin inhibitors such as PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, AM-063, or BBT-877; Axl tyrosine kinase receptor inhibitors such as bemcentinib (BGB-324, R-428); Bax protein stimulators such as CBL-514; bioactive lipids such as DS-102; cannabinoid receptor type 1 (CNR1) inhibitors, such as namacizumab, GWP-42004, REV-200, or CRB-4001; caspase inhibitors, such as emricasan; pan-cathepsin B inhibitors such as VBY-376; pan-cathepsin inhibitors such as VBY-825; CCR2 / CCR5 chemokine antagonists such as cenicriviroc, maraviroc, CCX-872, or WXSH-0213; CCR2 chemokine antagonists such as propagermanium; 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 + senibiliviroc); CCR3 chemokine antagonists such as bertilimumab; Chloride channel stimulants such as cobiprostone or lubiprostone; CD3 antagonists such as NI-0401 (foralumab); CXCR4 chemokine antagonists such as AD-214; diglyceride acyltransferase 1 (DGAT1) inhibitors, such as GSK-3008356; diacylglycerol O-acyltransferase 1 (DGAT1) / cytochrome P450 2E1 (CYP2E1) inhibitors, such as SNP-610; diglyceride 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 bertilimumab 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, and 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 icosapentate (Vascepa®); 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 (myricholant); 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 odebixibat (A-4250), borixibat potassium ethanolate 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 ligands / 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 tipelukast (MN-001), DS-102 (AF-102); lipoprotein lipase inhibitors, such as CAT-2003; LPL gene stimulators 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 mercaptamines; mitochondrial uncouplers such as 2,4-dinitrophenol or HU6; mixed lineage kinase-3 inhibitors such as URMC-099-C; myelin basic protein stimulators 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 agonists, such as CER-209; PDE 3 / 4 inhibitors such as tipelukast (MN-001); PDE 5 inhibitors such as sildenafil or MSTM-102; PDGF receptor beta 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 stimulators such as HepaStem; PPAR agonists (including PPAR alpha agonists, PPAR alpha / delta agonists, PPAR alpha / delta / gamma agonists, PPAR delta agonists) such as elafibranor (GFT-505), MBX-8025, deuterated pioglitazone R-enantiomer, pioglitazone, DRX-065, saroglitazar, or IVA-337; PPAR alpha agonists such as aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, pemafibrate, lonifibrate, simfibrate, omega-3 fatty acids (fish oils, e.g., ethyl icosapentate (Vascepa®), or docosahexaenoic acid), pirinixic acid, GW409544, AZ 242, LY518674, NS-220, AVE8134, BMS-711939, aleglitazar, muraglitzar, or saroglitazar; PPAR alpha / delta agonists such as elafibranor; PPAR alpha / delta / gamma agonists such as lanifibranor; PPAR delta agonists such as Seradelpar; 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 aramchol; thyroid hormone receptor (THR) beta agonists such as Resmetriom (MGL-3196), MGL-3745, or VK-2809; TLR-2 / TLR-4 antagonists such as VB-201 (CI-201); TLR-4 antagonists, e.g., JKB-121; tyrosine kinase receptor modulators such as CNX-025 or GFE-2137 (repurposed nitazoxanide); GPCR modulators, e.g., 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 the one or more additional therapeutic agents include: ACE inhibitors such as benzepari and imidapril, Adenosine A3 receptor antagonists such as FM-101, adrophin 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 therapy, such as ORBCEL-M; Allogeneic expanded adipose-derived stem cell therapy such as Elixcyte™; AMP-activated protein kinase stimulators / proprotein convertase PC9 inhibitors such as O-304; AMP-activated protein kinase stimulators such as DZCY-01, MK-8722, and PXL-770; angiotensin II AT-1 receptor / CCR2 chemokine antagonists such as DMX-200; angiotensin II AT-2 receptor antagonists such as MOR-107 and irbesartan; angiotensin II receptor antagonists such as losartan, Angiotensinogen ligand inhibitors such as ALN-AGT, Anti-C1 antibodies such as BIVV-009 (stimulimab); Anti-CB1 antibodies, e.g., GFB-024, anti-CX3CR1 nanobodies, such as BI-655088; Anti-IL-6 antibodies, e.g., COR-001; anti-VEGF-B antibodies such as CSL-346; APOA1 gene stimulators / bromodomain-containing protein 2 / bromodomain-containing protein 4 inhibitors such as apabetalone; Bone morphogenetic protein-7 ligand modulators, such as BMP-7; calcium channel blockers such as TBN (xiaotongqin); cannabinoid CB1 receptor antagonists, such as JNJ-2463; CB1 inverse agonists such as CRB-4001, chymase inhibitors such as furasimustat (BAY-1142524); Cyclooxygenase 1 inhibitors such as GLY-230, cyclooxygenase-2 / epoxide hydrolase inhibitors, such as COX-2 / soluble epoxide hydrolase; cytochrome P450 11B2 inhibitors, such as aldosterone synthase inhibitors; ectonucleotide pyrophosphatase-PDE-2 inhibitors such as BLD-0409; endothelin ET-A / endothelin ET-B receptor antagonists, such as aprocitentan; enteropeptidase inhibitors, such as SCO-792; erythropoietin receptor antagonists, such as EPO-018B; Farnesoid X receptor agonists, such as LMB-763; FGF / PDGF / beta receptor antagonists / p38 MAP kinase inhibitors such as pirfenidone; GHR / IGF1 gene inhibitors such as atesidorsen sodium; GPR40 antagonists / GPR84 antagonists such as PBI-4050; G protein beta subunit inhibitors such as gallon; G protein-coupled receptor 84 modulators, such as PBI-4425; growth hormone ligands / growth hormone receptor agonists, such as Jintropin AQ™; 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 and lancaciguat; 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-associated factor 2 stimulators, such as SFX-01; LDHA gene inhibitors such as nedosiran, 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™; NADPH oxidase 1 / 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 stimulators / TGF beta ligand inhibitors, such as CU01-1001; Nuclear factor kappa B inhibitors such as mefnidone 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 receptors (PPARs), such as PBI-4547; PRKAA2 gene stimulators / AMPK activators such as PF-06679142 and PF-06685249; Prostacyclin (PGI2) agonists such as YS-1402, Protein C activators / glycoprotein Ib (GPIb) antagonists such as AB-002, protein NOV homologue modulators such as BLR-200, protein tyrosine phosphatase-1B inhibitors, such as MSI-1436; reactive oxygen species modulator inhibitors, such as SUL-121; Renin inhibitors such as imarikiren hydrochloride, Rho-associated protein kinase 2 inhibitors, such as ANG-4201 and RXC-007; Sodium glucose transporter-2 inhibitors such as canagliflozin, dapagliflozin propanediol, and empagliflozin; thromboxane A2 receptor antagonists / thromboxane synthesis inhibitors, such as SER-150; tissue transglutaminase inhibitors, such as ZED-1227; TRP cation channel C5 inhibitors such as GFB-887, TRP cation channel C6 inhibitors such as ALGX-2224; cell adhesion molecule inhibitors, such as glycosidic bacterial adhesin antagonists; urate anion exchanger 1 (URAT1) / SLC22A12 inhibitors, such as verinurad (RDEA3170); VIP1 / VIP2 receptor agonists such as LBT-3627, and Xanthine oxidase inhibitors such as TMX-049 and TMX-049DN.

[0107] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of A-4250, AC-3174, acetylsalicylic acid, AK-20, alipogen tiparvovec, AMX-342, AN-3015, aramchol, ARI-3037MO, ASP-8232, AZD-2693, bertilimumab, betaine anhydrous, BI-1467335, BMS-986036, BMS-986171, BMT-053011, BOT-191, BTT-1023, CAT-2003, cenicriviroc, CBW-511, CER-209, CF-102, CGS21680, C NX-014, CNX-023, CNX-024, CNX-025, cobiprostone, colesevelam, 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, fluasterone (ST-002), FT-4101, GKT-831, GNF-5120, GRI-0621, GR-MD-02, GS-300, GS-4997, GS-9674, HTD-1801, HST-202, HST-201, hydrochlorothiazide, icosabtate (PRC-4016), icosapentaenoic acid ethyl ester, IMM-124-E, INT-767, INV-240, IONIS-DGAT2Rx, ipragliflozin, irbesarta, propagermanium, IVA-337, JKB-121, KB-GE-001, KBP-042, KD-025, M790, M780, M450, metformin, sildenafil, LC-280126, linagliptin, liraglutide, LJ N-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, namacizumab, NC-101, NDI-010976, ND-L02-s0201 (BMS-986263), NGM-282, NGM-313, NGM-386, NGM-395, NP-160, norursodeoxycholic acid, NVP-022, O-304, obeticholic acid (OCA),25HC3S, olesoxime, PAT-505, PAT-048, PBI-4547, peg-ilodecaquin, pioglitazone, pirfenidone, PRI-724, PX20606, Px-102, PX-L603, PX-L493, PXS-4728A, PZ-235, RDX-009, remogliflozin etabonate, RG-125 (AZD4076), RPI-500, saroglitazar, semaglutide, simtuzumab, solithromycin, sotagliflozin, statins (atorvastatin, fluvastatin, pitavastatin, pravastatin) statin, rosuvastatin, simvastatin), synergistic agents, TCM-606F, TEV-45478, TQA-3526, tipelukast (MN-001), TLY-012, TRX-318, TVB-2640, UD-009, ursodeoxycholic acid, VBY-376, VBY-825, VK-2809, vismodegib, vorixib potassium ethanolate 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 an apoptosis signal-regulating kinase 1 (ASK1) inhibitor and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of compounds 1-13 provided herein, or a pharma- ceutical acceptable salt thereof.

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

[0110] ASK1 inhibitors can be synthesized and characterized using methods known to those of skill in the art, such as those described in U.S. Patent Application Publication No. 2007 / 0276050, U.S. Patent Application Publication No. 2011 / 0009410, and U.S. 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 pharma- ceutical acceptable salt thereof.

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

[0113] ACC inhibitors can be synthesized and characterized using methods known to those skilled in the art, such as those described in US Pat. No. 9,453,026 and US Pat. No. 10,183,951.

[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 (filsocostat, 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 pharma- ceutically 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, clofibrate, clofibride, fenofibrate, gemfibrozil, pemafibrate, lonifibrate, simfibrate, pirinixic acid, GW409544, AZ 242, LY518674, NS-220, AVE8134, BMS-711939, aleglitazar, muraglitazar, and saroglitazar. In some embodiments, the PPAR agonist (e.g., PPAR alpha agonist) is a fibrate. In some embodiments, the PPAR agonist (e.g., 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., seradelpar). In some embodiments, the fish oil is an omega-3 fatty acid or docosahexaenoic acid. In some embodiments, the fish oil is ethyl icosapentate (e.g., Vascepa®).

[0115] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of a farnesoid X receptor (FXR) agonist and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of compounds 1-13 provided herein, or a pharma- ceutical 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 structure: [ka] or a pharma- ceutically acceptable salt thereof.

[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 pharma- ceutically 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, where the LPAR1 antagonist is a compound of compounds 1-13 provided herein, or a pharma- ceutically 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, for example, those described in PCT Publication 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), for example, TGFβ1-LAP. The TGFβ1-LAP-specific antibody can be prepared and characterized using methods known to those of skill in the art, for example, 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 activation of latent TGFβ (e.g., latent TGFβ1) localized in the extracellular matrix, e.g., connective tissue of the liver. In some embodiments, the TGFβ antagonist blocks activation of latent TGFβ (e.g., latent TGFβ1) localized in the thymus, lymph nodes, or tumor microenvironment (e.g., patients with liver cancer). In some embodiments, the TGFβ antagonist blocks activation of latent TGFβ (e.g., latent TGFβ1) by latent TGFβ binding protein (LTBP).In some embodiments, the TGFβ antagonist blocks activation of latent TGFβ (e.g., latent TGFβ1) by Glycoprotein-A Repeats Predominant protein (GARP), e.g., as described in U.S. Pat. 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), e.g., of connective tissue in the liver. In some embodiments, the anti-LAP antibody specifically binds to the LAP-TGFβ complex on the surface of certain immunosuppressive cell types, such as regulatory T cells (Tregs), tumor-associated macrophages, or myeloid-derived suppressor cells, e.g., in the tumor microenvironment. In some embodiments, the anti-LAP antibody is a TLS-01 antibody. In some embodiments, the anti-LAP antibody specifically binds to the LAP-TGFβ complex in any context. In some embodiments, the anti-LAP antibody is a TLS-02 antibody. In some embodiments, the TGFβ antagonist comprises a TGFβ receptor. In some embodiments, the TGFβ antagonist is a TGFβ receptor-Fc fusion protein. In some embodiments, the TGFβ antagonist is an antibody comprising a TGFβ receptor. TGFβ antagonists comprising a TGFβ receptor that may be useful in connection with the compositions and methods provided herein are described, for example, in PCT Publication Nos. WO 2019 / 113123(A1) and WO 2019 / 113464(A1).

[0120] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of an LPAR1 antagonist in combination with an ACE inhibitor, an adenosine A3 receptor antagonist, an adropin stimulator, an albumin modulator, an aldosterone antagonist, an AMP-activated protein kinase stimulator, angiotensin II AT-2 receptor agonist, angiotensin II receptor antagonist, 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 P450 ...11B2 inhibitors, ectonucleotide pyrophosphatase-PDE-2 inhibitors, endothelin ET-A receptor antagonists, endothelin ET-B receptor antagonists, enteropeptidase inhibitors, epoxide hydrolase inhibitors, erythropoietin receptor antagonists, farnesoid X receptor agonists, FGF receptor antagonists, free fatty acid receptor 1 agonists, GHR gene inhibitors, glycoprotein Ib (GPIb) antagonists, GPR40 agonists, GPR84 antagonists, G protein beta subunit inhibitors, G protein coupled receptor 120 agonists, G protein coupled receptor 84 modulators, growth hormone ligands, growth hormone receptor agonists, guanylate cyclase receptor agonists, guanylate cyclase stimulators, heme oxygenase 1 modulators, HIF prolyl hydroxylases Inhibitors of phospholipase, IGF1 gene inhibitors, IgG receptor FcRn large subunit p51 modulators, IL-6 receptor antagonists, integrin alpha-V / beta-3 antagonists, interleukin 33 ligand inhibitors, Kelch-like ECH-related protein 1 modulators, LDHA gene inhibitors, 5-lipoxygenase activating protein inhibitors, lysophosphatidic acid-1 receptor antagonists, matrix extracellular phosphoglycoprotein modulators, membrane copper amine oxidase inhibitors, midkine ligand inhibitors, mineralocorticoid receptor antagonists, myosin 2 inhibitors, NADPH oxidase 1 inhibitors, NADPH oxidase 4 inhibitors, NADPH oxidase inhibitors, NK1 receptor antagonists, nuclear erythroid 2-related factor 2 stimulators, nuclear factor kappa B inhibitors, opioid receptor kappa agonists, opioid receptor mu antagonist p38MAP kinase inhibitors, PDE4 inhibitors, PDGF receptor antagonists, PDGF receptor beta modulators, phosphatonin receptor agonists, PRKAA2 gene stimulators, proprotein convertase PC9 inhibitors, prostacyclin (PGI2) agonists, protein C activators, protein NOV homologue modulators, protein tyrosine phosphatase-1B inhibitors, reactive oxygen species modulator inhibitors, renin inhibitors, Rho-associated protein kinase 2 inhibitors, SLC22A12 inhibitors, sodium glucose transporter-2 inhibitors, solute carrier family inhibitors and a therapeutically effective amount of an additional therapeutic agent selected from a therapeutically effective agonist, a TGF beta ligand inhibitor, a TGF beta receptor antagonist, a thromboxane A2 receptor antagonist, a thromboxane synthesis inhibitor, a tissue transglutaminase inhibitor, a TRP cation channel C5 inhibitor, a TRP cation channel C6 inhibitor, a tryptophanase inhibitor, a nonspecific cell adhesion molecule inhibitor, a urate anion exchanger 1 inhibitor, a vasopressin V1a receptor antagonist, a VEGF receptor antagonist, a VIP1 receptor agonist, a VIP2 receptor agonist, and a xanthine oxidase inhibitor.

[0121] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of an LPAR1 antagonist and a VEGFR inhibitor, an FGFR inhibitor, a PDGFR inhibitor, an autotaxin inhibitor, a GPR84 agonist, a PASK inhibitor, a CFTR agonist, a JAK1 inhibitor, an ADAMTS5 inhibitor, a TOL2 / 3 inhibitor, a CTGF inhibitor, a soluble PTX2, an anti-galectin-3 antibody, an integrin-α V -β6 / α V and a therapeutically effective amount of an additional therapeutic agent selected from a β1 antagonist, a JNK1 inhibitor, a mineralocorticoid receptor antagonist, an Nrf2 activator, a chymase inhibitor, a PDE inhibitor, a NOX1 / 4 inhibitor, a leukotriene / thromboxane receptor antagonist, a SLC22A12 inhibitor, a sGC inhibitor, and a xanthine oxidase inhibitor.

[0122] 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 nintedanib, pirfenidone, pamrevlumab, PRM-151, GB-0139, PLN-74809, CC-90001, finerenone, BAY1142524, PCS-499, setanaxib, SER150, RDEA3170, praliciguat, TMX-049, GLPG1690, GLPG1205, GLPG1972, GLPG4059, GLPG2737, GLPG3970, and filgotinib.

[0123] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of an LPAR1 antagonist and a combination of 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 targeted antisense oligonucleotide therapy, MK-2060, MPC-300-IV, NAV-003, Neo-Kidney Enhancement™ (Neo-Kidney Enhancement™), or combinations thereof. and a therapeutically effective amount of an additional therapeutic agent selected from: 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, beverimer, VS-105, and XRx-221. EXAMPLES

[0124] The following examples are included to demonstrate certain 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 work well in the implementation of the present disclosure, and therefore can be considered to constitute specific modes for its implementation. However, those skilled in the art should understand that in light of the present disclosure, these examples are illustrative and not exhaustive. Many modifications can be made in the specific embodiments disclosed and still obtain similar or similar results without departing from the spirit and scope of the present disclosure.

[0125] The compounds disclosed herein can be prepared according to the procedures of the following examples using suitable materials, and are further exemplified 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 this disclosure, inspection of the structure of the compound to be synthesized provides the identity of each substituent. In some cases, the identity of the final product can be revealed by the inspection process of the identity of the necessary starting materials in view of the examples herein. The compounds can be isolated in the form of their pharma-ceutically acceptable salts, such as those described above. The compounds described herein are typically stable and isolatable at room temperature and pressure.

[0126] Illustrative preparations of the compounds disclosed herein are set forth below. Unless otherwise indicated, the variables have the same meanings as above. The examples provided below are intended to illustrate certain embodiments of the disclosure. Suitable starting materials, building blocks, and reagents used in the syntheses as described below are commercially available from, for example, AbovChem, Acros Organics, Astatech, Combi Blocks, Oakwood Chemical, or Sigma-Aldrich, or can be found in the literature, for example, in "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) [ka] 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 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, then tert-butyl (6-bromopyridin-3-yl)carbamate (50 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex (5 mmol) in complex 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 x 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 x 2). The precipitate was dried under reduced pressure to give 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 h. 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) acid in THF (1 mL) was added triethylamine (0.38 mmol) dropwise, followed by (1R-1-(3-fluorophenyl)ethanol (0.13 mmol). The reaction mixture was heated at 80° C. for 2 h, 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) [ka] 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-bromo-2-methylpyridin-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 resulting in a clear solution after 5-30 min. (S)-2-Fluoro-1-(3-fluorophenyl)ethan-1-ol (3.2 mmol) was added and the reaction was heated at 70° C. for 1-2 h. After cooling, water and ethyl acetate were added and the layers were separated. The organic phase was concentrated under reduced pressure, and then the residue was purified by column chromatography to give 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 hydrogen chloride solution (10 mL, 4M in dioxane) for 1 h. The mixture was then concentrated in vacuo to give (S)-2-fluoro-1-(3-fluorophenyl)ethyl (4-(5-amino-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-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 min, the reaction was concentrated, dissolved in tetrahydrofuran (2 mL) and 1 M aqueous sodium hydroxide (2 mL) and stirred vigorously for 10 min. 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 (400MHz, methanol-d4) δ8.07-7.75(m,2H),7.61-7.45(m,1H),7.34(dd,J=17.3,8.8Hz,2H),7.17(td,J=8.4,2.5H z,1H),6.01(t,J=8.2Hz,1H),4.48(t,J=8.5Hz,1H),4.19(t,J=8.0Hz,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) [ka] Step 1: (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) To a mixture of 4-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1, 9.4 mmol), 1-propanephosphonic acid cyclic anhydride (50% in THF, 14.1 mmol), and azidotrimethylsilane (14.1 mmol) acid in THF (100 mL) was added dropwise triethylamine (23.5 mmol). The reaction mixture was heated at 70° C. for 1 h, and (R)-1-(2-chloropyridin-3-yl)ethan-1-ol (18.8 mmol) was added at the same temperature. After heating for 24 hours, the reaction was cooled to room temperature, concentrated, and purified by silica gel chromatography to give (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). (MS(m / z) 474.12 [M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 8.67 (s, 1H), 8.31 (s, 1H), 8.08 (s, 1H), 7.94 (dd, J = 8.7, 2.6 Hz, 1H), 7.84 (dd, J = 8.6, 0.8 Hz, 1H), 7.47 (s, 1H), 6.07 (d, J = 6.7 Hz, 1H), 3.98 (s, 3H), 1.75-1.46 (m, 12H).

[0135] Step 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 hours. The reaction 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) was added 1-hydroxychloropropanecarboxylic acid (0.064 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.091 mmol). The reaction mixture was left with magnetic stirring for 2 h, 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) [ka] The title compound (compound 4) was prepared in a manner similar to 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) by substituting 1-methoxycyclopropane-carboxylic acid for 1-hydroxycyclopropanecarboxylic acid in step 3. (MS(m / z) 467.1 [M+H] + ). 1 H NMR (400MHz, methanol-d4) δ8.92(s,1H),8.49-7.79(m,4H),7.47(s,1H),6.23-5.88(m ,1H),3.99(s,3H),3.47(s,3H),1.61(s,3H),1.38-1.31(m,2H),1.27-1.19(m,2H).

[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) [ka] Step 1: Preparation of tert-butyl N-(6-bromo-2-chloro-3-pyridyl)carbamate (Intermediate 8) A 50 mL round bottom flask equipped with a stir bar was charged with 6-bromo-2-chloro-pyridin-3-amine (4.8 mmol) and tetrahydrofuran (10 mL). The solution was placed under a nitrogen atmosphere and cooled to -5°C. A 1 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (54 mmol) was added dropwise and stirred for 10 minutes. Di-tert-butyl dicarbonate (6.3 mmol) was then added dropwise as a solution in THF (10 mL) and the solution was allowed to warm to room temperature. Acetic acid (15 mmol) was then added along with 15 mass equivalents of silica. The crude mixture was concentrated to dryness and purified by silica gel column chromatography to give the title intermediate.

[0139] Step 2: Preparation of 5-[5-(tert-butoxycarbonylamino)-6-chloro-2-pyridyl]-3-methyl-triazole-4-carboxylic acid (Intermediate 9) The title intermediate was prepared according to the procedure below by substituting tert-butyl N-(6-bromo-2-chloro-3-pyridyl)carbamate for tert-butyl (6-bromopyridin-3-yl)carbamate (50 mmol) and substituting chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) for [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II] complexed with dichloromethane to provide 4-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1).

[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-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- The title intermediate was prepared via a procedure similar to that which 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), replacing fluoro-1-(3-fluorophenyl)ethan-1-ol.

[0141] Step 4: [(1R)-1-(2,5-difluoro-3-pyridyl)ethyl]N-[5-(5-acetamido-6-chloro-2-pyridyl)-3-methyl-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) The title example was prepared similarly to (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (compound 3) by substituting [(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) for (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 substituting 1-cyanocyclopropanecarboxylic acid for 1-hydroxycyclopropanecarboxylic acid. (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) [ka] Step 1: 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 (Intermediate 12) To a mixture of 4-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (Intermediate 1, 10.6 mmol), 1-propanephosphonic acid cyclic anhydride (50% in THF, 16 mmol), and azidotrimethylsilane (16 mmol) acid in THF (15 mL) was added dropwise triethylamine (27 mmol). The reaction mixture was heated at 70° C. for 0.5 h, and (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol (21 mmol) was added at the same temperature. After heating for 24 hours, the reaction was cooled to room temperature, concentrated, and purified by silica gel chromatography to give 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.

[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 hours. 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) (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 7) was replaced 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 1- The title example was prepared similarly to (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) by substituting 6-cyclopropylpyridine-3-carboxylic acid for hydroxycyclopropane carboxylic acid. (MS (m / z) 521.0 [M+H] + ). 1 H NMR (400MHz, methanol-d4) δ9.09-8.83(m,2H),8.23(ddd,J=8.3,6.1,2.5Hz,2H),8.16-7.61(m,3H),7.41(dd,J=8.3,0.8H z,1H),5.96(d,J=6.7Hz,1H),4.00(s,3H),2.22(tt,J=8.0,5.1Hz,1H),1.62(s,3H),1.12(ddt,J=12.2,7.5,2.6Hz,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) [ka] Step 1: Preparation of (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) The title intermediate was prepared in a manner similar to the preparation of 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) by replacing (S)-2-fluoro-1-(3-fluorophenyl)ethan-1-ol with (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol.

[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 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) is 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- The title example was prepared similarly to (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) by replacing hydroxycyclopropane carboxylic acid with 2-cyclopropyloxazole-5-carboxylic acid. (MS (m / z) 521.0 [M+H] + ). 1 H NMR (400MHz, methanol-d4) δ8.04(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=6.7Hz,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) [ka] Step 1: (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) The title intermediate was prepared from (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) in a similar manner to (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 (Example 6, Step 3) by substituting 2-chloropyrimidine-5-carboxylic acid for 6-cyclopropylpyridine-3-carboxylic acid.

[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) A vial equipped with a stir bar was charged with (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.). 1,4-Dioxane (2 mL) and distilled water (0.2 mL) were added via syringe and the reaction was stirred for 5 min by bubbling argon through the solution while mixing. The mixture was degassed. The vial was sealed with a septum cap and the mixture was heated to 90° C. Upon complete consumption of the starting material, 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 layer was collected, the volatiles were removed in vacuo, and 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 (400MHz, methanol-d4) δ9.39(s,2H),8.98(s,1H),8.63-8.40(m,2H),8.28(dd,J=8.6,2.6Hz ,1H),8.21-7.64(m,3H),7.64-7.47(m,2H),5.97(d,J=7.0Hz,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) [ka] The title example was prepared from (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, 59 μmol) in a similar manner to (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 (Example 7, step 3) by replacing 2-cyclopropyloxazole-5-carboxylic acid with 1-[(tert-butoxycarbonylamino)methyl]-3,3-difluoro-cyclobutanecarboxylic acid (88 μmol, 1.5 equivalents). The resulting intermediate (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-(1-(((tert-butoxycarbonyl)amino)methyl)-3,3-difluorocyclobutane-1-carboxamido)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Intermediate 17) was deprotected with trifluoroacetic acid in dichloromethane prior to concentration and flash chromatography (silica gel). (MS(m / z) 537.0 [M+H] + ). 1 H NMR (400MHz, methanol-d4) δ7.92(m,4H),5.97(s,1H),4.01(s,3H),3.39(s,2H) ,3.21(dt,J=15.7,13.1Hz,2H),2.92-2.71(m,2H),2.48(s,3H),1.62(s,3H).

[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) [ka] The title example was prepared from (R)-1-(2,5-difluoropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate hydrochloride (1361 μmol intermediate) in a similar manner to (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 (Example 6, step 3) by replacing 6-cyclopropylpyridine-3-carboxylic acid with 3-phenylbicyclo[1.1.1]pentane-1-carboxylic acid (91 μmol, 1.5 equivalents). (MS(m / z) 546.1 [M+H] + ). 1 H NMR (400MHz, methanol-d4) δ8.89(s,1H),8.30-7.60(m,4H),7.41-7.20(m,5H),5.95(d,J=7.7Hz,1H),4.00(s,3H),2.43(s,6H),1.62(s,3H).

[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) [ka] The title example was prepared from (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, 61 μmol) in a similar manner to (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 (Example 6, step 3) by replacing 6-cyclopropylpyridine-3-carboxylic acid with 4-(1-bicyclo[1.1.1]pentanyl)benzoic acid (91 μmol, 1.5 equivalents). (MS(m / z) 546.1 [M+H] + ). 1 H NMR (400MHz, methanol-d4) δ8.96(s,1H),8.23(dd,J=8.6,2.6Hz,1H),8.18-7.63(m,5H),7.4 9-7.30(m,2H),5.96(d,J=6.7Hz,1H),4.00(s,3H),2.60(s,1H),2.17(s,6H),1.62(s,3H).

[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) [ka] The title example was prepared from (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, 1.1 mmol) in a similar manner to (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 (Example 6, step 3) by replacing 6-cyclopropylpyridine-3-carboxylic acid with acetic acid (1.3 mmol, 1.2 equiv.). After concentration, instead of silica gel purification, the residue was subjected to reverse phase HPLC to obtain (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-acetamidopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Example 12). (MS(m / z) 418.1 [M+H] + ). 1 H NMR(400MHz,DMSO-d6)δ10.22(s,1H),9.79(bs,1H),8.68(s,1H),8.20(s,1H),8.07(dd,J=8.6,2. 6Hz,1H),7.98(s,1H),7.89(d,J=8.6Hz,1H),5.79(s,1H),3.88(s,3H),2.10(s,3H),1.56(s,3H).

[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-yl methanesulfonate (compound 13) [ka] Step 1: (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) (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-(1-hydroxychloropropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate (Example 3, step 3) was prepared similarly to (R)-1-(2-chloropyridin-3-yl)ethyl(4-(5-aminopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)carbamate by replacing 1-hydroxycyclopropanecarboxylic acid with 3-hydroxybicyclo[1.1.1]pentane-1-carboxylic acid (0.13 mmol). The title intermediate was prepared from (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 7, 0.11 mmol). After concentration of the reaction mixture, the residue was subjected to reverse phase HPLC. The residue was co-evaporated from a solution of hydrogen chloride in dioxane (4 M, 10 mL) and concentrated under reduced pressure to give (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). (MS(m / z) 484.1[M+H] + ).

[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-yl methanesulfonate (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. To the stirred mixture was added methanesulfonyl chloride (0.40 mmol). When the reaction was judged 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 into 384-well tissue culture plates (Grenier #781091) in a total volume of 25 μL of Dulbecco's Modified Eagle Medium (DMEM) containing 10% fetal bovine serum, 1× PenStrepGlutamine, 300 μg / ml hygromycin, and 800 μg / ml G418 and incubated overnight at 37°C. Prior to testing, 25 μL of calcium loading dye component A (FLIPR Calcium 6 Assay Kit Molecular Devices No. R8190) in Hanks Balanced Salt Solution (Corning No. 21-023-CV) and 2.5 mM probenecid (Invitrogen No. P36400, freshly prepared), 20 mM HEPES (Corning No. 25-060-CI), 0.1% bovine serum albumin (Sigma-Aldrich No. A7906-500G) were added to the cells for 60 min at 37°C.

[0159] Record an agonist dose curve of LPA 18:2 (Avanti Polar Lipids catalogue no. 857138, 0.5 nM to 10 µM) to determine the EC value of LPA 18:2 for subsequent antagonist assays. 80 was determined. For agonist dose curves, 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 into the assay.

[0160] To determine the LPAR1 antagonist activity of test compounds, cells were preincubated with test compounds at doses ranging from 0.5 nM to 10 μM, followed by EC 80The cells were preincubated 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 min. Antagonist activity was measured on a FLIPR Tetra. Calcium mobilization was monitored for 3.5 min and 10 μL of 6×EC in HBSS was added. 80 LPA, 20 mM HEPES, and 0.1% BSA were added to cells for 5 seconds in the assay. Signal amplitude (maximum minus minimum) values ​​were calculated as log of antagonist concentration using a dose response tool (Gilead Sciences Inc.). 10 Plot against EC 50 It was determined that:

[0161] To evaluate the antagonist potential of the exemplified compounds, 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 those of Examples 1 to 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] Thus, while the present disclosure has been specifically disclosed in terms of preferred embodiments, it is to be understood that any features, modifications, improvements, and variations of the disclosure embodied herein disclosed herein may be reused by one of ordinary skill in the art, and such modifications, improvements, and variations are deemed to be within the scope of the present disclosure. The materials, methods, and examples provided herein are representative of preferred embodiments, are illustrative, and are not intended as limitations on the scope of the present disclosure.

[0164] The present disclosure has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the present disclosure. This includes the general description of the present disclosure with any conditional or negative limitation removing any subject matter from the genus, regardless of whether the excised material is specifically set forth herein.

[0165] While the present disclosure has been described in conjunction with the above embodiments, 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 this disclosure pertains.

Claims

【Request 1】 【Chemical 38】 【Chemical 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 or a pharma- ceutically acceptable salt thereof.

2. The compound is 【Chemistry 43】 2. The compound of claim 1, wherein:

3. The compound is 【Chemistry 44】 2. The compound of claim 1, wherein:

4. The compound is 【Chemistry 45】 2. The compound of claim 1, wherein:

5. The compound is 【Chemistry 46】 2. The compound of claim 1, wherein:

6. The compound is 【Chemistry 47】 2. The compound of claim 1, wherein:

7. The compound is 【Chemistry 48】 2. The compound of claim 1, wherein:

8. The compound is 【Chemistry 49】 2. The compound of claim 1, wherein:

9. The compound is 【Chemistry 50】 2. The compound of claim 1, wherein:

10. The compound is 【Chemistry 51】 2. The compound of claim 1, wherein:

11. The compound is 【Chemistry 52】 2. The compound of claim 1, wherein:

12. The compound is 【Chemistry 53】 2. The compound of claim 1, wherein:

13. The compound is 【Chemical 54】 2. The compound of claim 1, wherein:

14. The compound is 【Chemistry 55】 2. The compound of claim 1, wherein:

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

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

17. 15. A composition for treating, stabilizing, or reducing the severity or progression of an LPAR1 mediated disease or condition, comprising a compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein the LPAR1 mediated disease or condition is interstitial lung disease (ILD) or non-alcoholic steatohepatitis (NASH).

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