LPA receptor antagonists and their use

Abstract

The present application relates to pyrazole derivatives of general formula (I) that bind to lysophosphatidic acid receptor 1 (LPAR1) and act as antagonists of LPAR1. The compounds are useful in the treatment of diseases and conditions including fibrosis and liver disease, such as nonalcoholic steatohepatitis (NASH), interstitial lung disease (ILD), or chronic kidney disease (CKD). JPEG2024517016000123.jpg73128

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 186,890, filed May 11, 2021, the entire disclosure of which is incorporated herein by reference for all purposes.

[0002]

Background Art

[0003] ​Lysophosphatidic acid (mono-acyl-glycerol-3-phosphate, LPA) is a class of biologically active phospholipids that can be generated, for example, from lysophosphatidyl choline (LPC) by the enzyme autotaxin. A typical LPA has glycerol, an ester-linked fatty acid at the sn-1 position, and a phosphate head group at the sn-3 position. LPAs with various fatty acids have been identified, including palmitoyl LPA (16:0), stearoyl LPA (18:0), oleoyl LPA (18:1), linoleoyl LPA (18:2), and arachidonyl LPA (20:4). LPA exerts a wide range of cellular responses such as proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis through a family of rhodopsin-like G protein-coupled receptors (GPCRs). Six LPA receptors have been characterized and found to differ in their tissue distribution and downstream signaling pathways. These six LPA receptors are often referred to interchangeably as LPAR1-6 (genes) or LPA1-6 (proteins). LPA receptor-mediated signaling has been shown to affect many biological processes such as wound healing, immunity, carcinogenesis, angiogenesis, and neurogenesis.

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

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

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

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

Chemical formula

[0008] In some embodiments, a pharmaceutical composition comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable Add agent or carrier is provided herein. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable Add agent 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 pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition further comprises a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents, or pharmaceutically acceptable salts thereof.

[0010] In some embodiments, the present disclosure provides a method of inhibiting LPAR1 activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0011] In some embodiments, the present disclosure provides a method of treating a patient having an LPAR1-mediated condition, the method comprising administering to the patient a therapeutically effective amount of a compound provided herein (e.g., a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

Mode for Carrying Out the Invention

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

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

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

[0015] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Note that as used in this specification and the appended claims, the singular forms “a,” “and,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound” includes a plurality of such compounds, and reference to “an assay” includes reference to one or more assays known to those of ordinary skill in the art and their equivalents.

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

[0017] A dash ("-") not between two letters or symbols is used to indicate the point of attachment for substituents. For example, -CONH2 is attached via a carbon atom. Dashes at the front or end of a chemical group are for convenience, and the chemical groups can be shown with or without one or more dashes without losing their normal meaning. A wavy line drawn across a line in a structure indicates the point of attachment of a group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality. A solid line protruding from the center of a ring indicates that the point of attachment of a substituent in that ring can be at any of the ring atoms. For example, R in the following structure a can be attached to any of the five carbon ring atoms, or the hydrogen attached to the nitrogen ring atom can be replaced by R a as follows: [Chemical formula] is.

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

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

[0020] The "compounds disclosed herein" or "the compounds of the present disclosure" or "the compounds provided herein" or "the compounds described herein" refer to the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl). Specific compounds 1 - 55 provided herein (e.g., Examples 1 - 35) are also included.

[0021] References to "about" values or parameters herein include (and describe) embodiments that relate 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, in relation to that term, "about X" includes the description of "X". Also, the singular forms "a" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "a compound" includes a plurality of such compounds, and a reference to "an assay" includes references to one or more assays known to those of skill in the art and their equivalents.

[0022] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 - 20 carbon atoms (i.e., C 1~20 alkyl), 1 - 8 carbon atoms (i.e., C 1~8 alkyl), 1 - 6 carbon atoms (i.e., C 1~6 alkyl), 1 - 4 carbon atoms (i.e., C 1~4 alkyl), or 1 - 3 carbon atoms (i.e., C 1~3It has an alkyl group. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl group having a specific number of carbons is named by its chemical name or identified by its molecular formula, all positional isomers having that number of carbons may be included. Thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), iso-butyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

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

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

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

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

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

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

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

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

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

Chemical formula

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

Chemical formula

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

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

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

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

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

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

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

[0040] Whenever the depiction of a group ends with a singly-bonded nitrogen atom, that group represents an -NH2 group, unless otherwise indicated. Similarly, unless otherwise specified, hydrogen atoms are implied and considered to be present as necessary to complete valences or provide stability, taking into account the knowledge of one of ordinary skill in the art.

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

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

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

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

Chemical Formula

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

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

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

[0048] The present disclosure also includes all salts of the compounds of the present disclosure that, due to low physiological compatibility, are not directly suitable for use in pharmaceuticals but can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts. Acids and bases useful for reaction with the parent compound to form pharmaceutically acceptable salts (acid addition salts or base addition salts, respectively) are known to those skilled in the art. Similarly, methods for preparing pharmaceutically acceptable salts from the parent compound (at the time of disclosure) 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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0067] "Subject" refers to an animal such as a mammal (including humans) that has been, or may be, the subject of treatment, observation, or experimentation. 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.

[0068] The term "therapeutically effective amount" or "effective amount" of a compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, means an amount sufficient to provide a therapeutic benefit, such as improvement of symptoms or retardation of the progression of a disease, when administered to a subject. For example, a therapeutically effective amount may be an amount sufficient to reduce the symptoms of a disease or condition in response to an LPAR1 antagonist. The therapeutically effective amount can vary depending on the subject, the disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the mode of administration, and can be readily determined by one of ordinary skill in the art. [Table 3]

[0069] 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 known methods 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.

[0070] As used herein, "ACC inhibitor" refers to any agent that can bind to and inhibit 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 known methods in the art such as those described and cited in U.S. Patent No. 8,969,557 and / or U.S. Patent No. 10,208,063, which are hereby incorporated by reference in their entirety.

[0071] As used herein, an "ASK1 inhibitor" can be any agent that is capable of inactivating apoptosis signal regulating kinase 1 (ASK1) protein. The agent can be a chemical compound or a biological molecule (e.g., a protein or an antibody). ASK1 protein activity can be measured by several different methods. For example, the activity of the ASK1 protein can be determined based on the ability of the ASK1 protein to phosphorylate a substrate protein. Methods for identifying ASK1 inhibitors are known (see, e.g., 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 the ASK1 protein, e.g., the phosphorylation level of the threonine residue in the ASK1 protein corresponding to threonine 838 (T838) of the human full-length ASK1 protein or threonine 845 (T845) of the mouse full-length ASK1 protein. For example, if the ASK1 protein contains the full-length human ASK1 protein sequence, an ASK1 inhibitor can attenuate the phosphorylation of T838 in the full-length human ASK1 protein sequence. Site-specific antibodies against human ASK1 T838 or mouse ASK1 T845 can be used to detect the phosphorylation level.

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

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

Chemical formula

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

Chemical formula

[0075] In some embodiments of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, R 1A2 is hydrogen.

[0076] In some embodiments of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, R 3 is C optionally substituted with 1 to 3 identical or different substituents independently selected from cyano and F 1~3 alkyl. In some embodiments of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, R 3 is -CH3.

[0077] In some embodiments of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, X 1 is CH, and X 2 is CH.

[0078] In some embodiments of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, X 1 is N, and X 2 is N.

[0079] In some embodiments of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, X 1 is N, and X 2 is CH.

[0080] In some embodiments of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, X 1 is N, and X 2 is C(R 2 ).

[0081] In some embodiments of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, Y 2 is hydrogen.

[0082] In some embodiments, the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, is a compound of formula (IIa),

Chemical formula

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

Chemical formula

[0084] In some embodiments, the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, is a compound of formula (IIc),

Chemical formula

[0085] In some embodiments, the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, is a compound of formula (IId),

Chemical formula

[0086] In some embodiments, the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, is a compound of formula (IIe),

Chemical formula

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

Chemical formula

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

Chemical formula

[0089] In some embodiments, the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, is a compound of formula (IIh),

Chemical formula

[0090] In some embodiments, the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, is a compound of formula (IIi),

Chemical formula

[0091] In some embodiments, the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, is a compound of formula (IIj),

Chemical formula

[0092] In some embodiments, the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, is a compound of formula (IIk),

Chemical formula

[0093] In some embodiments, the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, is a compound of formula (IIl),

Chemical formula

[0094] In some embodiments of the compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), or (IIk), or a pharmaceutically acceptable salt thereof, R 1A1 is hydrogen.

[0095] In some embodiments of the compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), or (IIk), or a pharmaceutically acceptable salt thereof, R 1A1 is the same or different and is 1 to 4 R groups1B C optionally replaced by 1~6 alkyl, C 2~6 alkenyl, or C 2~6 alkynyl, and each R 1B is independently selected from halogen, cyano, nitro, oxo, C 1~4 alkyl, C 3~10 cycloalkyl, nitrogen, oxygen, and sulfur, a 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected therefrom, a 6- to 10-membered aryl, nitrogen, oxygen, or sulfur, a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected therefrom, -N(R 1C1 )(R 1C2 ), -O-R 1C1 ), -S-R 1C1 ), -C(O)N(R 1C1 )(R 1C2 ), -NR 1C1 C(O)R 1C2 ), -NR 1C1 C(O)N(R 1C2 )(R 1C3 ), -S(O) 0-2 R 1C1 ), -S(O)2N(R 1C1 )(R 1C2 ), and -NR 1C1 S(O)2R 1C2 ), and each R 1C1 ), R 1C2 ), and R 1C3 is independently hydrogen, C 1~6 alkyl, or C 3~6 cycloalkyl, and each R 1B alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be the same or different and may be optionally substituted with 1 to 4 R 1D ), and each R 1D is independently C 1~4 alkyl, halogen, cyano, -O-R 1E1 ), or -N(R 1E1 )(R 1E2 ), and in the formula, each R 1E1 and R 1E2 is independently hydrogen or C 1~6 alkyl, and in the formula, each R 1C1 ), R 1C2 ), and R1C3 Alkyl, and each R 1C1 , R 1C2 , and R 1C3 Cycloalkyl is optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), or (IIk), or pharmaceutically acceptable salts thereof, R 1A1 is C 1B alkyl optionally substituted with 1 to 4 R 1~6 's, each R 1B being independently selected from halogen, cyano, hydroxy, C 1~4 alkoxy, and C 3~6 cycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), or (IIk), or pharmaceutically acceptable salts thereof, R 1A1 is -CH3,

Chemical formula

[0096] In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIg), (IIh), or (IIi), or pharmaceutically acceptable salts thereof, R 1A1 is -O-R 1F1 or -N(R 1F1 )(R 1F2 ), wherein each R 1F1 and R 1F2 is independently hydrogen, C 1~6 alkyl, or C 3~6 cycloalkyl, each C 1~6 alkyl or C 3~6 cycloalkyl being optionally substituted with 1 to 4 R 1G 's, each R 1G being halogen, cyano, hydroxy, oxo, C 1~4 alkyl, C3~10 A 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected from cycloalkyl, nitrogen, oxygen, and sulfur, a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, -O-R 1H1 , -N(R 1H1 )(R 1H2 ), -C(O)N(R 1H1 )(R 1H2 ), -NR 1H1 C(O)R 1H2 , -S(O) 0-2 R 1H1 , -S(O)2N(R 1H1 )(R 1H2 ), and -NR 1H1 S(O)2R 1H2 independently selected from, wherein each R 1H1 and R 1H2 is independently hydrogen or C 1~6 alkyl, and each R 1G alkyl, cycloalkyl, aryl, and heteroaryl may be the same or different and may be optionally substituted with 1 to 3 R 1I , and each R 1I is independently C 1~4 alkyl, C 1~4 alkoxy, hydroxy, halogen, or cyano. In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIg), (IIh), or (IIi), or pharmaceutically acceptable salts thereof, R 1A1 is -O-R 1F1 , and R 1F1 is C 1~6 alkyl optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIg), (IIh), or (IIi), or pharmaceutically acceptable salts thereof, R 1A1 is

Chemical formula

[0097] In some embodiments of the compounds of formula (I), (Ia), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), or (IIk), or pharmaceutically acceptable salts thereof, R 1A1 is cycloalkyl optionally substituted with one to four R 1B 's, each R 1B being independently selected from halogen, cyano, nitro, oxo, C 1~4 alkyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl having one to four heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having one to four heteroatoms independently selected from nitrogen, oxygen, or sulfur, -N(R 1C1 )(R 1C2 ), -O-R 1C1 ), -S-R 1C1 ), -C(O)N(R 1C1 )(R 1C2 ), -NR 1C1 C(O)R 1C2 ), -NR 1C1 C(O)N(R 1C2 )(R 1C3 ), -S(O) 0-2 R 1C1 ), -S(O)2N(R 1C1 )(R 1C2 ), and -NR 1C1 S(O)2R 1C2 ; wherein each R 1C1 , R 1C2 , and R 1C3 is independently hydrogen, C 1~6 alkyl, or C 3~6 cycloalkyl; each R 1B alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one to four R 1D 's, each R 1D being independently C 1~4 alkyl, halogen, cyano, -O-R 1E1 , or -N(R 1E1 )(R 1E2 ); wherein each R 1E1 and R1E2 is independently hydrogen or C 1~6 alkyl, and each R 1C1 , R 1C2 , and R 1C3 alkyl as well as each R 1C1 , R 1C2 , and R 1C3 cycloalkyl is optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of formula (I), (Ia), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), or (IIk), or pharmaceutically acceptable salts thereof, R 1A1 is the same or different and is independently selected from -F, -CN, -CHF2, -CF3, -OCH3, and pyridyl, and is optionally substituted with 1 to 4 R 1B each, and is cyclopropyl or cyclobutyl. In some embodiments of the compounds of formula (I), (Ia), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), or (IIk), or pharmaceutically acceptable salts thereof, R 1A1 is

Chemical formula

Chemical formula

[0098] In some embodiments of the compounds of formula (I), (Ia), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), or (IIk), or pharmaceutically acceptable salts thereof, R 1A1 is a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with 1 to 4 identical or different R 1B each R 1B is halogen, cyano, nitro, oxo, C 1~4 alkyl, C 3~10 cycloalkyl, a 3- to 10-membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -N(R 1C1 )(R 1C2 ), -O-R 1C1 ), -S-R 1C1 ), -C(O)N(R 1C1 )(R 1C2 ), -NR 1C1 C(O)R 1C2 ), -NR 1C1 C(O)N(R 1C2 )(R 1C3 ), -S(O) 0-2 R 1C1 ), -S(O)2N(R 1C1 )(R 1C2 ), and -NR 1C1 S(O)2R1C2 Selected independently from, wherein each R 1C1 , R 1C2 , and R 1C3 are independently hydrogen, C 1~6 alkyl, or C 3~6 cycloalkyl, and each R 1B alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be the same or different and are optionally substituted with 1 to 4 R 1D , and each R 1D is independently C 1~4 alkyl, halogen, cyano, -O-R 1E1 , or -N(R 1E1 )(R 1E2 ), wherein each R 1E1 and R 1E2 are independently hydrogen or C 1~6 alkyl, and wherein each R 1C1 , R 1C2 , and R 1C3 alkyl, and each R 1C1 , R 1C2 , and R 1C3 cycloalkyl are optionally substituted with 1 to 3 halogens. In some embodiments of the compounds of formula (I), (Ia), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), or (IIk), or pharmaceutically acceptable salts thereof, R 1A1 is pyridinyl or pyrimidinyl optionally substituted with 1 to 3 substituents each independently selected from -Cl, -CHF2, and -CF3, which may be the same or different. In some embodiments of the compounds of formula (I), (Ia), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), or (IIk), or pharmaceutically acceptable salts thereof, R 1A1 is

Chemical formula

[0099] In some embodiments of the compound of formula (I), (Ia), (IId), (IIe), (IIf), (IIg), or (IIh), or a pharmaceutically acceptable salt thereof, R 2 is independently selected from deuterium, halogen, C 1~6 alkyl, C 3~6 cycloalkyl, -O-R 2A1 , and -N(R 2A1 )(R 2A2 ), wherein the C 1~6 alkyl is optionally substituted with one to three substituents independently selected from C 1~4 alkoxy and halogen, and each R 2A1 and R 2A2 is independently hydrogen or C 1~4 alkyl optionally substituted with one to three halogens, which may be the same or different. In some embodiments of the compound of formula (I), (Ia), (IId), (IIe), (IIf), (IIg), or (IIh), or a pharmaceutically acceptable salt thereof, R 2 is independently selected from halogen, cyano, C 1~4 alkoxy, and C 3~10 cycloalkyl, and is optionally substituted with one to three substituents, which may be the same or different, and is independently selected from halogen or C 1~6 alkyl. In some embodiments of the compound of formula (I), (Ia), (IId), (IIe), (IIf), (IIg), or (IIh), or a pharmaceutically acceptable salt thereof, R 2 is independently selected from -F and -CH3. In some embodiments of the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0100] In some embodiments of the compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or a pharmaceutically acceptable salt thereof, Y1 is independently optionally substituted with 1 to 3 same or different substituents selected from hydrogen, deuterium, halogen, cyano, C 2~3 alkynyl, C 1~4 alkoxy, and -C(O)NH-(C 1~4 H 3~9 ) and is optionally substituted C 1~6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or pharmaceutically acceptable salts thereof, Y 1 is hydrogen. In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or pharmaceutically acceptable salts thereof, Y 1 is methyl optionally substituted with 1 to 3 same or different substituents each independently selected from -F, -Cl, -CN, and -O-CH3. In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or pharmaceutically acceptable salts thereof, Y 1 is -CH3.

[0101] In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or pharmaceutically acceptable salts thereof, Z is C 1~4 aryl optionally substituted with 1 to 3 same or different substituents each independently selected from halogen, cyano, C 1~4 alkyl, C 3~6 alkoxy, and C 6~12 cycloalkyl, and the C 1~4 alkyl is C 1~4Optionally substituted with 1 to 3 substituents, the same or different, each independently selected from alkoxy and halogen. In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or pharmaceutically acceptable salts thereof, Z is phenyl substituted with 1 to 3 substituents, the same or different, each independently selected from -F and -Cl. In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or pharmaceutically acceptable salts thereof, Z is [Chemical formula] as follows.

[0102] In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or pharmaceutically acceptable salts thereof, Z is a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the heteroaryl is halogen and C 1~4It is optionally substituted with 1 to 3 substituents, which may be the same or different, each independently selected from alkyl. In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or pharmaceutically acceptable salts thereof, Z is pyridyl optionally substituted with 1 to 3 substituents, which may be the same or different, each independently selected from -F and -Cl. In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or pharmaceutically acceptable salts thereof, Z is

Chemical formula

[0103] In some embodiments of the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or pharmaceutically acceptable salts thereof, Y1 is -CH3 and Z is

Chemical formula

[0104] In some embodiments, the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or pharmaceutically acceptable salts thereof are

Chemical formula

Chemical formula

Chemical formula

[0105] In some embodiments, the compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or a pharmaceutically acceptable salt thereof, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or a pharmaceutically acceptable salt thereof, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or a pharmaceutically acceptable salt thereof, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, the compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or a pharmaceutically acceptable salt thereof, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments, the compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or a pharmaceutically acceptable salt thereof, is

Chem.

[0110] In some embodiments, the compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or a pharmaceutically acceptable salt thereof, is

Chem.

[0111] Pharmaceutical Compositions and Modes of Administration Furthermore, the present disclosure provides a pharmaceutical composition comprising, as an active ingredient, at least a compound of the present disclosure, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier.

[0112] The pharmaceutical composition of the present disclosure may further comprise one or more other compounds as active ingredients such as prodrug compounds or other enzyme inhibitors.

[0113] The composition is suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), intraocular (ophthalmic), intrapulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case depends on the nature and severity of the condition being treated and the nature of the active ingredient. The composition can be conveniently presented in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art.

[0114] In actual use, the compounds of the present disclosure can be combined as active ingredients in a homogeneous admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). When preparing a composition for an oral dosage form, for example, in the case of oral liquid preparations such as suspensions, elixirs, and solutions, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., or in the case of oral solid preparations such as powders, hard capsules, soft capsules, and tablets, carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc., any of the ordinary pharmaceutical media can be used, and solid oral preparations are preferred over liquid preparations.

[0115] For ease of administration, tablets and capsules represent the most advantageous oral unit dosage forms, in which case a solid pharmaceutical carrier is used. If desired, the tablets can be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of the active compound. The proportion of the active compound in these compositions can, of course, vary widely and can conveniently be from about 2 percent to about 60 percent by unit weight. The amount of the active compound in such therapeutically useful compositions is an amount such that an effective dosage is obtained. The active compound can also be administered nasally, for example, as droplets or a spray.

[0116] Tablets, pills, capsules, etc. may also contain binders such as gum tragacanth, acacia, corn starch, or gelatin, excipients such as dicalcium phosphate, disintegrants such as corn starch, potato starch, alginic acid, lubricants such as magnesium stearate, and sweeteners such as sucrose, lactose, or saccharin. When the unit dosage form is a capsule, it may contain a liquid carrier such as fatty oil in addition to the materials of the above types.

[0117] Various other materials may be present as coatings or to improve the physical form of the unit dosage form. For example, tablets may be coated with shellac, sugar, or both. Syrups or elixirs may contain, in addition to the active ingredient, sucrose as a sweetener, methylparaben and propylparaben as preservatives, dyes, and flavoring agents such as cherry or orange flavor.

[0118] In some embodiments, the compounds of the present disclosure may also be used as salts having various counter cations to obtain orally available formulations.

[0119] The compounds of the present disclosure may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can be prepared in glycerol in oil, liquid polyethylene glycols, and mixtures thereof. Under normal conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms.

[0120] Pharmaceutical forms suitable for use by injection include sterile aqueous solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that it is easy to place in a syringe. The form must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0121] Any suitable route of administration can be used to provide a mammalian, particularly a human, with an effective dose of the compounds of the present disclosure. For example, oral, rectal, topical, parenteral, intraocular, intralung, intranasal, etc. can be used. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc. In some embodiments, the compounds of the present disclosure are administered orally.

[0122] Kit Also provided herein are kits comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogue thereof, and a suitable package. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit comprises a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogue thereof, and a label and / or instructions for use of the compound in the treatment of an indication comprising a disease or condition described herein.

[0123] Also provided herein are articles of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogue thereof, in a suitable container. The container can be a vial, bottle, ampule, prefilled syringe, and infusion bag.

[0124] 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 binding of LPAR1 by the compounds. Further, the present disclosure relates to the use of the compounds for the preparation of a medicament for the treatment and / or prevention of diseases and / or conditions through binding of LPAR1 by the compounds.

[0125] The medicaments referred to herein can be prepared by conventional processes comprising a combination of a compound according to the present disclosure and a pharmaceutically acceptable carrier.

[0126] 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 a therapeutically effective amount of a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or a pharmaceutically acceptable salt thereof.

[0127] In some embodiments, LPAR1-mediated diseases or conditions include those in which there is an absolute or relative excess of LPA present and / or observed.

[0128] In some embodiments, LPAR1-mediated diseases or conditions include fibrosis, wound healing, cancer, pain, respiratory disorders, allergic disorders, nervous system disorders, cardiovascular disorders, or inflammatory disorders.

[0129] In some embodiments, the LPAR1-mediated disease or condition is interstitial lung disease (ILD). In some embodiments, the interstitial lung disease (ILD) is nonspecific interstitial pneumonitis (NSIP), sarcoidosis, asbestosis, ILD associated with occupational exposure, progressive fibrotic ILD, idiopathic interstitial pneumonia (IIP), connective tissue disease-associated interstitial lung disease (CTD-ILD), rheumatoid arthritis-associated ILD, scleroderma-associated ILD, or exogenous alveolitis.

[0130] 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.

[0131] In some embodiments, the LPAR1-mediated disease or condition includes fibrosis. In some embodiments, the fibrosis includes pulmonary fibrosis, renal fibrosis, hepatic fibrosis, ocular fibrosis, or cardiac fibrosis.

[0132] In some embodiments, the LPAR1-mediated disease or condition includes pulmonary fibrosis. In some embodiments, the pulmonary fibrosis includes idiopathic pulmonary fibrosis (IPF). In some embodiments, the pulmonary fibrosis includes Progressive Fibrotic interstitial lung disease (PF-ILD). In some embodiments, the pulmonary fibrosis includes secondary pulmonary fibrosis secondary to systemic inflammatory diseases such as rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrosing alveolitis, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, chronic asthma, silicosis, asbestos-induced pulmonary or pleural fibrosis, acute lung injury and acute respiratory distress (including those induced by bacterial pneumonia, trauma, viral pneumonia, ventilator-induced, non-pulmonary sepsis-induced, and aspiration-induced).

[0133] In some embodiments, the LPAR1-mediated disease or condition includes renal fibrosis. In some embodiments, the renal fibrosis includes chronic kidney disease associated with injury / fibrosis (renal fibrosis), such as glomerulonephritis secondary to systemic inflammatory diseases such as lupus and scleroderma, diabetes, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allografts, and Alport; intestinal fibrosis, such as scleroderma and radiation-induced intestinal fibrosis.

[0134] In some embodiments, the LPAR1-mediated disease or condition includes liver fibrosis. In some embodiments, the liver fibrosis includes cirrhosis, alcohol-induced liver fibrosis, non-alcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis, infectious diseases, or virus-induced liver fibrosis (e.g., chronic HCV infection), and autoimmune hepatitis.

[0135] In some embodiments, the LPAR1-mediated disease or condition includes, for example, radiation-induced head and neck fibrosis.

[0136] In some embodiments, the LPAR1-mediated disease or condition includes, for example, LASIK (laser-assisted in situ keratomileusis), corneal transplantation, or trabeculectomy. In some embodiments, a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or a pharmaceutically acceptable salt thereof, is used to improve decreased corneal sensitivity resulting from corneal surgery such as LASIK or cataract surgery, decreased corneal sensitivity resulting from corneal degeneration, and dry eye syndrome resulting therefrom. In some embodiments, a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or a pharmaceutically acceptable salt thereof, is used for the treatment or prevention of ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis, and papillary conjunctivitis. In some embodiments, a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or a pharmaceutically acceptable salt thereof, is used for the treatment or prevention of Sjogren's disease or inflammatory diseases with dry eye.

[0137] In some embodiments, the LPAR1-mediated disease or condition includes, for example, hypertrophic scars and keloids of burns or surgery, sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, mixed connective tissue disease, and other fibrotic conditions such as Peyronie's disease.

[0138] In some embodiments, the LPAR1-mediated disease or condition includes pain. In some embodiments, the pain includes neuropathic pain. In some embodiments, the pain includes acute pain. In some embodiments, the pain includes chronic pain.

[0139] In some embodiments, the LPAR1-mediated disease or condition includes cancer. In some embodiments, the cancer includes ovarian cancer, colon cancer, prostate cancer, breast cancer, melanoma, head and neck cancer, bowel cancer (colorectal cancer), and thyroid cancer. In some embodiments, the cancer includes solid tumors or hematological tumors (such as leukemia) of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas, or other endocrine organs (thyroid), prostate, skin (melanoma or basal cell carcinoma), etc., at any stage of the disease, regardless of the presence or absence of metastasis. In some embodiments, the cancer includes acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendiceal cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brainstem glioma, brain tumor, brain and spinal cord tumor, breast cancer, bronchial tumor, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T cell lymphoma, fetal tumor, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromaltumors, GIST), gastrointestinal stromal tumors, germ cell tumors, gliomas, hairy cell leukemia, head and neck cancers, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenström macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, oral cancer, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, low malignant potential ovarian tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, moderately differentiated pineal parenchymal tumor, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasma cell tumor / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, Kaposi, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell cancer, stomach (gastric) cancer, supratentorial primitive, neuroectodermal tumor, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic cancer, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, and Wilms tumor.

[0140] In some embodiments, the LPAR1-mediated disease or condition includes a respiratory or allergic disorder. In some embodiments, the respiratory or allergic disorder includes asthma, peribronchiolar fibrosis, bronchiolitis obliterans, and chronic obstructive pulmonary disease (COPD). In some embodiments, COPD includes chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or airway inflammation, and cystic fibrosis. In some embodiments, the respiratory disease includes adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, hyperventilation with hypocapnia, childhood-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, and hypoxemia.

[0141] In some embodiments, the LPAR1-mediated disease or condition includes a neurological disorder. In some embodiments, the neurological disorder includes Alzheimer's disease, cerebral edema, cerebral ischemia, stroke, multiple sclerosis, neuropathy, Parkinson's disease, neurological conditions found after blunt or surgical trauma (including postoperative cognitive dysfunction and spinal cord or brainstem injury), and the neurological aspects of disorders such as degenerative disc disease and sciatica.

[0142] In some embodiments, the LPAR1-mediated disease or condition includes a cardiovascular disorder. In some embodiments, the cardiovascular disorder includes arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina pectoris; cardiac dysfunction; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis; stroke; peripheral obstructive arterial disease of the limb, organ, or tissue; reperfusion injury after ischemia of the brain, heart, or other organ or tissue; endotoxin, surgical, or traumatic shock; hypertension; valvular heart disease; heart failure; abnormal blood pressure; shock; vasoconstriction (including those related to migraine); vascular abnormalities, and cardiovascular insufficiency limited to a single organ or tissue.

[0143] In some embodiments, the LPAR1-mediated disease or condition includes pulmonary fibrosis, kidney fibrosis, liver fibrosis, scarring, asthma, rhinitis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, interstitial lung fibrosis, arthritis, allergy, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, pain, proliferative disorders, and inflammatory conditions.

[0144] In some embodiments, the LPAR1-mediated disease or condition is a metabolic disorder or a liver disease. In some embodiments, the liver disease is hepatitis C, liver cancer, familial combined hyperlipidemia, non-alcoholic fatty liver disease (NAFLD), progressive familial intrahepatic cholestasis, primary biliary cirrhosis (PBC), or primary sclerosing cholangitis (PSC). In some embodiments, the liver disease is PSC. In some embodiments, the liver disease includes portal hypertension. In some embodiments, liver cancer includes hepatocellular carcinoma (HCC), cholangiocarcinoma, angiosarcoma, or hemangiosarcoma. In some embodiments, liver cancer includes HCC. In some embodiments, NAFLD includes steatosis. In some embodiments, NAFLD includes NASH. In some embodiments, NAFLD or NASH includes liver fibrosis. In some embodiments, NAFLD or NASH includes cirrhosis. In some embodiments, NAFLD or NASH includes compensated cirrhosis. In some embodiments, NAFLD or NASH includes decompensated liver fibrosis. In some embodiments, NAFLD includes HCC. In some embodiments, the liver disease is NASH.

[0145] In some embodiments, provided herein is a method for treating and / or preventing non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) in a patient in need of treatment and / or prevention of NAFLD or NASH, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or a pharmaceutically acceptable salt thereof. In some embodiments, NAFLD or NASH includes liver fibrosis. In some embodiments, NAFLD or NASH includes cirrhosis. In some embodiments, the cirrhosis is compensated cirrhosis. In some embodiments, the cirrhosis is decompensated cirrhosis. In some embodiments, NAFLD or NASH includes HCC.

[0146] In some embodiments, provided herein is a method for preventing liver disease in a patient in need of prevention of liver disease, the method comprising administering a therapeutically effective amount of a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or a pharmaceutically acceptable salt thereof. In some embodiments, the liver disease or condition is liver fibrosis. In some embodiments, the liver disease or condition is cirrhosis. In some embodiments, the cirrhosis is compensated cirrhosis. In some embodiments, the cirrhosis is decompensated cirrhosis. In some embodiments, the liver disease or condition is HCC.

[0147] In some embodiments, the present disclosure relates to the use of a compound according to formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention and / or treatment of an LPAR1-mediated disease or condition disclosed herein.

[0148] Dosage The effective dosage of the active ingredient used may vary depending on the particular compound used, the mode of administration, the condition being treated, and the severity of the condition being treated. Such dosages can be readily ascertained by one of ordinary skill in the art.

[0149] When treating or preventing an LPAR1-mediated disease or condition for which a compound of the present disclosure is needed, generally satisfactory results are obtained when the compound of the present disclosure is administered at a daily dosage of about 0.1 milligram to about 300 milligrams per kilogram of body weight of the animal. In some embodiments, the compounds of the present disclosure are administered as a single daily dose or as divided doses of 2 to 6 times per day, or in sustained release form. For most large mammals, the total daily dosage is from about 1 milligram to about 1000 milligrams, or from about 1 milligram to about 50 milligrams. In the case of a 70 kg adult human, the total daily dosage will generally be from about 0.1 milligram to about 200 milligrams. This dosage regimen can be adjusted to provide an optimal therapeutic response. In some embodiments, the total daily dosage is about 1 milligram to about 900 milligrams, about 1 milligram to about 800 milligrams, about 1 milligram to about 700 milligrams, about 1 milligram to about 600 milligrams, about 1 milligram to about 400 milligrams, about 1 milligram to about 300 milligrams, about 1 milligram to about 200 milligrams, about 1 milligram to about 100 milligrams, about 1 milligram to about 50 milligrams, about 1 milligram to about 20 milligrams, or about 1 milligram to about 10 milligrams.

[0150] The compounds or compositions thereof of the present application can be administered once, twice, three times, or four times a day using any of the suitable modes described above. Also, the administration or treatment with the compounds can be continued for several days. For example, usually, the treatment will continue for at least 7 days, 14 days, or 28 days for one treatment cycle. The treatment cycles alternate periodically with a rest period of about 1 to 28 days, usually about 7 days or about 14 days, between cycles. The treatment cycles can also be continuous in other embodiments.

[0151] In some embodiments, the method includes administering an initial daily dose of about 1 to 800 mg of the compounds described herein to a subject and increasing the dose in increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dose can be increased daily, every other day, twice a week, or once a week.

[0152] Combination In some embodiments, the compounds of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl) provided herein, or pharmaceutically acceptable salts thereof, are administered in combination with one or more additional therapeutic agents for treating or preventing the diseases or conditions disclosed herein. In some embodiments, the one or more additional therapeutic agents are 1, 2, 3, or 4 additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are 1 additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are 2 additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are 3 additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are 4 additional therapeutic agents.

[0153] In some embodiments, the pharmaceutical compositions provided herein have a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl) provided herein, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are 1, 2, 3, or 4 additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are 1 additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are 2 additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are 3 additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are 4 additional therapeutic agents.

[0154] In some embodiments, one or more additional therapeutic agents are angiotensin converting enzyme (ACE) inhibitors, adenosine A3 receptor agonists, adiponectin receptor agonists, AKT protein kinase inhibitors, AMP kinase activators, AMP-activated protein kinase (AMPK) activators, amylin receptor agonists, angiotensin II AT-1 receptor antagonists, androgen receptor agonists, apoptosis signal-regulating kinase 1 (ASK1) inhibitors, ATP citrate lyase inhibitors, apolipoprotein C3 (APOC3) antagonists, autophagy protein modulators, autotaxin inhibitors, Axl tyrosine kinase receptor inhibitors, Bax protein stimulators, bioactive lipids, calcitonin agonists, cannabinoid receptor modulators, caspase inhibitors, caspase-3 stimulators, cathepsin inhibitors (e.g., cathepsin B inhibitors), caveolin 1 inhibitors, CCR2 chemokine antagonists, CCR3 chemokine antagonists, CCR5 chemokine antagonists, CD3 antagonists, chloride channel stimulators, cholesterol solubilizers, CNR1 inhibitors, cyclin D1 inhibitors, cytochrome P450 7A1 inhibitors, cytochrome P450 2E1 (CYP2E1) inhibitors, diacylglycerol O acyltransferase 1 (DGAT1) inhibitors, diacylglycerol O acyltransferase 1 (DGAT2) inhibitors, CXCR4 chemokine antagonists, dipeptidyl peptidase IV inhibitors, endothelin modulators, endothelial nitric oxide synthase stimulators, eotaxin ligand inhibitors, extracellular matrix protein modulators, farnesoid X receptor agonists, fatty acid synthase inhibitors, FGF1 receptor agonists, fibroblast activationprotein, fibroblast activation protein (FAP) inhibitor, fibroblast growth factor receptor ligand (e.g., FGF-15, FGF-19, FGF-21), fish oil, galectin-3 inhibitor, glucagon receptor agonist, glucagon-like peptide 1 receptor agonist, glucocorticoid receptor antagonist, glucose 6-phosphate 1-dehydrogenase inhibitor, glutaminase inhibitor, glutathione precursor, G protein-coupled bile acid receptor 1 agonist, G protein-coupled receptor 84 antagonist, Hedgehog (Hh) modulator, hepatitis C virus NS3 protease inhibitor, hepatocyte nuclear factor 4 alpha modulator (HNF4A), hepatocyte growth factor modulator, histone deacetylase inhibitor, HMG CoA reductase inhibitor, 11β-hydroxysteroid dehydrogenase (11β-HSD1) inhibitor, hypoxia-inducible factor-2 alpha inhibitor, IL-1β antagonist, IL-6 receptor agonist, IL-10 agonist, IL-11 antagonist, IL-17 antagonist, ileal sodium bile acid cotransporter inhibitor, insulin sensitizer, insulin ligand agonist, insulin receptor agonist, integrin modulator, integrin antagonist interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, Jak2 tyrosine kinase inhibitor, ketohexokinase (KHK) inhibitor, Klotho beta stimulator, leptin, leptin analog, 5-lipoxygenase inhibitor, lipoprotein lipase inhibitor, liver X receptor, LPL gene stimulator, lysophosphatidate-1 receptor (LPAR-1) antagonist, lysyl oxidase homolog 2 (LOXL2) inhibitor, LXR inverse agonist, macrophage mannose receptor 1 modulator, matrix metalloproteinase (Matrixmetalloproteinase, MMP) inhibitor, MCH receptor-1 antagonist, MEKK-5 protein kinase inhibitor, membrane copper amine oxidase (VAP-1) inhibitor, methionine aminopeptidase-2 inhibitor, methyl CpG binding protein 2 modulator, MicroRNA-132 (miR-132) antagonist, MicroRNA-21 (miR-21) inhibitor, mitochondrial uncoupler, mixed lineage kinase-3 inhibitor, myelin basic protein stimulator, NACHT LRR PYD domain protein 3 (NACHT LRR PYD domain protein 3, NLRP3) inhibitor, NAD-dependent deacetylase sirtuin-1 stimulator, NADPH oxidase inhibitor (NADPH oxidase, NOX), nicotinic acid receptor 1 agonist, P2X7 purinergic receptor modulator, P2Y13 purinergic receptor stimulator, PDE 3 inhibitor, PDE 4 inhibitor, PDE 5 inhibitor, PDGF receptor beta modulator, peptidylprolyl cis-trans isomerase A inhibitor, phenylalanine hydroxylase stimulator, phospholipase C inhibitor, PPAR alpha agonist, PPAR gamma agonist, PPAR delta agonist, PPAR gamma modulator, PPAR alpha / delta agonist, PPAR alpha / gamma / delta agonist, protease-activated receptor 2 antagonist, protein kinase modulator, Rho-associated protein kinase 2 (ROCK2) inhibitor, S-nitrosoglutathione reductase (Snitrosoglutathione reductase, GSNOR) enzyme inhibitor, sodium glucose transporter-2 (sodium glucose transporter-2, SGLT2) inhibitor, SREBP transcription factor inhibitor, STAT-1 inhibitor, STAT-3 modulator, stearoyl-CoA desaturase-1 inhibitor, S-nitrosoglutathione reductase (GSNOR) enzyme inhibitor, suppressor of cytokine signaling-1 stimulator, suppressor of cytokine signaling-3 stimulator, spleen tyrosine kinase (Spleen tyorosine kinase, SYK) inhibitor, transforming growth factor beta (Transforming growth factorselected from β, TGF-β), TGF-β antagonists (e.g., TGF-β1 antagonist, TGF-β2 antagonist, TGF-β3 antagonist, latent TGF β complex modulator), TGF-β receptor antagonist, transforming growth factor β activated Kinase 1 (TAK1), thyroid hormone receptor beta agonist, Toll-like receptor (TLR)-4 antagonist, transglutaminase inhibitor, Tumor necrosis factor alpha (TNFα) ligand inhibitor, Tumor Progression Locus 2 (Tpl2) kinase inhibitor, tyrosine kinase receptor modulator, GPCR modulator, nuclear hormone receptor modulator, WNT modulator, YAP / TAZ modulator, and zonulin inhibitor.

[0155] Non-limiting examples of one or more additional therapeutic agents include the following. ACE inhibitors such as enalapril; acetyl-CoA carboxylase (ACC) inhibitors such as NDI-010976 (filsocostat), DRM-01, gemcabene, PF-05175157, QLT-091382 or PF-05221304; acetyl-CoA carboxylase / diacylglycerol O-acyltransferase 2 inhibitors such as PF-07055341; aldehyde dehydrogenase inhibitors such as ADX-629; adenosine receptor agonists such as CF-102 (namodenoson), CF-101, CF-502, or CGS21680; adiponectin receptor agonists such as ADP-355 or ADP-399; amylin / calcitonin receptor agonists such as KBP-042 or KBP-089; AMP-activated protein kinase stimulators such as PXL-770 or O-304; AMP kinase activators / ATP citrate lyase inhibitors such as bempedoic acid (ETC-1002, ESP-55016); AMP-activated protein kinase / endothelial nitric oxide synthase / NAD-dependent deacetylase sirtuin-1 stimulators such as NS-0200 (leucine + metformin + sildenafil); Androgen receptor agonists such as LPCN-1144; Angiotensin II AT-1 receptor antagonists such as irbesartan; Angiopoietin-related protein-3 inhibitors such as IONIS-ANGPTL3-LRx; Autotaxin inhibitors such as PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, AM-063, or BBT-877; Axl tyrosine kinase receptor inhibitors such as bemcentinib (BGB-324, R-428); Bax protein stimulators such as CBL-514; Bioactive lipids such as DS-102; Type 1 cannabinoid receptor (CNR1) inhibitors such as namasizumab, GWP-42004, REV-200, or CRB-4001; Caspase inhibitors such as emricasan; Cathepsin B inhibitors such as VBY-376; Cathepsin inhibitors such as VBY-825; CCR2 / CCR5 chemokine antagonists such as cenicriviroc, maraviroc, CCX-872, or WXSH-0213; CCR2 chemokine antagonists such as propargermanium; CCR2 chemokine / angiotensin II AT-1 receptor antagonists such as DMX-200 or DMX-250; CCR2 / CCR5 chemokine antagonists and FXR agonists such as LJC-242 (tropifexor + cenicriviroc); CCR3 chemokine antagonists such as belchlimab; Chloride channel stimulants such as cobiprostone or lubiprostone; CD3 antagonists such as NI-0401 (folalumab); CXCR4 chemokine antagonists such as AD-214; Diacylglycerol acyltransferase 1 (DGAT1) inhibitors such as GSK-3008356; Diacylglycerol O-acyltransferase 1 (DGAT1) / cytochrome P450 2E1 (CYP2E1) inhibitors such as SNP-610, Diacylglycerol acyltransferase 2 (DGAT2) inhibitors such as IONIS-DGAT2Rx or PF-06865571; Dipeptidyl peptidase IV inhibitors such as linagliptin or evogliptin; Eotaxin ligand inhibitors such as belimumab or CM-101; Extracellular matrix protein modulators such as CNX-024; Farnesoid X receptor (FXR) agonists such as AGN-242266, AGN-242256, EP-024297, RDX-023, BWL-200, AKN-083, EDP-305, GNF-5120, GS-9674, LMB-763, obeticholic acid, Px-102, Px-103, M790, M780, M450, M-480, MET-409, PX20606, EYP-001, TERN-101, TC-100, INT-2228; Farnesoid X receptor (FXR) / G protein-coupled bile acid receptor 1 (TGR5) agonists such as INT-767, Fatty acid synthase inhibitors such as TVB-2640; FGF receptor agonists / Klotho beta stimulants such as BFKB-8488A (RG-7992); Fibroblast growth factor 19 (rhFGF19) / cytochrome P450 (CYP) 7A1 inhibitors such as NGM-282; Fibroblast growth factor 21 (FGF-21) ligands such as BMS-986171, BIO89-100, B-1344, or BMS-986036; Fibroblast growth factor 21 (FGF-21) / glucagon like peptide 1 (GLP-1) agonists such as YH-25723 (YH-25724, YH-22241) or AKR-001; Fish oil compositions such as ethyl eicosapentaenoate (Vascepa (registered trademark)); Galectin-3 inhibitors such as GR-MD-02, GB-1107 (Gal-300), or GB1211 (Gal-400); Glucagon-like peptide 1 receptor (GLP1R) agonists such as AC-3174, liraglutide, cotadutide (MEDI-0382), exenatide, SAR-425899, LY-3305677, HM-15211, YH-25723, YH-GLP1, RPC-8844, PB-718, or semaglutide; Glucocorticoid receptor antagonists such as CORT-118335 (milicortilant); Glucose 6-phosphate 1-dehydrogenase inhibitors such as ST001; G protein-coupled bile acid receptor 1 (TGR5) agonists such as RDX-009 or INT-777; Heat shock protein 47 (HSP47) inhibitors such as ND-L02-s0201; HMG CoA reductase inhibitors such as atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin; Hypoxia-inducible factor-2 alpha inhibitors such as PT-2567; IL-10 agonists such as peg-ilodecakin; Ileal sodium-bile acid cotransporter inhibitors such as odesivixibat (A-4250), polyxibat potassium ethanol adduct hydrate (SHP-262), GSK2330672, CJ-14199, or elobixibat (A-3309); Insulin sensitizers such as KBP-042, MSDC-0602K, MSDC-5514, Px-102, RG-125 (AZD4076), VVP-100X, CB-4211, or ETI-101; Insulin ligand / ds insulin receptor agonists such as ORMD-0801; Integrin antagonists such as IDL-2965; IL-6 receptor agonists such as KM-2702; Ketohexokinase (KHK) inhibitors such as PF-06835919; Beta Klotho (KLB)-FGF1c agonists such as MK-3655 (NGM-313); 5-Lipoxygenase inhibitors such as tepelcast (MN-001), DS-102 (AF-102); Lipoprotein lipase inhibitors such as CAT-2003; LPL gene stimulants such as alipogene tiparvovec; Liver X receptor (LXR) modulators such as PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, or SR-9238; Lysophosphatidic acid-1 receptor antagonists such as BMT-053011, UD-009 (CP-2090), AR-479, ITMN-10534, BMS-986020, or KI-16198; Lysyl oxidase homolog 2 inhibitors such as simtuzumab or PXS-5382A (PXS-5338); Macrophage mannose receptor 1 modulators such as tilmanocept-Cy3 (technetium Tc 99m tilmanocept); Membrane copper amine oxidase (VAP-1) inhibitors such as TERN-201; Inhibitors of MEKK-5 protein kinase (ASK-1), such as GS-4997, SRT-015, or GS-444217, GST-HG-151; MCH receptor-1 antagonists, such as CSTI-100 (ALB-127158); Methionine aminopeptidase-2 inhibitors, such as ZGN-839, ZGN-839, or ZN-1345; Methyl CpG-binding protein 2 modulators, such as mercaptamine; Mitochondrial uncoupling agents, such as 2,4-dinitrophenol or HU6; Mixed lineage kinase-3 inhibitors, such as URMC-099-C; Myelin basic protein stimulants, such as olesoxime; NADPH oxidase 1 / 4 inhibitors, such as GKT-831 or APX-311; Nicotinic acid receptor 1 agonists, such as ARI-3037MO; Nitazoxinide; NACHT LRR PYD domain-containing protein 3 (NLRP3) inhibitors, such as KDDF-201406-03, NBC-6, IFM-514, or JT-194 (JT-349); Nuclear receptor modulators, such as DUR-928 (DV-928); P2X7 purinergic receptor modulators, such as SGM-1019; P2Y13 purinergic receptor stimulants, such as CER-209; PDE 3 / 4 inhibitors, such as tipepidast (MN-001); PDE 5 inhibitors, such as sildenafil or MSTM-102; PDGF receptor β modulators, such as BOT-191 or BOT-509; Peptidyl-prolyl cis-trans isomerase inhibitors, such as CRV-431 (CPI-432-32), NVP-018, or NV-556 (NVP-025); Phenylalanine hydroxylase stimulants, such as HepaStem; PPAR agonists such as elafibranor (GFT-505), MBX-8025, deuterated pioglitazone R-enantiomer, pioglitazone, DRX-065, saroglitazar, or IVA-337 (including PPAR alpha agonists, PPAR alpha / delta agonists, PPAR alpha / delta / gamma agonists, PPAR delta agonists); clofibrate aluminum, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, pemafibrate, ronifibrate, simfibrate, omega-3 fatty acids (fish oil, e.g., eicosapentaenoic acid ethyl (Vascepa (registered trademark)), or docosahexaenoic acid), pyritinic acid, GW409544, AZ 242, LY518674, NS-220, AVE8134, BMS-711939, aleglitazar, muraglitzar, or saroglitazar, etc., PPAR alpha agonists; PPAR alpha / delta agonists such as elafibranor; PPAR alpha / delta / gamma agonists such as ranifibranor; PPAR delta agonists such as ceradelpar; Protease-activated receptor-2 antagonists such as PZ-235; Protein kinase modulators such as CNX-014; Rho-associated protein kinase (ROCK) inhibitors such as REDX-10178 (REDX-10325) or KD-025; Semicarbazide-sensitive amine oxidase / vascular adhesion protein-1 (SSAO / VAP-1) inhibitors such as PXS-4728A; S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors such as SL-891; Sodium glucose transporter-2 (SGLT2) inhibitors such as ipragliflozin, remogliflozin etabonate, ertugliflozin, dapagliflozin, tofogliflozin, or sotagliflozin, SREBP transcription factor inhibitors such as CAT-2003 or MDV-4463; Stearoyl-CoA desaturase-1 inhibitors such as alamethicol; Thyroid hormone receptor (THR) beta agonists such as resmetrio (MGL-3196), MGL-3745, or VK-2809; TLR-2 / TLR-4 antagonists such as VB-201 (CI-201); TLR-4 antagonists, for example, JKB-121; Tyrosine kinase receptor modulators such as CNX-025 or GFE-2137 (repurposed nitazoxanide); GPCR modulators, for example, CNX-023; Nuclear hormone receptor modulators such as Px-102; Xanthine oxidase / urate anion exchanger 1 (URAT1) inhibitors such as RLBN-1001, RLBN-1127; and Zonulin inhibitors such as lorazotide acetate (INN-202) may be mentioned.

[0156] Additional non-limiting examples of one or more additional therapeutic agents include the following. ACE inhibitors such as benazepril, imidapril, Adenosine A3 receptor antagonists such as FM-101, Adropin stimulants such as RBT-2, Albumin modulators such as SYNT-002, Adenosine / mineralocorticoid receptor antagonists such as MT-3995, Allogeneic bone marrow-derived mesenchymal stromal cell therapies such as ORBCEL-M, Allogeneic expanded adipose-derived stem cell therapies such as Elixcyte (trademark), AMP-activated protein kinase stimulators / precursor protein convertase PC9 inhibitors such as O-304, AMP-activated protein kinase stimulators such as DZCY-01, MK-8722, PXL-770; Angiotensin II AT-1 receptor / CCR2 chemokine antagonists such as DMX-200, Angiotensin II AT-2 receptor antagonists such as MOR-107, irbesartan, Angiotensin II receptor antagonists such as losartan, Angiotensinogen ligand inhibitors such as ALN-AGT, Anti-C1 antibodies such as BIVV-009 (stimuvumab), Anti-CB1 antibodies, e.g., GFB-024; Anti-CX3CR1 nanobodies such as BI-655088, Anti-IL-6 antibodies, e.g., COR-001; Anti-VEGF-B antibodies such as CSL-346, APOA1 gene stimulators / bromodomain-containing protein 2 / bromodomain-containing protein 4 inhibitors such as apabetalone, Bone morphogenetic protein-7 ligand modulators such as BMP-7, Calcium channel inhibitors such as TBN (xiatongqin), Cannabinoid CB1 receptor antagonists such as JNJ-2463, CB1 inverse agonists such as CRB-4001, Chymase inhibitors such as flasimirstat (BAY-1142524), Cyclooxygenase 1 inhibitors such as GLY-230, Cyclooxygenase 2 / epoxide hydrolase inhibitors such as COX-2 / soluble epoxide hydrolase, Cytochrome P450 11B2 inhibitors such as aldosterone synthase inhibitors, Ectonucleotide pyrophosphatase-PDE-2 inhibitors such as BLD-0409, Endothelin ET-A / endothelin ET-B receptor antagonists such as aprositentan, Enteropeptidase inhibitors such as SCO-792, Erythropoietin receptor antagonists such as EPO-018B, Farnesoid X receptor agonists such as LMB-763, FGF / PDGF / beta receptor antagonists / p38 MAP kinase inhibitors such as pirfenidone, GHR / IGF1 gene inhibitors such as atesidorsen sodium, GPR40 antagonists / GPR84 antagonists such as PBI-4050, G protein beta subunit inhibitors such as gallon, G protein-coupled receptor 84 modulators such as PBI-4425, Growth hormone ligand / growth hormone receptor agonists such as Jintropin AQ (trademark), Growth hormone receptor agonists such as LAT-8881, Guanylate cyclase receptor agonists / guanylate cyclase stimulators such as praliciguat, Guanylate cyclase stimulators such as MRL-001, lanciguat, Heme oxygenase 1 modulators such as RBT-1, HIF prolyl hydroxylase inhibitors such as TRGX-154, Insulin sensitizers / kallikrein 1 modulators such as DM-199, Integrin alpha-V / beta-3 antagonists such as VPI-2690B, Interleukin 33 ligand inhibitors such as MEDI-3506, Kelch-like ECH-associated protein 1 modulators / nuclear erythroid 2-related factor 2 stimulators such as SFX-01, LDHA gene inhibitors such as nedoceran, 5-lipoxygenase activating protein inhibitors such as AZD-5718, lysophosphatidic acid-1 receptor antagonists such as BMS-002, EPGN-696, matrix extracellular phosphoglycoprotein modulators / phosphatonin receptor agonists such as TPX-200, MEKK-5 protein kinase inhibitors such as seronceltib, membrane copper amine oxidase inhibitors such as UD-014, midkine ligand inhibitors such as CAB-101, mineralocorticoid receptor antagonists such as AZD-9977, esaxerenone, finerenone, KBP-5074, myosin 2 inhibitors such as DeciMab (trademark), NADPH oxidase 1 inhibitors / NADPH oxidase 4 inhibitors such as setanaxib, NADPH oxidase inhibitors such as APX-115, NK1 receptor antagonists / opioid receptor kappa agonists / opioid receptor mu antagonists such as AV-104, nuclear erythroid 2-related factor 2 stimulants / TGF beta ligand inhibitors such as CU01-1001, nuclear factor kappa B inhibitors such as mefenidone, bardoxolone methyl (NSC-713200), PDE 4 inhibitors such as ART-648, PCS-499, PDGF receptor beta modulators such as BOT-191, PDGF / VEGF receptor antagonists such as ANG-3070, PR84 antagonists / GPR40 (FFAR1) / GPR120 (FFAR4) agonists / and partial activators of peroxisome proliferator-activated receptor (PPAR) such as PBI-4547, PRKAA2 gene stimulants / AMPK activators such as PF-06679142, PF-06685249, Prostacyclin (PGI2) agonists such as YS-1402, Protein C activators / glycoprotein Ib (GPIb) antagonists such as AB-002, Protein NOV homolog modulators such as BLR-200, Protein tyrosine phosphatase-1B inhibitors such as MSI-1436, Reactive oxygen species modulator inhibitors such as SUL-121, Renin inhibitors such as imalixiren hydrochloride, Rho-associated protein kinase 2 inhibitors such as ANG-4201, RXC-007, Sodium glucose transporter-2 inhibitors such as canagliflozin, dapagliflozin propanediol, empagliflozin, Thromboxane A2 receptor antagonists / thromboxane synthesis inhibitors such as SER-150, Tissue transglutaminase inhibitors such as ZED-1227, TRP cation channel C5 inhibitors such as GFB-887, TRP cation channel C6 inhibitors such as ALGX-2224, Cell adhesion molecule inhibitors such as glycoside bacterial adhesin antagonists, Urate anion exchanger 1 (URAT1) / SLC22A12 inhibitors such as belinurad (RDEA3170), VIP1 / VIP2 receptor agonists such as LBT-3627, and Xanthine oxidase inhibitors such as TMX-049, TMX-049DN.

[0157] In some embodiments, one or more additional therapeutic agents are A-4250, AC-3174, acetylsalicylic acid, AK-20, alipogene tiparvovec, AMX-342, AN-3015, alamchol, ARI-3037MO, ASP-8232, AZD-2693, belimumab, anhydrous betaine, BI-1467335, BMS-986036, BMS-986171, BMT-053011, BOT-191, BTT-1023, CAT-2003, cenicriviroc, CBW-511, CER-209, CF-102, CGS21680, CNX-014, CNX-023, CNX-024, CNX-025, cobiprostone, 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, flurasterone (ST-002), FT-4101, GKT-831, GNF-5120, GRI-0621, GR-MD-02, GS-300, GS-4997, GS-9674, HTD-1801, HST-202, HST-201, hydrochlorothiazide,icosabutate (PRC-4016), ethyl ester of icosapent acid, IMM-124-E, INT-767, INV-240, IONIS-DGAT2Rx, ipragliflozin, irbesartan, propagermanium, IVA-337, JKB-121, KB-GE-001, KBP-042, KD-025, M790, M780, M450, metformin, sildenafil, LC-280126, linagliptin, liraglutide, LJN-452 (tropifexor), LM-011, LM-002 (CVI-LM-002), LMB-763, LYN-100, MBX-8025, MDV-4463, mercaptamine, MGL-3196, MGL-3745, MP-301, MSDC-0602K, namilumab, NC-101, NDI-010976, ND-L02-s0201 (BMS-986263), NGM-282, NGM-313, NGM-386, NGM-395, NP-160, norursodeoxycholic acid, NVP-022, O-304, obeticholic acid (OCA),Selected from 25HC3S, olesoxime, PAT-505, PAT-048, PBI-4547, peg-ilodecakin, pioglitazone, pirfenidone, PRI-724, PX20606, Px-102, PX-L603, PX-L493, PXS-4728A, PZ-235, RDX-009, lesmoglibose etabonate, RG-125 (AZD4076), RPI-500, saroglitazar, semaglutide, simtuzumab, solithromycin, sotagliflozin, statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), symbiotic agents, TCM-606F, TEV-45478, TQA-3526, tipepidust (MN-001), TLY-012, TRX-318, TVB-2640, UD-009, ursodeoxycholic acid, VBY-376, VBY-825, VK-2809, besimodegib, bolixibat potassium ethanol adduct hydrate (SHP-626), VVP-100X, WAV-301, WNT-974, XRx-117, ZGN-839, ZG-5216, ZSYM-008, ZYSM-007.

[0158] In some embodiments, the methods and pharmaceutical compositions provided herein comprise a therapeutically effective amount of an apoptosis signal-regulating kinase 1 (ASK1) inhibitor and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl) provided herein, or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the ASK1 inhibitor is GS-4997 (seroncel tib, SEL).

[0160] ASK1 inhibitors can be synthesized and identified using methods known to those skilled in the art, such as those described in US Patent Application Publication No. 2007 / 0276050, US Patent Application Publication No. 2011 / 0009410, and US Patent Application Publication No. 2013 / 0197037.

[0161] 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, and the LPAR1 antagonist is a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl) provided herein, or a pharmaceutically acceptable salt thereof.

[0162] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the ACC inhibitor is GS-0976 (firsocostat, FIR).

[0163] ACC inhibitors can be synthesized and identified using methods known to those skilled in the art, such as those described in US Patent No. 9,453,026 and US Patent No. 10,183,951.

[0164] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of a PPAR agonist (e.g., a PPAR alpha agonist, a PPAR alpha / delta agonist, a PPAR alpha / delta / gamma agonist, a PPAR delta agonist) or fish oil, a therapeutically effective amount of an acetyl-CoA carboxylase (ACC) inhibitor such as GS-0976 (firsocostat, FIR), and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl) provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the PPAR agonist is a PPAR alpha agonist. In some embodiments, the PPAR alpha agonist is selected from aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clofibride, fenofibrate, gemfibrozil, pemafibrate, lonafibrate, simfibrate, pirinixic acid, GW409544, AZ 242, LY518674, NS-220, AVE8134, BMS-711939, aleglitazar, muraglitazar, and saroglitazar. In some embodiments, the PPAR agonist (e.g., a PPAR alpha agonist) is a fibrate. In some embodiments, the PPAR agonist (e.g., a PPAR alpha agonist) is fenofibrate. In some embodiments, the PPAR agonist is a PPAR alpha / delta agonist (e.g., elafibranor). In some embodiments, the PPAR agonist is a PPAR alpha / delta / gamma agonist (e.g., lanifibranor). In some embodiments, the PPAR agonist is a PPAR delta agonist (e.g., seladelpar). In some embodiments, the fish oil is omega-3 fatty acid or docosahexaenoic acid. In some embodiments, the fish oil is eicosapentaenoic acid ethyl (e.g., Vascepa®).

[0165] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of a farnesoid X receptor (FXR) agonist and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl) provided herein, or a pharmaceutically acceptable salt thereof.

[0166] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the FXR agonist is GS-9674 (cilofexor, CILO).

[0167] In some embodiments of the methods and pharmaceutical compositions disclosed herein, the FXR agonist is a compound having the following structure,

Chemical formula

[0168] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of a GLP-1 receptor agonist and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl) provided herein, or a pharmaceutically acceptable salt of the compound. In some embodiments, the GLP-1 receptor agonist is liraglutide or semaglutide. In some embodiments, the GLP-1 receptor agonist is semaglutide.

[0169] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of a TGFβ antagonist and a therapeutically effective amount of an LPAR1 antagonist, wherein the LPAR1 antagonist is a compound of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl) provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the TGFβ antagonist is a TGFβ-specific antibody. The TGFβ-specific antibody can be prepared and characterized using methods known to those of skill in the art, such as those described in PCT International Publication No. WO 2018 / 129329 and U.S. Patent No. 9,518,112. In some embodiments, the TGFβ antagonist binds to a TGFβ latency-associated peptide (LAP), such as TGFβ1-LAP. The TGFβ1-LAP-specific antibody can be prepared and characterized using methods known to those of skill in the art, such as those described in U.S. Patent No. 8,198,412 or U.S. Patent No. 10,017,567. In some embodiments, the TGFβ antagonist binds to TGFβ (e.g., TGFβ1) in a context-dependent manner (e.g., independent of the presentation of TGFβ in a particular tissue or organ). In some embodiments, the TGFβ antagonist binds to TGFβ (e.g., TGFβ1) in a context-dependent manner. In some embodiments, the TGFβ antagonist blocks the activation of latent TGFβ (e.g., latent TGFβ1) localized in the extracellular matrix, such as the connective tissue of the liver. In some embodiments, the TGFβ antagonist blocks the activation of latent TGFβ (e.g., latent TGFβ1) localized in the thymus, lymph nodes, or tumor microenvironment (e.g., in a patient with liver cancer). In some embodiments, the TGFβ antagonist blocks the activation of latent TGFβ (e.g., latent TGFβ1) by a latent TGFβ binding protein (LTBP).In some embodiments, the TGFβ antagonist blocks the activation of latent TGFβ (e.g., latent TGFβ1) by Glycoprotein-A Repetitions Predominant protein (GARP), as described, for example, in U.S. Patent No. 10,000,572. In some embodiments, the TGFβ antagonist is ARGX-115. In some embodiments, the TGFβ antagonist is an anti-latency-associated peptide (LAP) antibody that specifically binds to the LAP-TGFβ complex. In some embodiments, the anti-LAP antibody specifically binds to the LAP-TGFβ complex in the extracellular matrix (ECM) of connective tissue in the liver, for example. In some embodiments, the anti-LAP antibody specifically binds to the LAP-TGFβ complex on the surface of certain immunosuppressive cell types, such as regulatory T cells (Tregs), tumor-associated macrophages, or myeloid-derived suppressor cells, in the tumor microenvironment, for example. In some embodiments, the anti-LAP antibody is the TLS-01 antibody. In some embodiments, the anti-LAP antibody specifically binds to the LAP-TGFβ complex in any context. In some embodiments, the anti-LAP antibody is the TLS-02 antibody. In some embodiments, the TGFβ antagonist comprises a TGFβ receptor. In some embodiments, the TGFβ antagonist is a TGFβ receptor-Fc fusion protein. In some embodiments, the TGFβ antagonist is an antibody comprising a TGFβ receptor. TGFβ antagonists comprising a TGFβ receptor that may be useful in connection with the compositions and methods provided herein are described, for example, in PCT International Publication Nos. 2019 / 113123 (A1) and 2019 / 113464 (A1).

[0170] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of an LPAR1 antagonist and an ACE inhibitor, an adenosine A3 receptor antagonist, an adiponectin stimulator, an albumin modulator, an aldosterone antagonist, an AMP-activated protein kinase stimulator, an angiotensin II AT-2 receptor agonist, an angiotensin II receptor antagonist, an angiotensinogen ligand inhibitor, an APOA1 gene stimulator, an apolipoprotein L1 modulator, a bone morphogenetic protein-7 ligand modulator, a bromodomain-containing protein 2 inhibitor, a bromodomain-containing protein 4 inhibitor, a calcium channel inhibitor, a cannabinoid CB1 receptor antagonist, a CB1 inverse agonist, a CCR2 chemokine antagonist, a chymase inhibitor, a complement C1s subcomponent inhibitor, a CX3CR1 chemokine antagonist, a cyclooxygenase 1 inhibitor, a cyclooxygenase 2 inhibitor, a cytochrome P45011B2 inhibitor, ectonucleotide pyrophosphatase - PDE - 2 inhibitor, endothelin ET - A receptor antagonist, endothelin ET - B receptor antagonist, enteropeptidase inhibitor, epoxide hydrolase inhibitor, erythropoietin receptor antagonist, farnesoid X receptor agonist, FGF receptor antagonist, free fatty acid receptor 1 agonist, GHR gene inhibitor, glycoprotein Ib (GPIb) antagonist, GPR40 agonist, GPR84 antagonist, G protein beta subunit inhibitor, G protein - coupled receptor 120 agonist, G protein - coupled receptor 84 modulator, growth hormone ligand, growth hormone receptor agonist, guanylate cyclase receptor agonist, guanylate cyclase stimulator, heme oxygenase 1 modulator, HIF prolyl hydroxylase inhibitor, IGF1 gene inhibitor, IgG receptor FcRn large subunit p51 modulator, IL - 6 receptor antagonist, integrin alpha - V / beta - 3 antagonist, interleukin 33 ligand inhibitor, Kelch - like ECH - associated protein 1 modulator, LDHA gene inhibitor, 5 - lipoxygenase activating protein inhibitor, lysophosphatidic acid - 1 receptor antagonist, matrix extracellular phosphoglycoprotein modulator, membrane copper amine oxidase inhibitor, midkine ligand inhibitor, mineralocorticoid receptor antagonist, myosin 2 inhibitor, NADPH oxidase 1 inhibitor, NADPH oxidase 4 inhibitor, NADPH oxidase inhibitor, NK1 receptor antagonist, nuclear erythroid 2 - related factor 2 stimulator, nuclear factor kappa B inhibitor, opioid receptor kappa agonist, opioid receptor mu antagonist p38A therapeutically effective amount of an additional therapeutic agent selected from a MAP kinase inhibitor, a PDE4 inhibitor, a PDGF receptor antagonist, a PDGF receptor beta modulator, a phosphatonin receptor agonist, a PRKAA2 gene stimulator, a proprotein convertase PC9 inhibitor, a prostacyclin (PGI2) agonist, a protein C activator, a protein NOV homolog modulator, a protein tyrosine phosphatase-1B inhibitor, a reactive oxygen species modulator inhibitor, a renin inhibitor, a Rho-associated protein kinase 2 inhibitor, an SLC22A12 inhibitor, a sodium glucose transporter-2 inhibitor, a solute carrier family inhibitor, a TGF beta ligand inhibitor, a TGF beta receptor antagonist, a thromboxane A2 receptor antagonist, a thromboxane synthase inhibitor, a tissue transglutaminase inhibitor, a TRP cation channel C5 inhibitor, a TRP cation channel C6 inhibitor, a tryptophanase inhibitor, an unspecified cell adhesion molecule inhibitor, a urate anion exchanger 1 inhibitor, a vasopressin V1a receptor antagonist, a VEGF receptor antagonist, a VIP1 receptor agonist, a VIP2 receptor agonist, and a xanthine oxidase inhibitor.

[0171] In some embodiments, the methods and compositions provided herein comprise a therapeutically effective amount of an LPAR1 antagonist and a therapeutically effective amount of an additional therapeutic agent selected from a VEGFR inhibitor, an FGFR inhibitor, a PDGFR inhibitor, an autotaxin inhibitor, a GPR84 agonist, a PASK inhibitor, a CFTR agonist, a JAK1 inhibitor, an ADAMTS5 inhibitor, a TOL2 / 3 inhibitor, a CTGF inhibitor, soluble PTX2, an anti-galectin-3 antibody, an integrin-α V -β6 / α V -β1 antagonist, a JNK1 inhibitor, a mineralocorticoid receptor antagonist, an Nrf2 activator, a kinase inhibitor, a PDE inhibitor, a NOX1 / 4 inhibitor, a leukotriene / thromboxane receptor antagonist, an SLC22A12 inhibitor, an sGC inhibitor, and a xanthine oxidase inhibitor.

[0172] In some embodiments, the methods and compositions provided herein include a therapeutically effective amount of an LPAR1 antagonist and a therapeutically effective amount of an additional therapeutic agent selected from nintedanib, pirfenidone, pembrolizumab, PRM-151, GB-0139, PLN-74809, CC-90001, finerenone, BAY1142524, PCS-499, cetinaxib, SER150, RDEA3170, praliciguat, TMX-049, GLPG1690, GLPG1205, GLPG1972, GLPG4059, GLPG2737, GLPG3970, and filgotinib.

[0173] In some embodiments, the methods and compositions provided herein include a therapeutically effective amount of an LPAR1 antagonist and a therapeutically effective amount of an additional therapeutic agent selected from A-717, ACF-TEI, alanyl-glutamine, ALLN-346, anti-SCF248 antibody, anti-TAGE monoclonal antibody, anti-TGF beta antibody, AST-120, BAY-2327949, BI-685509, DP-001, DZ-4001, GDT-01, LNP-1892, MEDI-8367, microRNA target antisense oligonucleotide therapy, MK-2060, MPC-300-IV, NAV-003, Neo-Kidney Augment (NKA), NP-135, NP-160, NP-251, NRF-803, PBI-4610, PHN-033, R-HSC-010, salvianolic acid, SGF-3, SPD-01, Sugaheal variant, SZ-005, TCF-12, UMC119-06, VAR-400, bevelimer, VS-105, and XRx-221.

Example

[0174] The following examples are included to demonstrate specific embodiments of the present disclosure. It should be understood by those skilled in the art that the techniques disclosed in the following examples represent techniques that will function well in the practice of the present disclosure and, accordingly, can be considered to constitute specific modes for its practice. However, those skilled in the art should understand that, in light of the present disclosure, these examples are illustrative and not exhaustive. Without departing from the spirit and scope of the present disclosure, many modifications can be made in the specific embodiments that are disclosed and still obtain similar or like results.

[0175] The compounds disclosed herein can be prepared using suitable materials according to the procedures of the following schemes and examples, and are further illustrated by the following specific examples. Additionally, by using the procedures described herein in conjunction with a person of ordinary skill in the art, additional compounds of the present disclosure claimed herein can be readily prepared. The examples further illustrate the details of the preparation of the compounds of the present disclosure. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparation procedures can be used to prepare these compounds. To synthesize the compounds that are embodiments described in the present disclosure, examination of the structure of the compound being synthesized provides the identity of each substituent. In some cases, the identity of the final product can be clarified by the examination process of the identity of the required starting materials, considering the examples herein. The compounds can be isolated in the form of their pharmaceutically acceptable salts, such as those described above. The compounds described herein are typically stable and isolable at room temperature and pressure.

[0176] Examples of the preparation of the compounds disclosed in this specification are shown below. Unless otherwise indicated, the variables have the same meaning as above. The examples presented below are intended to illustrate specific embodiments of the present disclosure. Suitable starting materials, building blocks, and reagents used in the syntheses as described below are commercially available, for example, from AbovChem, Acros Organics, Astatech, Combi Blocks, Oakwood Chemical, or Sigma-Aldrich, or can be routinely prepared by procedures described in the literature, for example, "March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 5 th Edition; John Wiley & Sons or T. Eicher, S. Hauptmann "The Chemistry of Heterocycles; Structures, Reactions, Synthesis and Application", 2 nd edition, Wiley-VCH 2003; Fieser et al. "Fiesers’ Reagents for organic Synthesis" John Wiley & Sons 2000. General Scheme [Chemical formula]

[0177] Scheme A provides the general synthesis of aryl or heteroaryl pyrazole carbamate (V). In the schemes disclosed herein, "A" can be a halogen such as Cl, Br, or I. "B" can be a halogen or a boronic acid ester. "W" can be hydrogen, or an alkyl group (e.g., methyl, ethyl, or tert-butyl).

[0178] Process 1 describes the general synthesis of aryl or heteroaryl pyrazole carboxylic acids or esters (III) via cross-coupling reactions. The halogenated aryl or heteroaryl (I) is first converted to the corresponding boronic acid ester such as pinacol boronate via Miyaura borylation, and then subjected to Suzuki reaction conditions using bromopyrazole carboxylic acid or ester (II) to obtain the desired aryl or heteroaryl pyrazole carboxylic acid or ester (III). Alternatively, the bromopyrazole carboxylic acid or ester (II) can first be converted to a boronic acid ester via Miyaura borylation and then reacted with the halogenated aryl or heteroaryl (I) via Suzuki cross-coupling to provide the desired aryl or heteroaryl pyrazole carboxylic acid or ester (III). Alternatively, the bromopyrazole carboxylic acid or ester (II) can first be converted to an organozinc species via lithium-halogen exchange and trapping with zinc chloride. Next, the desired aryl or heteroaryl pyrazole carboxylic acid or ester (III) is obtained by Negishi cross-coupling with the halogenated aryl or heteroaryl (I).

[0179] Process 2 describes the general synthesis of pyrazole carbamate aryl and heteroaryl carboxyamides (V). The aryl or heteroaryl pyrazole carboxylic acid (III) undergoes a Curtius rearrangement when treated with diphenylphosphoryl azide (DPPA) or alternatively when treated with a solution of 1-propanephosphonic anhydride (T3P) and azidotrimethylsilane. The intermediate isocyanate is then trapped with an alcohol (IV) to obtain the desired aryl or heteroaryl pyrazole carbamate (V).

[0180] R 1When it is a protected functional group such as a tert-butyl ester or a tert-butyl carbamate, Step 3 describes a method of further functionalizing the product V by first deprotecting it with an acid such as hydrogen chloride (HCl) to obtain an aryl or heteroaryl pyrazole carbamate amine hydrochloride (VI) or an aryl or heteroaryl pyrazole carboxylic acid (VII).

[0181] Step 4 describes the general synthesis of pyrazole carbamate aryl and heteroaryl amides (VI). The pyrazole carbamate amine (VI) can be treated with an acid chloride or with a carboxylic acid using standard peptide coupling conditions such as the use of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) to obtain the corresponding amide (VIII). Alternatively, the pyrazole carbamate acid (VII) can be treated with an amine using standard peptide coupling conditions such as the use of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) to obtain the corresponding amide (IX).

Chemical formula

[0182] Scheme B provides an alternative general synthesis of aryl or heteroaryl pyrazole carbamate (V). Step 1 describes the general synthesis of pyrazole carbamate (X). The pyrazole carboxylic acid (IV) undergoes a Curtius rearrangement when treated with diphenylphosphoryl azide (DPPA) or alternatively with a solution of 1-propanephosphonic anhydride (T3P) and azidotrimethylsilane. The intermediate isocyanate is then trapped with an alcohol (IV) to provide the desired pyrazole carbamate (X).

[0183] Step 2 describes the general synthesis of aryl or heteroaryl pyrazole carbamate (V) via cross-coupling reactions. The halogenated aryl or heteroaryl (I) is first converted to the corresponding boronic acid ester such as pinacol boronic acid via Miyaura borylation, and then subjected to Suzuki reaction conditions using bromopyrazole carbamate (X) to obtain the desired aryl or heteroaryl pyrazole carbamate (V). Alternatively, bromopyrazole carbamate (X) can first be converted to a boronic acid ester via Miyaura borylation and then reacted with the halogenated aryl or heteroaryl (I) via Suzuki cross-coupling to provide the desired aryl or heteroaryl pyrazole carbamate (V). Alternatively, bromopyrazole carbamate (X) can first be converted to an organozinc species via lithium-halogen exchange and trapping with zinc chloride. Next, the desired aryl or heteroaryl pyrazole carbamate (V) is obtained by Negishi cross-coupling with the halogenated aryl or heteroaryl (I).

[0184] When R1 is a protected functional group such as tert-butyl ester or tert-butyl carbamate, the product V can be further functionalized as described in Steps 3-4 of Scheme A.

[0185] Example 1: Preparation of (R)-1-(2-chlorophenyl)ethyl (1-methyl-4-(4-(methylsulfonamido)phenyl)-1H-pyrazol-5-yl)carbamate (Compound 1)

Chem.

[0186] Step 2: (R)-1-(2-Chlorophenyl)ethyl (4-bromo-1-methyl-1H-pyrazol-5-yl)carbamate A mixture of [(1R)-1-(2-chlorophenyl)ethyl] N-(4-bromo-2-methyl-pyrazol-3-yl)carbamate (0.50 mmol), [4-(methanesulfonamido)phenyl]boronic acid (0.53 mmol), and tetrakis(triphenylphosphine)palladium(0) (38 μmol) in 1,4-dioxane (3 mL) and 2 M aqueous sodium carbonate solution (1.4 mmol) was heated in a microwave reactor at 125 °C for 75 min. The mixture was partitioned between water and aqueous citric acid solution. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed once with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by automated flash chromatography (silica gel) to afford the title compound. (MS (m / z) 449.1 [M+H]+). 1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.66 - 7.59 (m, 3H), 7.58 - 7.54 (m, 2H), 7.47 (m, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.3 Hz, 2H), 6.00 (d, J = 6.8 Hz, 1H), 3.61 (s, 3H), 2.97 (s, 3H), 1.55 (d, J = 6.6 Hz, 3H).

[0187] Example 2: Preparation of benzyl (1-methyl-4-(4-(methylsulfonamido)phenyl)-1H-pyrazol-5-yl)carbamate (Compound 2) [Chemistry] According to Example 1, Step 2, benzyl (4-bromo-1-methyl-1H-pyrazol-5-yl)carbamate was used instead of [(1R)-1-(2-chlorophenyl)ethyl] N-(4-bromo-2-methyl-pyrazol-3-yl)carbamate to prepare the title compound. (MS (m / z) 401.1 [M+H]+). 1H NMR (400 MHz, methanol-d4) δ 7.72 (s, 1H), 7.58 - 7.07 (m, 9H), 5.23 (d, J = 4.0 Hz, 2H), 3.74 (s, 3H), 2.96 (s, 3H).

[0188] Example 3: Preparation of (R)-2-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)-4-methylpyrimidin-5-ylmethanesulfonate (Compound 3) [Chemistry] Step 1: tert-Butyl 4-bromo-1-methyl-1H-pyrazole-5-carboxylate A mixture of 4-bromo-2-methyl-pyrazole-3-carboxylic acid (20 mmol) in toluene (200 mL) was heated on a 90 °C block, during which dimethylformamide di-tert-butyl acetal (100 mmol) was added via syringe. The mixture was heated at that temperature for 4 hours, cooled, and washed once each with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound. (MS (m / z) 260.8 [M+H]+).

[0189] Step 2: tert-Butyl 1-methyl-4-(4,4,5,5-tetramethyl-5,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate A mixture of tert-butyl 4-bromo-1-methyl-1H-pyrazole-5-carboxylate (35 mmol), potassium acetate (110 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (53 mmol) in 1,4-dioxane (120 mL) was degassed with argon for 15 minutes. A 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) complex (1.8 mmol) with dichloromethane was introduced, and after bubbling argon for an additional 10 minutes, the mixture was heated to 100 °C for 16 hours. After cooling, the mixture was partitioned between water and dichloromethane (each about 120 mL). The aqueous layer was extracted twice with dichloromethane (50 mL × 2). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound. (MS (m / z) 309.0 [M+H]+).

[0190] Step 3: tert-butyl 4-(5-bromo-4-methylpyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate A mixture of tert-butyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-3-carboxylate (4.1 mmol), 5-bromo-2-iodo-4-methyl-pyrimidine (4.9 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.41 mmol) in acetonitrile (8 mL) and aqueous sodium carbonate solution (2 M, 4.1 mL) was irradiated at 100 °C for 1 hour in an Anton Paar Monowave 450 reactor. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined organic extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by automated flash chromatography (silica gel) to afford the title compound. (MS (m / z) 352.8 [M+H]+).

[0191] Step 4: (2-(5-(tert-Butoxycarbonyl)-1-methyl-1H-pyrazol-4-yl)-4-methylpyrimidin-5-yl)boronic acid To a mixture of tert-butyl 4-(5-bromo-4-methylpyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.7 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane (2.6 mmol), and potassium acetate (5.1 mmol) in THF (8 mL) was added 1,1’-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.09 mmol). The reaction vessel was heated at 80 °C for 6 hours and then cooled. An additional amount of the following reagents was added: 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane (2.6 mmol), potassium acetate (5.1 mmol), and 1,1’-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.09 mmol). After heating for an additional 13 hours, the reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted 3 times with ethyl acetate. The combined organic extracts were washed once with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound. (MS (m / z) 318.9 [M+H]+).

[0192] Step 5: tert-Butyl 4-(5-hydroxy-4-methylpyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate A solution of (2-(5-(tert-Butoxycarbonyl)-1-methyl-1H-pyrazol-4-yl)-4-methylpyrimidin-5-yl)boronic acid (1.1 mmol) in ethyl acetate (20 mL) was added with hydrogen peroxide solution (30% aqueous solution, 2.4 mL, 21 mmol). After stirring at room temperature for 90 minutes, the reaction mixture was cooled to 0 °C and quenched by slowly adding a saturated aqueous sodium thiosulfate solution. Then, the layers were separated and the aqueous phase was extracted twice with ethyl acetate. The aqueous phase was acidified to pH 4 - 5 with 10% aqueous hydrochloric acid and extracted once again with ethyl acetate. The combined organic extracts were washed once with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound. (MS (m / z) 290.8 [M+H]+).

[0193] Step 6: tert-Butyl 1-methyl-4-(4-methyl-5-((methylsulfonyl)oxy)pyrimidin-2-yl)-1H-pyrazole-5-carboxylate A solution of tert-butyl 4-(5-hydroxy-4-methylpyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.1 mmol) in dichloromethane (20 mL) was sequentially treated with triethylamine (5.5 mmol) and methanesulfonyl chloride (2.2 mmol).

[0194] The mixture was quenched with isopropanol (about 3 mL) and stirred overnight. The mixture was concentrated under reduced pressure and purified by automated flash chromatography (silica gel) to afford the title compound. (MS (m / z) 368.8 [M+H]+).

[0195] Step 7: 1-Methyl-4-(4-methyl-5-((methylsulfonyl)oxy)pyrimidin-2-yl)-1H-pyrazole-5-carboxylic acid A solution of tert-butyl 1-methyl-4-(4-methyl-5-((methylsulfonyl)oxy)pyrimidin-2-yl)-1H-pyrazole-5-carboxylate (1.1 mmol) was dissolved in dichloromethane (3 mL) and treated with hydrogen chloride solution (4 N in dioxane, 3.0 mL, 12 mmol). After stirring overnight, the mixture was concentrated under reduced pressure to afford the title compound. (MS (m / z) 313.1 [M+H]+).

[0196] Step 8: (R)-2-(5-(((1-(2-Chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)-4-methylpyrimidin-5-yl methanesulfonate To a mixture of 1-methyl-4-(4-methyl-5-((methylsulfonyl)oxy)pyrimidin-2-yl)-1H-pyrazole-5-carboxylic acid (0.31 mmol) in THF (0.6 mL) were successively added azidotrimethylsilane (0.37 mmol), propanephosphonic anhydride solution (50% w / w in DMF, 0.37 mmol), and triethylamine (0.62 mmol). After 5 minutes, (1R)-1-(2-chloro-3-pyridyl)ethanol (0.62 mmol) was added and the mixture was heated at 75 °C for 60 minutes. The mixture was concentrated and purified by reverse phase HPLC to afford the title compound. (MS (m / z) 467.0 [M+H]+). 1H NMR (400 MHz, DMSO-d6) δ 9.67 (bs, 1H), 8.60 (s, 1H), 8.36 (m, 1H), 8.02 (partially obscured by singlet, bs, 1H), 8.01 (s, 1H), 7.51 (m, 1H), 5.91 (s, 1H), 3.70 (s, 3H), 3.59 (s, 3H), 2.42 (s, 3H), 1.52 (m, 3H).

[0197] Example 4: Preparation of (R)-1-(2-Chloropyridin-3-yl)ethyl (4-(5-hydroxy-4-methylpyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (Compound 4)

Chemical formula

[0198] Project 2: tert-Butyl 1-methyl-4-(4-methyl-5-((methylsulfonyl)oxy)pyrimidin-2-yl)-1H-pyrazole-5-carboxylate According to Example 3, Step 6, the title compound was prepared from tert-butyl 4-(5-hydroxy-4-methylpyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.0 mmol) and methanesulfonyl chloride (2.1 mmol). (MS (m / z) 368.8 [M+H]+).

[0199] Project 3: 1-Methyl-4-(4-methyl-5-((methylsulfonyl)oxy)pyrimidin-2-yl)-1H-pyrazole-5-carboxylic acid According to Example 3, Step 7, the title compound was prepared from tert-butyl 1-methyl-4-(4-methyl-5-((methylsulfonyl)oxy)pyrimidin-2-yl)-1H-pyrazole-5-carboxylate (1.0 mmol). (MS (m / z) 313.1 [M+H]+).

[0200] Project 4: (R)-2-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)-4-methylpyrimidin-5-yl methanesulfonate According to Example 3, Step 8, the title compound was prepared from 1-methyl-4-(4-methyl-5-((methylsulfonyl)oxy)pyrimidin-2-yl)-1H-pyrazole-5-carboxylic acid (0.26 mmol) and (R)-1-(2-chloropyridin-3-yl)ethan-1-ol (0.51 mmol). However, instead of subjecting the reaction mixture to reverse-phase HPLC, it was quenched with saturated aqueous sodium hydrogen carbonate and extracted three times with ethyl acetate. The combined organic extracts were washed once with saturated aqueous sodium chloride, dried over anhydrous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound. (MS (m / z) 467.0 [M+H]+).

[0201] Step 5: (R)-1-(2-Chloropyridin-3-yl)ethyl (4-(5-hydroxy-4-methylpyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (R)-2-(5-(((1-(2-Chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)-4-methylpyrimidin-5-yl methanesulfonate (presumed 0.26 mmol) was diluted with THF (3 mL), treated with aqueous lithium hydroxide solution (1 M, 1 mL), and stirred at room temperature overnight. The mixture was diluted with acetic acid (1 mL) and concentrated under reduced pressure, and then subjected to reverse-phase HPLC to provide the title compound. (MS (m / z) 389.0 [M+H]+). 1H NMR (400 MHz, DMSO-d6) δ 10.02 (bs, 1H), 9.48 (bs, 1H), 8.37 (bs, 1H), 8.09 (m, 1H), 7.86 (s, 1H), 7.54 (bs, 1H), 5.90 (bs, 1H), 3.66 (s, 3H), 2.26 (s, 3H), 1.56 (bs, 3H).

[0202] Example 5: Preparation of (R)-2-(5-(((1-(2-chloro-5-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)pyrimidin-5-yl ethanesulfonate (Compound 5)

Chemical Structure

[0203] Step 2: tert-Butyl 4-(5-((ethylsulfonyl)oxy)pyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate According to Step 6 of Example 3, the title compound was prepared from tert-butyl 4-(5-hydroxypyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (0.87 mmol) and ethanesulfonyl chloride (1.7 mmol). (MS (m / z) 368.8 [M+H]+).

[0204] Step 3: 4-(5-((ethylsulfonyl)oxy)pyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid According to Step 7 of Example 3, the title compound was prepared by reacting a solution of tert-butyl 4-(5-((ethylsulfonyl)oxy)pyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.1 mmol) in dichloromethane (3 mL) with a hydrogen chloride solution (4N in dioxane, 13 mmol). (MS (m / z) 313.1 [M+H]+).

[0205] Step 4: (R)-2-(5-(((1-(2-chloro-5-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)pyrimidin-5-yl ethanesulfonate According to Example 3, Step 8, the title compound was prepared from 4-(5-((ethylsulfonyl)oxy)pyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (0.45 mmol) and (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethan-1-ol (0.90 mmol). (MS (m / z) 485.1 [M+H]+). 1H NMR (400 MHz, DMSO-d6) δ 9.76 (bs, 1H), 8.73 (s, 2H), 8.44 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 5.84 (m, 1H), 3.71 (s, 3H), 3.70 - 3.64 (partially obscured by singlet, m, 2H), 1.70 - 1.45 (m, 3H), 1.41 (t, J = 7.3 Hz, 3H).

[0206] Example 6: Preparation of (R)-2-(5-(((1-(2-chloro-5-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)pyrimidin-5-ylmethanesulfonate (Compound 6)

Chemical formula

[0207] Step 2: 1-Methyl-4-(5-((methylsulfonyl)oxy)pyrimidin-2-yl)-1H-pyrazole-5-carboxylic acid According to Example 3, Step 7, the title compound was prepared from tert-butyl 1-methyl-4-(5-((methylsulfonyl)oxy)pyrimidin-2-yl)-1H-pyrazole-5-carboxylate (0.87 mmol). (MS (m / z) 299.0 [M+H]+).

[0208] Step 3: (R)-2-(5-(((1-(2-Chloro-5-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)pyrimidin-5-ylmethanesulfonate According to Step 8 of Example 3, the title compound was prepared from 1-methyl-4-(5-((methylsulfonyl)oxy)pyrimidin-2-yl)-1H-pyrazole-5-carboxylic acid (0.44 mmol) and (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethan-1-ol (0.87 mmol). (MS (m / z) 471.1 [M+H]+). 1H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.75 (s, 2H), 8.44 (s, 1H), 8.05 (s, 1H), 8.02 - 7.77 (m, 1H), 5.84 (m, 1H), 3.71 (s, 3H), 3.54 (s, 3H), 1.67 (m, 3H).

[0209] Example 7: Preparation of (R)-2-(5-(((1-(2-Fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)pyrimidin-5-ylcyclopropanesulfonate (Compound 7)

Chemical formula

[0210] Step 2: 4-(5-((Cyclopropylsulfonyl)oxy)pyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid According to Example 3, Step 7, the title compound was prepared from tert-butyl 4-(5-((cyclopropylsulfonyl)oxy)pyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.1 mmol). (MS (m / z) 325.1 [M+H]+).

[0211] Step 3: (R)-2-(5-(((1-(2-Fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)pyrimidin-5-yl cyclopropanesulfonate According to Example 3, Step 8, the title compound was prepared from 4-(5-((cyclopropylsulfonyl)oxy)pyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (0.25 mmol) and (R)-1-(2-fluoropyridin-3-yl)ethan-1-ol (0.50 mmol). (MS (m / z) 463.0 [M+H]+). 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.73 (s, 2H), 8.17 (s, 1H), 8.03 (s, 1H), 7.42 (s, 1H), 5.84 (d, J = 7.8 Hz, 1H), 3.69 (s, 3H), 3.22 (tt, J = 8.0, 4.7 Hz, 1H), 1.66 (m, 3H), 1.24 (m, 2H), 1.07 (m, 2H).

[0212] Example 8: Preparation of (R)-2-(5-(((1-(2-Fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)pyrimidin-5-yl methanesulfonate (Compound 8)

Chemical Structure

[0213] Example 9: Preparation of (R)-2-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)pyrimidin-5-ylmethanesulfonate (Compound 9)

Chemical formula

[0214] Example 10: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (4-(3-fluoro-5-hydroxypyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (Compound 10)

Chemical formula

[0215] Example 11: Preparation of (R)-6-(5-(((1-(2,5-Difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyridin-3-yl methanesulfonate (Compound 11)

Chemical Structure

[0216] Example 12: Preparation of (R)-6-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyridin-3-ylmethanesulfonate (Compound 12) [Chemical formula] Step 1: tert-Butyl 4-(3-fluoro-5-hydroxypyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate According to the conditions described in Step 3 of Example 3, the title compound was prepared from tert-butyl 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylate (7.8 mmol) and 6-chloro-5-fluoropyridin-3-ol (8.4 mmol). (MS (m / z) 293.8 [M+H]+).

[0217] Step 2: tert-Butyl 4-(3-fluoro-5-((methylsulfonyl)oxy)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate According to Step 6 of Example 3, the title compound was prepared from tert-butyl 4-(3-fluoro-5-hydroxypyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.2 mmol) and methanesulfonyl chloride (2.5 mmol). (MS (m / z) 371.8 [M+H]+).

[0218] Step 3: 4-(3-Fluoro-5-((methylsulfonyl)oxy)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid According to Step 7 of Example 3, the title compound was prepared from tert-butyl 4-(3-fluoro-5-((methylsulfonyl)oxy)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.0 mmol). (MS (m / z) 316.1 [M+H]+).

[0219] Step 4: (R)-6-(5-(((1-(2-Chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyridin-3-ylmethanesulfonate According to Example 3, Step 8, the title compound was prepared from 4-(3-Fluoro-5-((methylsulfonyl)oxy)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (0.30 mmol) and (R)-1-(2-chloropyridin-3-yl)ethan-1-ol (0.61 mmol). (MS (m / z) 470.0 [M+H]+). 1H NMR (400 MHz, DMSO-d6) δ 9.78 (bs, 1H), 8.41 (m, 1H), 8.38 (bs, 1H), 8.00 (s, 1H), 7.94 (dd, J = 11.0, 2.3 Hz, 1H), 7.84 (d, J = 2.7 Hz, 1H), 7.56 (s, 1H), 5.86 (s, 1H), 4.01 (s, 3H), 3.70 (s, 3H), 3.51 (s, 3H), 1.55 (s, 3H).

[0220] Example 13: Preparation of (R)-1-(3-Fluorophenyl)ethyl (1-methyl-4-(6-methyl-5-(methylsulfonamido)pyridin-2-yl)-1H-pyrazol-5-yl)carbamate (Compound 13) [Chemical formula] Step 1: Methyl 4-(5-((tert-Butoxycarbonyl)amino)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate A vial containing a suspension of methyl 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methyl-pyrazole-3-carboxylate (3.6 mmol), tert-butyl N-(6-bromo-2-methyl-3-pyridyl)carbamate (3.5 mmol), bis(dibenzylideneacetone)palladium(0) (0.17 mmol, 5 mol%), XPhos (0.69 mmol, 20 mol%), and potassium carbonate (10 mmol) in water (5 mL) and dioxane (10 mL) was irradiated in a microwave reactor (high absorber setting) at 180 °C for 20 minutes. The aqueous solution was acidified with 10% aqueous citric acid and extracted three times with ethyl acetate. The combined extracts were washed once with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a cloudy red semi-solid. The residue was purified by flash chromatography (Isco CombiFlash (registered trademark)) to afford the title compound. LC / MS m / z = 346.99 (M+H) + 。

[0221] Step 2: 4-(5-((tert-Butoxycarbonyl)amino)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid A solution of methyl 4-[5-(tert-butoxycarbonylamino)-6-methyl-2-pyridyl]-2-methyl-pyrazole-3-carboxylate (3.5 mmol) in THF / MeOH / water (2:2:1, 15 mL) was treated with lithium hydroxide monohydrate (10 mmol) and stirred at room temperature. The mixture was acidified with 10% aqueous citric acid and extracted three times with ethyl acetate. The combined extracts were washed once with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. LC / MS m / z = 333.00 (M+H) + 。

[0222] Step 3: tert-Butyl (R)-(6-(5-(((1-(4-fluorophenyl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)-2-methylpyridin-3-yl)carbamate A suspension of 4-(5-((tert-butoxycarbonyl)amino)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (3.2 mmol) was suspended in toluene (32 mL) in a 200 mL round-bottom flask containing a stir bar. Triethylamine (3.5 mmol) was added, followed by diphenylphosphoryl azide (0.73 mL, 3.4 mmol), followed by (R)-1-(3-fluorophenyl)ethan-1-ol (3.4 mmol). The vessel was heated overnight in a bead bath at 120 °C. The mixture was concentrated and the residue was purified by flash chromatography to afford the title compound. LC / MS m / z = 470.11 (M+H) + 。

[0223] Step 4: (R)-1-(3-Fluorophenyl)ethyl (4-(5-amino-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate dihydrochloride A suspension of tert-butyl (R)-(6-(5-(((1-(3-fluorophenyl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)-2-methylpyridin-3-yl)carbamate (0.49 mmol) in DCM (2 mL) was treated with hydrogen chloride solution (4 N in dioxane, 3 mL, 12 mmol). The mixture was heated at 45 °C for 4 h to afford a white suspension. The title compound was isolated by vacuum filtration. LC / MS m / z = 370.08 (M+H) + 。

[0224] Step 5: (R)-1-(3-Fluorophenyl)ethyl (1-methyl-4-(6-methyl-5-(methylsulfonamido)pyridin-2-yl)-1H-pyrazol-5-yl)carbamate (R)-1-(3-Fluorophenyl)ethyl (4-(5-amino-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (0.95 mmol) was taken as a suspension in dichloromethane (4 mL), and N,N-diisopropylethylamine (2.0 mmol) was added to make it almost homogeneous. The reaction mixture was treated with methanesulfonyl chloride (0.63 mmol) and left overnight at room temperature. The mixture was concentrated under reduced pressure. The residue was taken up in tetrahydrofuran (10 mL) and treated with 1 M aqueous lithium hydroxide solution (5 mL). The mixture was heated to reflux briefly using a gun and then cooled. An aliquot of the mixture was taken up in AcOH for LC / MS analysis. The mixture was acidified by the addition of concentrated HCl. It was extracted three times with ethyl acetate. The combined extracts were successively washed once each with water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated to dryness under reduced pressure, and subjected to reverse-phase HPLC to give the title compound. (MS (m / z) 448.07 [M+H]+). 1H NMR (400 MHz, DMSO-d6) δ 9.69 (bs, 1H), 9.34 (s, 1H), 7.93 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.19 - 7.05 (m, 4H), 5.76 (s, 1H), 3.66 (s, 3H), 3.02 (s, 3H), 2.48 (s, 3H), 1.53 (bs, 3H).

[0225] Example 14: Preparation of (R)-1-(3-fluorophenyl)ethyl (4-(5-((methoxycarbonyl)amino)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (Compound 14)

Chemical Structure

[0226] Example 15: Preparation of (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl (1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-pyrazol-5-yl)carbamate (Compound 15)

Chemical formula

[0227] Step 2: Methyl 1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-pyrazole-5-carboxylate Into a microwave vial were added methyl 4-bromo-1-methyl-1H-pyrazole-5-carboxylate (1.49 mmol), 6-chloro-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (1.79 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (10 mol%), sodium carbonate (7.45 mmol), acetonitrile (7.5 mL), and water (3.2 mL). The vial was sealed and heated in a microwave reactor to 100 °C for 1 hour. The reaction mixture was cooled to room temperature and partitioned between saturated aqueous sodium bicarbonate and EtOAc. The aqueous layer was extracted with EtOAc (3 × 20 mL). The organics were washed with brine (20 mL), dried over sodium sulfate, and concentrated to give methyl 1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-pyrazole-5-carboxylate, which was used in the next step without further purification.

[0228] Step 3: (R)-1-(2-Chloro-5-fluoropyridin-3-yl)ethyl (1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-pyrazol-5-yl)carbamate Methyl 1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-pyrazole-5-carboxylate (1.97 mmol), lithium hydroxide monohydrate (5.92 mmol), THF (4.0 mL), MeOH (4.0 mL), and water (2.0 mL) were added to a vial. The vial was capped and sonicated at room temperature for 15 minutes. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and isopropyl acetate. The aqueous layer was washed with isopropyl acetate (2 × 25 mL), acidified to pH = 2 with 12N HCl, and a solid was precipitated. The mixture was filtered and the solid was dried in an oven at 90 °C overnight to give 1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-pyrazole-5-carboxylic acid. 1-Methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-pyrazole-5-carboxylic acid (0.16 mmol), azidotrimethylsilane (0.20 mmol), and T3P (50% in THF) (0.20 mmol) were dissolved in MeCN (0.32 mL). Triethylamine (0.33 mmol) was added dropwise at room temperature and a homogeneous solution resulted after 5 - 30 minutes. The reaction was heated to 70 °C for 20 minutes, then (1R)-1-(2-chloro-5-fluoropyridin-3-yl)ethanol (0.33 mmol) was added and the reaction mixture was heated at 70 °C overnight. The organics were concentrated and purified by reverse phase HPLC to give (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl (1-methyl-4-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-1H-pyrazol-5-yl)carbamate. (MS (m / z) 447.1 [M + H]+). 1 H NMR (400 MHz, acetonitrile-d3) δ 8.66 (s, 1H), 8.25 (s, 1H), 7.83 (s, 1H), 7.27 - 7.06 (m, 2H), 5.99 (q, J = 6.6 Hz, 1H), 4.75 (s, 3H), 3.73 (s, 3H), 1.58 (s, 3H).

[0229] Example 16: Preparation of (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(3-5-(3-fluorobicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (Compound 16)

Chemical Structure

[0230] Step 2: Methyl 4-(5-((tert-butoxycarbonyl)amino)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate In a microwave vial, methyl 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.18 mmol), tert-butyl (6-bromo-5-fluoropyridin-3-yl)carbamate (0.98 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (10 mol%), sodium carbonate (4.91 mmol), acetonitrile (4.9 mL), and water (2.4 mL) were added. The vial was sealed and heated in a microwave reactor to 100 °C for 1 hour. The reaction mixture was cooled to room temperature and partitioned between saturated aqueous sodium bicarbonate and EtOAc. The aqueous layer was extracted with EtOAc (3 × 20 mL). The organic matter was washed with brine (20 mL), dried over sodium sulfate, and concentrated to give methyl 4-(5-((tert-butoxycarbonyl)amino)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate, which was used in the next step without further purification.

[0231] Step 3: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(5-((tert-butoxycarbonyl)amino)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate Methyl 4-(5-((tert-butoxycarbonyl)amino)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.43 mmol), lithium hydroxide monohydrate (4.30 mmol), THF (2.0 mL), MeOH (2.0 mL), and water (1.0 mL) were added to a vial. The vial was capped and sonicated at room temperature for 15 minutes. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and isopropyl acetate. The aqueous layer was washed with isopropyl acetate (2 × 10 mL), then acidified to pH = 2 with 12 N HCl to precipitate a solid. The mixture was filtered and the solid was dried in an oven at 90 °C overnight to give 4-(5-((tert-butoxycarbonyl)amino)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid.

[0232] 4-(5-((tert-Butoxycarbonyl)amino)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (0.27 mmol), azidotrimethylsilane (0.32 mmol), and T3P (50% in THF) (0.32 mmol) were dissolved in MeCN (0.5 mL). Triethylamine (0.54 mmol) was added at room temperature, and a homogeneous solution occurred after 5 - 30 minutes. The reaction mixture was heated to 70 °C for 20 minutes, then (1R)-1-(2,5-difluoro-3-pyridyl)ethanol (0.80 mmol) was added, and the reaction mixture was heated at 70 °C overnight. Water and EtOAc were added, and the layers were separated. The combined organics were concentrated to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-((tert-butoxycarbonyl)amino)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-5-yl)carbamate, which was used in the next step without further purification.

[0233] Step 4: Boc-Deprotection and EDC Coupling (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(5-((tert-butoxycarbonyl)amino)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (0.54 mmol) dissolved in DCM (5.0 mL) was added to 4N HCl (1.35 mL) in dioxane. After the reaction mixture was stirred at room temperature for 2 h, it was concentrated to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-amino-3-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate, hydrochloride, which was used in the next reaction without further purification. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (0.21 mmol) was added to a stirred suspension of (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-amino-3-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate, as well as to a solution of hydrochloride (0.11 mmol) and 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (0.13 mmol) dissolved in pyridine (1.0 mL) and DCM (1.0 mL). After the reaction mixture was stirred at room temperature for 4 h, it was concentrated and purified by reverse phase HPLC to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(3-fluoro-5-(3-fluorobicyclo[1.1.1]pentane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate. (MS (m / z) 505.1 [M+H]+). 1 1H NMR (400 MHz, acetonitrile-d3) δ 8.53 (s, 2H), 8.08 - 7.97 (m, 1H), 7.87 - 7.81 (m, 2H), 5.90 (q, J = 6.8 Hz, 1H), 3.77 (s, 3H), 2.67 - 2.43 (m, 6H), 1.57 (d, J = 6.4 Hz, 3H).

[0234] Preparation of (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-(1-cyanocyclopropane-1-carboxamido)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (Compound 17) [Chemical Structure] According to the procedure of Example 16, Step 4, using 1-cyanocyclopropane-1-carboxylic acid instead of 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid, the title compound was prepared. MS (m / z) = 486.14 [M+H]+ 1H NMR (400 MHz, acetonitrile-d3) δ 8.75 (s, 1H), 8.52 (s, 1H), 8.03 (t, J = 2.5 Hz, 1H), 7.93 (dd, J = 12.7, 2.2 Hz, 1H), 7.87 (d, J = 3.5 Hz, 1H), 5.90 (q, J = 6.7 Hz, 1H), 3.77 (s, 3H), 1.79 - 1.67 (m, 4H), 1.57 (d, J = 6.6 Hz, 3H).

[0235] Preparation of (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-(2-difluoromethyl)pyrimidine-5-carboxamido)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (Compound 18) [Chemical Structure] According to the procedure of Example 16, Step 4, using 2-(difluoromethyl)pyrimidine-5-carboxylic acid instead of 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid, the title compound was prepared. MS (m / z) = 549.07 [M+H]+ 1H NMR (400 MHz, acetonitrile-d3) δ 9.50 - 9.22 (m, 2H), 8.66 (s, 1H), 8.22 - 8.08 (m, 2H), 7.97 - 7.79 (m, 2H), 6.86 (td, J = 54.2, 3.2 Hz, 1H), 5.98 - 5.83 (m, 1H), 3.79 (s, 3H), 1.59 (d, J = 7.4 Hz, 3H).

[0236] Example 19: Preparation of (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (Compound 19) [Chemical formula] Step 1: Methyl 4-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate Into a microwave vial, methyl 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.6 mmol), tert-butyl (6-chloropyridin-3-yl)carbamate (1.32 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (10 mol%), sodium carbonate (6.61 mmol), acetonitrile (6.6 mL), and water (3.3 mL) were added. The vial was sealed and heated to 100 °C for 1 hour in a microwave reactor. The reaction mixture was cooled to room temperature and partitioned between saturated aqueous sodium bicarbonate and EtOAc. The aqueous layer was extracted with EtOAc (3 × 20 mL). The organic matter was washed with brine (20 mL), dried over sodium sulfate, and concentrated to give methyl 4-(5-((tert-butoxycarbonyl)amino))pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate, which was used in the next step without further purification.

[0237] Step 2: (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate Methyl 4-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (2.4), lithium hydroxide monohydrate (7.3 mmol), THF (8.0 mL), MeOH (8.0 mL), and water (4.0 mL) were added to a vial. The vial was capped and sonicated at room temperature for 15 minutes. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and isopropyl acetate. The aqueous layer was washed with isopropyl acetate (2 × 10 mL), acidified to pH = 2 using 12N HCl, and a solid was precipitated. The mixture was filtered and the solid was dried in an oven at 90 °C overnight to give 4-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid.

[0238] 4-(5-((tert-Butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (0.78 mmol), azidotrimethylsilane (0.94 mmol), and T3P (50% in THF) (0.94 mmol) were dissolved in MeCN (# mL). Triethylamine (1.56 mmol) was added dropwise at room temperature and a homogeneous solution resulted after 5 - 30 minutes. The reaction was heated to 70 °C for 20 minutes, then (1R)-1-(2,5-difluoro-3-pyridyl)ethanol (1.56 mmol) was added and the reaction mixture was heated at 70 °C overnight. Water and EtOAc were added and the layers were separated. The combined organics were concentrated to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-pyrazole-5-yl)carbamate, which was used in the next step without further purification.

[0239] Step 3: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-pyrazole-5-yl)carbamate (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (2.4 mmol) dissolved in DCM (10 mL) was added with 4N HCl (6.0 mL) in dioxane. After the reaction mixture was stirred at room temperature for 2 hours, it was concentrated to obtain (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate, hydrochloride salt. This was used in the next reaction without further purification. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.07 mmol) was added to a stirred suspension of (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-aminopyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate, as well as to a solution of hydrochloride salt (0.54 mmol) and 1-cyanocyclopropanecarboxylic acid (0.64 mmol) dissolved in pyridine (3.5 mL) and DCM (3.5 mL). After the reaction mixture was stirred at room temperature for 4 hours, it was concentrated and purified by reverse-phase HPLC to obtain (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-(1-cyanocyclopropane-1-carboxamido)pyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate. (MS (m / z) 468.1 [M+H]+). 1 H NMR (400 MHz, acetonitrile-d3) δ 8.93 (d, J = 2.4 Hz, 1H), 8.86 (s, 1H), 8.19 (dd, J = 8.8, 2.4 Hz, 1H), 8.03 (d, J = 2.5 Hz, 1H), 7.95 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 5.90 (q, J = 6.6 Hz, 1H), 3.76 (s, 3H), 1.82 - 1.66 (m, 4H), 1.57 (d, J = 6.5 Hz, 3H).

[0240] Example 20: Preparation of (R)-1-(2-chloropyridin-3-yl)ethyl (1-methyl-4-(5-(methylsulfonamido)pyridin-2-yl)-1H-pyrazol-5-yl)carbamate (Compound 20) [Chemical] Step 1: Methyl 1-methyl-4-(5-(methylsulfonamido)pyridin-2-yl)-1H-pyrazole-5-carboxylate Into a microwave vial, methyl 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.65 mmol), N-(6-chloropyridin-3-yl)methanesulfonamide (1.59 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (10 mol%), sodium carbonate (7.96 mmol), acetonitrile (7.9 mL), and water (3.4 mL) were added. The vial was sealed and heated to 100 °C for 1 hour in a microwave reactor. The reaction mixture was cooled to room temperature and partitioned between saturated aqueous sodium bicarbonate and EtOAc. The aqueous layer was extracted with EtOAc (3 × 20 mL). The organic matter was washed with brine (20 mL), dried over sodium sulfate, and concentrated to give methyl 1-methyl-4-(5-(methylsulfonamido)pyridin-2-yl)-1H-pyrazole-5-carboxylate, which was used in the next step without further purification.

[0241] Step 2: (R)-1-(2-Chloropyridin-3-yl)ethyl (1-methyl-4-(5-(methylsulfonamido)pyridin-2-yl)-1H-pyrazol-5-yl)carbamate Methyl 1-methyl-4-(5-(methylsulfonamido)pyridin-2-yl)-1H-pyrazole-5-carboxylate (1.34 mmol), lithium hydroxide monohydrate (4.03 mmol), THF (4.0 mL), MeOH (4.0 mL), and water (2.0 mL) were added to a vial. The vial was capped and sonicated at room temperature for 15 minutes. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and isopropyl acetate. The aqueous layer was washed with isopropyl acetate (2 × 25 mL), acidified to pH = 2 with 12N HCl, and the solid was precipitated. The mixture was filtered and the solid was dried in an oven at 90 °C overnight to give 1-methyl-4-(5-(methylsulfonamido)pyridin-2-yl)-1H-pyrazole-5-carboxylic acid. 1-Methyl-4-(5-(methylsulfonamido)pyridin-2-yl)-1H-pyrazole-5-carboxylic acid (0.58 mmol), azidotrimethylsilane (0.69 mmol), and T3P (50% in DMF) (0.69 mmol) were dissolved in MeCN (1.15 mL). Triethylamine (1.15 mmol) was added dropwise at room temperature and a homogeneous solution resulted after 5 - 30 minutes. The reaction was heated to 70 °C for 20 minutes, then (1R)-1-(2-chloro-3-pyridyl)ethanol (1.15 mmol) was added and the reaction mixture was heated at 70 °C overnight. The organics were concentrated and purified by reverse phase HPLC to afford (R)-1-(2-chloropyridin-3-yl)ethyl (1-methyl-4-(5-(methylsulfonamido)pyridin-2-yl)-1H-pyrazol-5-yl)carbamate. (MS (m / z) 451.1 [M+H]+). 1 H NMR (400 MHz, acetonitrile-d3) δ 8.54 (d, J = 2.7 Hz, 1H), 8.35 (dd, J = 4.8, 1.9 Hz, 1H), 8.04 (s, 1H), 7.99 - 7.84 (m, 2H), 7.72 (d, J = 8.8 Hz, 1H), 7.41 (s, 1H), 6.03 (q, J = 6.6 Hz, 1H), 3.77 (s, 3H), 3.07 (s, 3H), 1.58 (d, J = 6.5 Hz, 3H).

[0242] Example 21: Preparation of (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-(1-cyanocyclopropanecarboxamido)pyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (Compound 21) [Chemical formula] Step 1: Tert-butyl (2-chloropyrimidin-5-yl)carbamate 2-Chloropyrimidin-5-amine (12 mmol) and 4-dimethylaminopyridine (1.2 mmol) were suspended in THF (15 mL), and di-tert-butyl dicarbonate (14 mmol) was added. The mixture was sonicated at room temperature for about 5 minutes and then stirred at room temperature overnight. Water was added to the mixture, and then it was extracted twice with ethyl acetate. The combined organic layers were washed once with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a residue, which was then purified by automated flash chromatography (silica gel) to obtain tert-butyl (2-chloropyrimidin-5-yl)carbamate.

[0243] Step 2: Methyl 4-(5-((tert-butoxycarbonyl)amino)pyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate In a microwave vial, methyl 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.83 mmol), tert-butyl (2-chloropyrimidin-5-yl)carbamate (1.52 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (10 mol%), sodium carbonate (7.62 mmol), acetonitrile (7.6 mL), and water (3.8 mL) were added. The vial was sealed and heated to 100 °C for 1 hour in a microwave reactor. The reaction mixture was cooled to room temperature and partitioned between saturated aqueous sodium bicarbonate and EtOAc. The aqueous layer was extracted with EtOAc (3 × 20 mL). The organic matter was washed with brine (20 mL), dried over sodium sulfate, and concentrated to give methyl 4-(5-((tert-butoxycarbonyl)amino)pyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate, which was used in the next step without further purification.

[0244] Step 3: 4-(5-((tert-Butoxycarbonyl)amino)pyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid Methyl 4-(5-((tert-butoxycarbonyl)amino)pyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.63 mmol), lithium hydroxide monohydrate (4.9 mmol), THF (4.0 mL), MeOH (4.0 mL), and water (2.0 mL) were added to a vial. The vial was capped and sonicated at room temperature for 15 minutes. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and isopropyl acetate. The aqueous layer was washed twice with isopropyl acetate, then acidified to pH = 2 using 12N HCl to precipitate a solid. The mixture was filtered and the solid was dried in an oven at 90 °C overnight to give 4-(5-((tert-butoxycarbonyl)amino)pyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid.

[0245] Step 4: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(5-((tert-butoxycarbonyl)amino)pyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate 4-(5-((tert-Butoxycarbonyl)amino)pyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (0.32 mmol), azidotrimethylsilane (0.39 mmol), and T3P (50% in THF) (0.39 mmol) were dissolved in MeCN (0.6 mL). Triethylamine (0.65 mmol) was added at room temperature, and a homogeneous solution formed after 5 - 30 minutes. The reaction mixture was heated to 70 °C for 20 minutes, then (1R)-1-(2,5-difluoro-3-pyridyl)ethanol (0.65 mmol) was added, and the reaction mixture was heated at 70 °C overnight. Water and EtOAc were added, and the layers were separated. The combined organics were concentrated to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-((tert-butoxycarbonyl)amino)pyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate, which was used in the next step without further purification.

[0246] Step 5: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(5-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (Intermediate 1A) To (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-((tert-butoxycarbonyl)amino)pyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (0.48 mmol) dissolved in DCM (5.0 mL) was added 4N HCl in dioxane (1.22 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated to give (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate hydrochloride (Intermediate 1A), which was used in the next reaction without further purification.

[0247] Step 6: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(5-(1-cyanocyclopropane-1-carboxamido)pyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (0.43 mmol) was added to a stirred suspension of (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate hydrochloride (0.22 mmol) and 1-cyanocyclopropanecarboxylic acid (0.26 mmol) in pyridine (1.0 mL) and DCM (1.0 mL). The reaction mixture was stirred at room temperature for 4 h, concentrated, and purified by reverse-phase HPLC to afford (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-(1-cyanocyclopropane-1-carboxamido)pyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate. (MS (m / z) 469.1 [M+H]+). 1 1H NMR (400 MHz, acetonitrile-d3) δ 8.87 (s, 2H), 8.61 (s, 1H), 8.19 - 7.85 (m, 2H), 5.93 (q, J = 6.7 Hz, 1H), 3.77 (s, 3H), 1.76 - 1.66 (m, 4H), 1.59 (d, J = 6.6 Hz, 3H).

[0248] Example 22: Preparation of (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (1-methyl-4-(5-(2-(trifluoromethyl)pyrimidine-5-carboxamido)pyrimidin-2-yl)-1H-pyrazol-5-yl)carbamate (Compound 22)

Chem.

[0249] Example 23: Preparation of Compounds 23 - 43 Compounds 23 - 43 were generally synthesized according to Example 22, using Intermediate 1A, 1B, 1C, or 1D, according to Scheme 1, Step 4A.

[0250] Intermediates 1B, 1C, and 1D were synthesized as follows.

Chemical Structure

[0251] Intermediate 1B was prepared according to Example 21, Steps 4 - 5, using (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethan-1-ol instead of (1R)-1-(2,5-difluoro-3-pyridyl)ethanol in Step 4.

Chemical Structure

[0252] Intermediate 1C was prepared according to Example 21, Steps 4 to 5, using (R)-1-(2-chloropyridin-3-yl)ethan-1-ol instead of (1R)-1-(2,5-difluoropyridin-3-yl)ethanol in Step 4.

Chemical formula

[0253] Intermediate 1D was prepared according to Example 21, Steps 4 to 5, using (R)-1-(2-fluoropyridin-3-yl)ethan-1-ol instead of (1R)-1-(2,5-difluoropyridin-3-yl)ethanol in Step 4.

[0254] Compounds 23 to 43 (Table 1) were similarly prepared by reacting the intermediate with the reagents listed in Table 2 according to Scheme 1, Step 4A, following Example 22.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

[0255] Example 24: Synthesis of 1-Methyl-4-(5-((methylsulfonyl)oxy)pyrimidin-2-yl)-1H-pyrazole-5-carboxylic Acid [Chemical formula] Step 1: 4-(5-Bromopyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic Acid In a 100 mL RBF, 4-bromo-2-methyl-pyrazole-3-carboxylic acid (4.9 mmol) was taken in THF (49 mL) and cooled in a dry ice / acetone bath with stirring under a nitrogen atmosphere. To the stirred solution, a solution of lithium bis(trimethylsilyl)amide (1.3 M in THF, 4.1 mL, 5.4 mmol) was added dropwise. After 5 minutes, a solution of n-butyllithium (1.6 M in hexane, 6.1 mL, 9.8 mmol) was added dropwise. After stirring at -78 °C for 2 hours, a solution of zinc(II) chloride (1.9 M in 2-MeTHF, 8.0 mL, 15 mmol) was added dropwise. After 5 minutes, the cooling bath was removed and replaced with a water bath, and the mixture was stirred for 1 hour. Then, 5-bromo-2-iodo-pyrimidine (4.9 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) complex (0.49 mmol, 10 mol%) in dichloromethane were added. The flask was equipped with a Findenser and heated overnight in a 70 °C block under a nitrogen atmosphere. The mixture was cooled to room temperature and quenched by the addition of 1 N aqueous potassium hydroxide solution (about 25 mL) to obtain a two-phase mixture with a precipitate. It was filtered through a polypropylene frit funnel and washed with water and isopropyl acetate. Additional solid precipitated from the filtrate and was recovered by filtering through it. The combined precipitate was dried to obtain the title compound.

[0256] Step 2: tert-Butyl 4-(5-bromopyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate A suspension of 4-(5-bromopyrimidin-2-yl)-2-methyl-pyrazole-3-carboxylic acid (1.6 mmol) in toluene (10 mL) was heated on a 90 °C block while DMF di-tert-butyl acetal (7.8 mmol) was added dropwise. After 15 minutes, the mixture was cooled, diluted with toluene, and poured into a separatory funnel. It was washed once each with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. Dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound.

[0257] Step 3: (2-(5-(tert-Butoxycarbonyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-5-yl)boronic acid To a mixture of tert-butyl 4-(5-bromopyrimidin-2-yl)-2-methyl-pyrazole-3-carboxylate (1.7 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane (2.6 mmol), and potassium acetate (5.1 mmol) in THF (8 mL) was added 1,1’-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.09 mmol, 5 mol%). The reaction vessel was transferred to a 78 °C heating block and stirred for 2 days. The reaction mixture was used directly in the next step.

[0258] Step 4: tert-Butyl 4-(5-hydroxypyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate The crude borylated mixture (presumably 1.7 mmol of [2-(5-tert-butoxycarbonyl-1-methyl-pyrazol-4-yl)pyrimidin-5-yl]boronic acid) diluted with EtOAc (ca. 20 mL) was treated with a hydrogen peroxide solution (30% aqueous solution, 1.9 mL, 17 mmol). The mixture was stirred for 5 minutes, after which an additional 1 mL aliquot (total additional 4 mL) of the H2O2 solution was added over 15 minutes. The mixture was stirred overnight at room temperature. The reaction mixture was cooled to 0 °C and quenched by slowly adding a saturated aqueous sodium thiosulfate solution. The biphasic mixture was filtered through a polypropylene frit funnel. The layers were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic extracts were washed once with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound.

[0259] Step 5: tert-Butyl 1-methyl-4-(5-((methylsulfonyl)oxy)pyrimidin-2-yl)-1H-pyrazole-5-carboxylate A solution of the crude tert-butyl 4-(5-hydroxypyrimidin-2-yl)-2-methyl-pyrazole-3-carboxylate (presumably 1.7 mmol) in DCM (20 mL) was treated successively with triethylamine (8.5 mmol) and methanesulfonyl chloride (3.4 mmol). The mixture was quenched with isopropanol (3 mL) and stirred overnight at room temperature. The mixture was concentrated and the residue was taken up in dichloromethane / toluene and purified by column chromatography to afford the title compound.

[0260] Step 6: 1-Methyl-4-(5-((methylsulfonyl)oxy)pyrimidin-2-yl)-1H-pyrazole-5-carboxylic acid tert-Butyl 2-methyl-4-(5-methylsulfonyloxypyrimidin-2-yl)pyrazole-3-carboxylate (1.1 mmol) was dissolved in dichloromethane (3 mL) and treated with a hydrogen chloride solution (4 N in dioxane, 3.0 mL, 12 mmol). The reaction was stirred overnight at room temperature. The suspension was concentrated under reduced pressure and dried in a vacuum oven at 60 °C to afford the title compound.

[0261] Example 25: Preparation of Compound 44 and Compound 45 (R)-1-(2-Chloropyridin-3-yl)ethyl (4-(5-hydroxypyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (Compound 44) Preparation [Chemical formula] Step 1: (R)-2-(5-(((1-(2-Chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)pyrimidin-5-yl methanesulfonate 1-Methyl-4-(5-((methylsulfonyl)oxy)pyrimidin-2-yl)-1H-pyrazole-5-carboxylic acid (0.30 mmol), azidotrimethylsilane (0.36 mmol), and T3P (50% in THF) (0.36 mmol) were dissolved in MeCN (0.6 mL). Triethylamine (0.60 mmol) was added at room temperature, and a homogeneous solution occurred after 5 - 30 minutes. The reaction was heated to 70 °C for 20 minutes, then (1R)-1-(2-chloro-3-pyridyl)ethanol (1.21 mmol) was added, and the reaction mixture was heated at 70 °C overnight. Water and EtOAc were added, and the layers were separated. The combined organics were concentrated to give (R)-2-(5-(((1-(2-chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)pyrimidin-5-yl methanesulfonate, which was used in the next step without further purification.

[0262] Step 2: (R)-1-(2-Chloropyridin-3-yl)ethyl (4-(5-hydroxypyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (R)-2-(5-(((1-(2-Chloropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)pyrimidin-5-ylmethanesulfonate (0.30 mmol), lithium hydroxide monohydrate (1.5 mmol), THF (1.0 mL), MeOH (1.0 mL), and water (0.50 mL) were added to a vial. The vial was capped and sonicated at room temperature for 15 minutes. The reaction mixture was acidified to pH = 2 using 12 N HCl and then purified by reverse-phase HPLC to obtain (R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-hydroxypyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate. (MS (m / z) 375.0 [M+H]+). 1 H NMR (400 MHz, acetonitrile-d3) δ 8.34 (s, 3H), 7.94 (s, 2H), 7.46 - 7.26 (m, 1H), 6.04 (q, J = 6.6 Hz, 1H), 3.74 (s, 3H), 1.58 (d, J = 6.5 Hz, 3H).

[0263] Preparation of (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-hydroxypyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (Compound 45)

Chemical Structure

[0264] Example 26: Preparation of ((R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-(3-cyanobicyclo[1.1.1]pentan-1-yl)carbamoyl)pyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (Compound 46)

Chemical formula

[0265] Step 2: 1-Methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.97 mmol) was added to a mixture of potassium acetate (78 mmol), 4-bromo-1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole (19 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (29 mmol) in dioxane (53 mL) that had been degassed with nitrogen for 20 minutes. After adding the catalyst, the mixture was heated at 85 °C overnight. After cooling, the mixture was partitioned between water and dichloromethane (each about 100 mL). The aqueous layer was extracted twice with dichloromethane (about 50 mL each time). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by automated flash chromatography (silica gel) to give the title intermediate. (MS (m / z) 323.3 [M+H]+).

[0266] Step 3: Ethyl 2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)pyrimidine-5-carboxylate The title intermediate was prepared from 1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.7 mmol) and ethyl 2-chloropyrimidine-5-carboxylate (4.7 mmol) according to the procedure described in Step 3 of Example 3. (MS (m / z) 347.1 [M+H]+).

[0267] Step 4: Ethyl 2-(5-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxylate A mixture of ethyl 2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)pyrimidine-5-carboxylate (3.75 mmol) and pyridinium p-toluenesulfonate (0.75 mmol) in ethanol (20 mL) was heated at 60 °C overnight and then concentrated under reduced pressure to afford the title intermediate. (MS (m / z) 263.1 [M+H]+).

[0268] Step 5: 4-(5-(Ethoxycarbonyl)pyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid To a mixture of ethyl 2-(5-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxylate (3.75 mmol) in MeCN (20 mL) and H2O (10 mL) were successively added (diacetoxyiodo)benzene (15 mmol) and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO, 3.75 mmol). The mixture was heated at 68 °C for 30 minutes, after which additional amounts of (diacetoxyiodo)benzene (6.2 mmol) and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO, 1.3 mmol) were added. After heating for a further 30 minutes, additional amounts of (diacetoxyiodo)benzene (6.2 mmol) and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO, 1.3 mmol) were added again. The mixture was concentrated under reduced pressure. The residue was triturated with aqueous ethanol, the solid was collected by suction filtration, washed with ethanol / water (1:1) and dried in a vacuum oven. (MS (m / z) 389.1 [M+H]+).

[0269] Step 6: Ethyl (R)-2-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxylate To a mixture of 4-(5-(ethoxycarbonyl)pyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (1.3 mmol) in THF (2.6 mL) was added sequentially azidotrimethylsilane (1.6 mmol) and 1-propanephosphonic anhydride solution (50% w / w in DMF, 1.6 mmol). Triethylamine (2.7 mmol) was added to the stirred mixture and after 10 minutes (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol (2.7 mmol) was added and the mixture was heated at 80 °C overnight. After cooling, the mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous phase was extracted three times with ethyl acetate. The combined organic extracts were washed once with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by automated flash chromatography (silica gel) to afford the title intermediate. (MS (m / z) 433.1 [M+H]+).

[0270] Step 7: (R)-2-(5-(((1-(2,5-Difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxylic acid Ethyl (R)-2-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxylate (1.0 mmol) was taken in THF / MeOH / water (2:2:1, 18 mL). Treated with lithium hydroxide monohydrate (3.0 mmol) and warmed at 50 °C for 15 minutes with stirring. The mixture was cooled and then acidified with 1N aqueous hydrochloric acid to give a solid which was collected by suction filtration, washed with water and dried overnight in a vacuum oven to afford the title intermediate. (MS (m / z) 405.0 [M+H]+).

[0271] Step 8: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(5-((3-cyanobicyclo[1.1.1]pentan-1-yl)carbamoyl)pyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (0.32 mmol) was added to a solution of (R)-2-(5-(((1-(2,5-difluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxylic acid (0.19 mmol) and 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride (0.22 mmol) in N,N-diisopropylethylamine (0.52) and DCM (1.5 mL). The reaction mixture was stirred at room temperature for 4 hours, then concentrated and purified by reverse-phase HPLC to give the title compound (0.01 mmol). (MS (m / z) 495.1 [M+H]+). 1 1H NMR (400 MHz, acetonitrile-d3) δ 8.97 (s, 2H), 8.16 - 7.96 (m, 2H), 7.81 (s, 1H), 5.93 (q, J = 6.6 Hz, 1H), 3.78 (s, 3H), 2.66 (s, 6H), 1.59 (d, J = 6.7 Hz, 3H).

[0272] Example 27: Preparation of ((R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-(3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)pyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (Compound 47)

Chemical formula

[0273] Example 28: Preparation of (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl (1-methyl-4-(5-(pyridin-4-ylcarbamoyl)pyrimidin-2-yl)-1H-pyrazol-5-yl)carbamate (Compound 48)

Chem.

[0274] Step 2: tert-Butyl (R)-6-(5-(((1-(2-chloro-5-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)nicotinate 4-(5-(tert-Butoxycarbonyl)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (0.24 mmol), azidotrimethylsilane (0.29 mmol), and T3P (50% in THF) (0.29 mmol) were dissolved in THF (1.5 mL). Triethylamine (0.5 mmol) was added at room temperature, and a homogeneous solution occurred after 5 - 30 minutes. The reaction mixture was heated to 70 °C for 20 minutes, then (1R)-1-(2-chloro-5-fluoro-3-pyridyl)ethanol (0.65 mmol) was added, and the reaction mixture was heated at 70 °C overnight. Water and EtOAc were added, and the layers were separated. The combined organics were concentrated to give tert-butyl (R)-6-(5-(((1-(2-chloro-5-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)nicotinate, which was used in the next step without further purification.

[0275] Step 3: (R)-6-(5-(((1-(2-chloro-5-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)nicotinic acid tert-Butyl (R)-6-(5-(((1-(2-chloro-5-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)nicotinate (0.43 mmol) was dissolved in dichloromethane (1 mL) and treated with hydrogen chloride solution (4 N in dioxane, 1.0 mL, 4 mmol). The reaction mixture was stirred at room temperature overnight. The suspension was concentrated under reduced pressure and dried in a vacuum oven at 60 °C to afford the title compound.

[0276] Step 4: (R)-1-(2-chloro-5-fluoropyridin-3-yl)ethyl (1-methyl-4-(5-(pyridin-4-ylcarbamoyl)pyridin-2-yl)-1H-pyrazol-5-yl)carbamate 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (0.30 mmol) was added to a solution of (R)-6-(5-(((1-(2-chloro-5-fluoropyridin-3-yl)ethoxy)carbonyl)amino)-1-methyl-1H-pyrazol-4-yl)nicotinic acid (0.18 mmol) and pyridin-4-amine (0.44 mmol) in triethylamine (0.36 mmol) and DCM (2.0 mL). The reaction mixture was stirred at room temperature for 4 hours, then concentrated and purified by reverse-phase HPLC to give the title compound. (MS (m / z) 496.2 [M+H]+).

[0277] Example 29: Preparation of ((R)-1-(3-fluorophenyl)ethyl (4-(5-(3-cyanobicyclo[1.1.1]pentan-1-yl)carbamoyl)pyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (Compound 49) [Chemical formula] According to Example 28, (R)-1-(3-fluorophenyl)ethan-1-ol was used instead of (1R)-1-(2-chloro-5-fluoro-3-pyridyl)ethanol in Step 2, and 3-aminobicyclo[1.1.1]pentane-1-carbonitrile was used instead of pyridin-4-amine in Step 3 to prepare the title compound. MS (m / z) = 475.1 [M+H]+. 1H NMR (400 MHz, acetonitrile-d3) δ 8.86 (d, J = 2.3 Hz, 1H), 8.38 (bs, 1H), 8.08 (dd, J = 8.4, 2.3 Hz, 1H), 7.94 (s, 1H), 7.72 (s, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.35 (dd, J = 8.2, 6.1 Hz, 1H), 7.15 (m, 2H), 7.03 (td, J = 8.4, 2.6 Hz, 1H), 5.78 (q, J = 6.6 Hz, 1H), 3.73 (s, 3H), 2.63 (s, 6H), 1.52 (d, J = 6.7 Hz, 3H).

[0278] Example 30: Preparation of ((R)-1-(2-chloropyridin-3-yl)ethyl (4-(5-(3-fluorobicyclo[1.1.1]pentan-1-yl)carbamoyl)pyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (Compound 50)

Chem.

[0279] Example 31: Preparation of (R)-1-(2-fluorophenyl)ethyl (1-methyl-4-(5-(methylsulfonamido)pyrimidin-2-yl)-1H-pyrazol-5-yl)carbamate (Compound 51)

Chem.

[0280] Step 2: (R)-1-(2-Fluorophenyl)ethyl (1-methyl-4-(5-(methylsulfonamido)pyrimidin-2-yl)-1H-pyrazol-5-yl)carbamate (R)-1-(2-Fluorophenyl)ethyl (4-(5-((tert-Butoxycarbonyl)amino)pyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (0.29 mmol) dissolved in DCM (3.0 mL) was added to 4N HCl (0.71 mL) in dioxane. After the reaction mixture was stirred at room temperature for 2 hours, it was concentrated to obtain (R)-1-(2-fluorophenyl)ethyl (4-(5-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate, hydrochloride. This was used in the next reaction without further purification. Methanesulfonic anhydride (0.14 mmol) was slowly added to a stirred solution of (R)-1-(2-fluorophenyl)ethyl (4-(5-aminopyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate, as well as to a solution of hydrochloride (0.11 mmol) and pyridine (0.34 mmol) dissolved in DCM (1.0 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for an additional 1 hour, after which the mixture was concentrated and purified by reverse-phase HPLC to obtain (R)-1-(2-fluorophenyl)ethyl (1-methyl-4-(5-(methylsulfonamido)pyrimidin-2-yl)-1H-pyrazol-5-yl)carbamate. (MS (m / z) 435.0 [M+H]+). 1H NMR (400 MHz, acetonitrile-d3) δ 8.58 (s, 2H), 8.14 (bs, 1H), 7.98 (s, 1H), 7.85 (s, 1H), 7.48 (bs, 1H), 7.39 - 7.28 (m, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.14 - 7.05 (m, 1H), 6.04 (q, J = 6.6 Hz, 1H), 3.72 (s, 3H), 3.01 (s, 3H), 1.57 (d, J = 6.7 Hz, 3H).

[0281] Example 32: Preparation of (R)-1-(3-Fluorophenyl)ethyl (1-methyl-4-(5-(methylsulfonamido)pyrimidin-2-yl)-1H-pyrazol-5-yl)carbamate (Compound 52) [Chemical formula] According to Example 31, the title compound was prepared by using (R)-1-(3-fluorophenyl)ethan-1-ol instead of (R)-1-(2-fluorophenyl)ethan-1-ol in Step 1. MS (m / z) = 435 [M+H]+. 1H NMR (400 MHz, acetonitrile-d3) δ 8.58 (s, 2H), 8.16 (bs, 1H), 7.99 (s, 1H), 7.84 (s, 1H), 7.38 (q, J = 7.4 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 7.15 (m, 1H), 7.08 - 6.87 (m, 1H), 5.81 (q, J = 6.6 Hz, 1H), 3.73 (s, 3H), 3.01 (s, 3H), 1.54 (d, J = 6.6 Hz, 3H).

[0282] Example 33: Preparation of (R)-1-(2,5-difluoropyridin-3-yl)ethyl (1-methyl-4-(5-(2,2,2-trifluoro-1-hydroxyethyl)pyrimidin-2-yl)-1H-pyrazol-5-yl)carbamate (Compound 53)

Chemical formula

[0283] Step 2: 2-Chloro-5-(2,2,2-trifluoro-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyrimidine Pyridinium p-toluenesulfonate (1.8 mmol) was added to a solution of 1-(2-chloropyrimidin-5-yl)-2,2,2-trifluoroethanol (presumed 17.5 mmol) and dihydropyran (35 mmol) in dichloromethane (20 mL). The reaction mixture was warmed on a heating block at 58 °C and stirred overnight. The homogeneous mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography eluting with hexane and ethyl acetate from 0:100 to 50:50 to give the title intermediate.

[0284] Step 3: Methyl 1-methyl-4-(5-(2,2,2-trifluoro-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyrimidin-2-yl)-1H-pyrazole-5-carboxylate In a microwave vial, methyl 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.24 mmol), 2-chloro-5-(2,2,2-trifluoro-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyrimidine (1.03 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (10 mol%), sodium carbonate (5.17 mmol), acetonitrile (5.10 mL), and water (2.55 mL) were added. The vial was sealed and heated to 100 °C for 1 hour in a microwave reactor. The reaction mixture was cooled to room temperature and partitioned between saturated aqueous sodium bicarbonate and EtOAc. The aqueous layer was extracted with EtOAc (3 × 20 mL). The organic matter was washed with brine (20 mL), dried over sodium sulfate, and concentrated to give methyl 1-methyl-4-(5-(2,2,2-trifluoro-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyrimidin-2-yl)-1H-pyrazole-5-carboxylate, which was used in the next step without further purification.

[0285] Step 4: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (1-methyl-4-(5-(2,2,2-trifluoro-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyrimidin-2-yl)-1H-pyrazol-5-yl)carbamate Methyl 1-methyl-4-(5-(2,2,2-trifluoro-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyrimidin-2-yl)-1H-pyrazole-5-carboxylate (1.37 mmol), lithium hydroxide monohydrate (4.9 mmol), THF (2.0 mL), MeOH (2.0 mL), and water (1.0 mL) were added to a vial. The vial was capped and sonicated at room temperature for 15 minutes. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and isopropyl acetate. The aqueous layer was washed with isopropyl acetate (2 × 10 mL), then acidified to pH = 2 using 12N HCl to precipitate a solid. The mixture was filtered and the solid was dried in an oven at 90 °C overnight to obtain 1-methyl-4-(5-(2,2,2-trifluoro-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyrimidin-2-yl)-1H-pyrazole-5-carboxylic acid. 1-Methyl-4-(5-(2,2,2-trifluoro-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyrimidin-2-yl)-1H-pyrazole-5-carboxylic acid (0.17 mmol), azidotrimethylsilane (0.21 mmol), and T3P (50% in THF) (0.21 mmol) were dissolved in MeCN (0.4 mL). Triethylamine (0.35 mmol) was added at room temperature and a homogeneous solution resulted after 5 - 30 minutes. The reaction was heated to 70 °C for 20 minutes, then (1R)-1-(2,5-difluoro-3-pyridyl)ethanol (0.52 mmol) was added and the reaction mixture was heated at 70 °C overnight. Water and EtOAc were added and the layers were separated. The combined organics were concentrated to give the title compound, which was used in the next step without further purification.

[0286] Step 5: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (1-methyl-4-(5-(2,2,2-trifluoro-1-hydroxyethyl)pyrimidin-2-yl)-1H-pyrazol-5-yl)carbamate To a vial were added (R)-1-(2,5-difluoropyridin-3-yl)ethyl (1-methyl-4-(5-(2,2,2-trifluoro-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyrimidin-2-yl)-1H-pyrazol-5-yl)carbamate (0.35 mmol), pyridinium p-toluenesulfonate (PPTS) (20 mol%), and EtOH (3.4 mL). The vial was sealed and heated at 90 °C for 3 days, then the mixture was concentrated and purified by reverse-phase HPLC to obtain (R)-1-(2,5-difluoropyridin-3-yl)ethyl (1-methyl-4-(5-(2,2,2-trifluoro-1-hydroxyethyl)pyrimidin-2-yl)-1H-pyrazol-5-yl)carbamate. (MS (m / z) 459.1 [M+H]+). 1 1H NMR (400 MHz, acetonitrile-d3) δ 8.77 (s, 2H), 8.08 (s, 1H), 8.04 - 7.99 (m, 1H), 7.80 (s, 1H), 5.93 (q, J = 6.7 Hz, 1H), 5.22 (q, J = 7.0 Hz, 1H), 3.78 (s, 3H), 1.59 (d, J = 6.6 Hz, 3H).

[0287] Example 34: Preparation of (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-(difluoromethyl)pyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (Compound 54)

Chemical formula

[0288] Step 2: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(5-(difluoromethyl)pyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate According to Example 28, in Step 2, instead of (1R)-1-(2-chloro-5-fluoro-3-pyridyl)ethanol, (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol was used to prepare the title compound. MS (m / z) = 411.06. 1H NMR (400 MHz, acetonitrile-d3) δ 8.81 (s, 2H), 8.28 (bs, 1H), 8.07 (s, 1H), 7.99 (t, J = 2.5 Hz, 1H), 7.76 (bs, 1H), 6.88 (t, J = 55.3 Hz, 1H), 5.90 (q, J = 6.6 Hz, 1H), 3.76 (s, 3H), 1.57 (d, J = 6.7 Hz, 3H).

[0289] Example 35: Preparation of (R)-1-(2,5-difluoropyridin-3-yl)ethyl (4-(5-(difluoromethoxy)pyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate (Compound 55)

Chemical Structure

[0290] Step 2: (R)-1-(2,5-Difluoropyridin-3-yl)ethyl (4-(5-(difluoromethyl)pyrimidin-2-yl)-1-methyl-1H-pyrazol-5-yl)carbamate According to Example 28, the title compound was prepared using (R)-1-(2,5-difluoropyridin-3-yl)ethan-1-ol instead of (1R)-1-(2-chloro-5-fluoro-3-pyridyl)ethanol in Step 2. MS (m / z) = 427.05 [M+H]+. 1H NMR (400 MHz, acetonitrile-d3) δ 8.56 (s, 2H), 8.07 (bs, 1H), 8.00 (m, 2H), 7.76 (s, 1H), 6.81 (t, J = 72.9 Hz, 1H), 5.90 (q, J = 6.6 Hz, 1H), 3.74 (s, 3H), 1.56 (d, J = 6.7 Hz, 3H).

[0291] Example 36: Calcium Assay In vitro LPAR1 activity was measured in an intracellular calcium mobilization assay.

[0292] CHO-K1 EDG2 cells (DiscoverX catalog number 93-0644C2) expressing human LPAR1 (NM_001401.3) were seeded at 15,000 cells / well in a total volume of 25 μL of Dulbecco's Modified Eagle Medium (DMEM) containing 10% fetal bovine serum, 1× PenStrepGlutamine, 300 μg / ml of hygromycin, and 800 μg / ml of G418 in a 384-well tissue culture plate (Grenier number 781091) and incubated overnight at 37°C. Prior to testing, 25 μL of calcium loading dye component A (FLIPR Calcium 6 assay kit Molecular Devices number R8190), 2.5 mM probenecid (Invitrogen number P36400, freshly prepared), 20 mM HEPES (Corning number 25-060-CI), and 0.1% bovine serum albumin (Sigma-Aldrich number A7906-500G) in Hank's balanced salt solution (Corning number 21-023-CV) were added to the cells at 37°C for 60 minutes.

[0293] An agonist dose-response curve of LPA 18:2 (Avanti Polar Lipids catalog number 857138, 0.5 nM to 10 μM) was recorded to determine the EC of LPA 18:2 for subsequent antagonist assays 80It was determined. For the agonist dose curve, the cells were removed from the incubator 2 hours after dye loading and transferred to a FLIPR Tetra instrument (Molecular Devices, San Jose, CA). Calcium mobilization was monitored for 5 minutes, and 10 μL of 6×LPA in HBSS / 20 mM HEPES / 0.1% bovine serum albumin (BSA) was added to the cells for 5 seconds during the assay.

[0294] To determine the LPAR1 antagonist activity of the test compound, the cells were pre-incubated with the test compound in the dose range of 0.5 nM to 10 μM, and then pre-incubated with LPA at the EC 80 concentration (100 nM). After dye loading, the cells were removed from the incubator, and 0.3 μL of 200× antagonist was added. The cells were incubated at 37 °C for 60 minutes. Antagonist activity was measured with a FLIPR Tetra. Calcium mobilization was monitored for 3.5 minutes, and 10 μL of 6×EC 80 LPA, 20 mM HEPES, and 0.1% BSA were added to the cells for 5 seconds during the assay. The signal amplitude (maximum minus minimum) value was plotted against the log of the antagonist concentration using a dose-response tool (Gilead Sciences Inc.) to determine the EC 10 50

[0295] To evaluate the antagonist potential of the exemplified compounds, the EC 50 values were determined for Compounds 1 to 55 in the LPAR1 calcium mobilization assay. The results are shown in Table 2 (LPAR1 EC 50 ). The compound numbers correspond to the compound numbers of Examples 1 to 35. N / A means not applicable.

Table 2-1

Table 2-2

[0296] ​​ 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.

[0297] Accordingly, although the present disclosure has been specifically disclosed by way of preferred embodiments, any features, modifications, improvements, and variations of the disclosure embodied herein that are disclosed in this specification may be reused by one of ordinary skill in the art, and it should be understood that such modifications, improvements, and variations are considered to be within the scope of the present disclosure. The materials, methods, and examples provided herein are representative of the preferred embodiments, are illustrative, and are not intended as limitations on the scope of the present disclosure.

[0298] The present disclosure has been described herein in a broad and comprehensive manner. Each of the more specific species and subgeneric groups falling within the scope of the comprehensive disclosure also forms part of the present disclosure. This includes the general description of the present disclosure with conditional or negative limitations removing any subject from the genus, whether or not the deleted material is specifically recited herein.

[0299] In addition, when a feature or aspect of the present disclosure is described in terms of a Markush group, one of ordinary skill in the art will recognize that the present disclosure is also described in terms of any individual member or subgroup of members of the Markush group.

[0300] The present disclosure has been described in conjunction with the above embodiments, but it should be understood that the foregoing description and examples are intended to be illustrative and not to limit the scope of the present disclosure. Other aspects, advantages, and modifications within the scope of the present disclosure will be apparent to one of ordinary skill in the art to which the present disclosure pertains. The present invention provides, for example, the following items. (Item 1) A compound of formula (I),

Chemical formula

Chemical formula

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Chemical formula

Claims

1. One compound of the following formulas (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), and (IIl), 【Chemical Formula 1-1】 【Chemical Formula 1-2】 or a pharmaceutically acceptable salt thereof, wherein, For formulas (IIb) to (IIk), R １Ａ１ is C １～６ alkyl, optionally substituted with 1 to 4 R １Ｂ which may be the same or different, where each R １Ｂ is independently selected from halogen, cyano, hydroxy, C １～４ alkoxy, and C ３～６ cycloalkyl, or For formulas (IIb), (IIg), (IIh) and (IIi), R １Ａ１ is -O-R １Ｆ１ wherein R １Ｆ１ is C １～６ alkyl, optionally substituted with one to three halogens, or For formulas (IIc) to (IIk), R １Ａ１ is cyclopropyl or cyclobutyl, and is optionally substituted with the same or different one to four Rs ２ each independently selected from -F, -CN, -CHF ３ -, -CF ３ -, -OCH １Ｂ -, and pyridyl, or For formulas (IIc) to (IIk), R １Ａ１ is bicyclopentanyl and is optionally substituted with the same or different one to three substituents each independently selected from -F, -CN, -CHF ２ and oxetanyl, or For formulas (IIc) to (IIk), R １Ａ１ is pyridinyl or pyrimidinyl, and is each independently selected from -Cl, -CHF ２ , and -CF ３ and is each optionally substituted with the same or different 1 to 3 substituents each independently selected therefrom Each R ２ is independently selected from deuterium, halogen, C １～６ alkyl, C ３～６ cycloalkyl, -O-R ２Ａ１ , and -N(R ２Ａ１ )(R ２Ａ２ ), and the C １～６ alkyl is optionally substituted with one to three substituents, the same or different, independently selected from C １～４ alkoxy and halogen, and each R ２Ａ１ and R ２Ａ２ is independently hydrogen or C １～３ alkyl optionally substituted with one to three halogens, the same or different. Y １ is methyl optionally substituted with 1 to 3 identical or different substituents each independently selected from hydrogen, or -F, -Cl, -CN, and -O-CH ３ and Z is C ６～１２ aryl, optionally substituted with the same or different 1 to 3 substituents each independently selected from halogen, cyano, C １～４ alkyl, C １～４ alkoxy, and C ３～６ cycloalkyl, where the C １～４ alkyl is optionally substituted with the same or different 1 to 3 substituents each independently selected from C １～４ alkoxy and halogen, or Z is a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where , wherein the heteroaryl is optionally substituted with the same or different 1 to 3 substituents each independently selected from halogen and C １～４ alkyl a compound, or a pharmaceutically acceptable salt thereof.

2. (a) For formula (IIb) to (IIk), R １Ａ１ is, -CH ３ , 【Chemical Formula 2-1】 or (b) For formulas (IIb), (IIg), (IIh), and (IIi), R １Ａ１ is 【Chemical Formula 2-2】 or (c) For formula (IIc) to (IIk), R １Ａ１ is 【Chemical 2-3】 or (d) For formula (IIc) to (IIk), R １Ａ１ is ​ or (e) For formulas (IIc) to (IIk), R １Ａ１ is 【Chemical 2-5】 or the compound according to Claim 1, or a pharmaceutically acceptable salt thereof.

3. (1) Each R ２ is independently selected from deuterium, halogen, C １～６ alkyl, C ３～６ cycloalkyl, -O-R ２Ａ１ , and -N(R ２Ａ１ )(R ２Ａ２ ), and the C １～６ alkyl is optionally substituted with one to three substituents, the same or different, independently selected from C １～４ alkoxy and halogen. In the formula, each R ２Ａ１ and R ２Ａ２ is independently hydrogen or C １～４ alkyl optionally substituted with one to three halogens, the same or different, or Each R ２ is independently selected from halogen, or halogen, cyano, C １～４ alkoxy, and C ３～１０ alkyl, which may be the same or different, and is optionally substituted with 1 to 3 substituents independently selected from cycloalkyl １～６ is independently selected from alkyl, or Each R ２ is independently selected from -F and -CH ３ and / or (2) Y １ is -CH ３ and / or (3) Z is phenyl optionally substituted with one to three substituents, the same or different, each independently selected from -F and -Cl, or Z is 【Chemical Formula 3-1】 or Z is pyridyl optionally substituted with one to three substituents, the same or different, each independently selected from -F and -Cl, or Z is 【Chemical Formula 3-2】 or (4) Y １ is -CH ３ and Z is [Chemical Formula 3-3] or the compound according to Claim 1, or a pharmaceutically acceptable salt thereof.

4. The following: 【Chemical Formula 4A-1】 【Chemical Formula 4A-2】 【Chemical Formula 4A-3】 【Chemical Formula 4A-4】 or a pharmaceutically acceptable salt thereof, [Chemical Formula 4B] or a pharmaceutically acceptable salt thereof, [Chemical Formula 4C] or a pharmaceutically acceptable salt thereof, 【Chemical 4D】 or a pharmaceutically acceptable salt thereof, 【Chemical Formula 4E】 or a pharmaceutically acceptable salt thereof, 【Chemical Formula 4F】 or a pharmaceutically acceptable salt thereof, [Chemical Formula 4G] or a pharmaceutically acceptable salt thereof The compound according to Claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of.

5. The following: 【Chemical Formula 5-1】 ​ A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

7. The pharmaceutical composition according to Claim 6, further comprising an additional therapeutic agent.

8. For use in a method of treating or stabilizing an LPAR1-mediated disease or condition, or reducing its severity or progression, in a patient in need thereof, the pharmaceutical composition according to Claim 6, wherein the LPAR1-mediated disease or condition is (A) selected from the group consisting of wound healing, cancer, pain, respiratory disorders, allergic disorders, nervous system disorders, cardiovascular disorders, and inflammatory disorders. (B) Interstitial lung disease (ILD), where optionally, the interstitial lung disease (ILD) is non-specific interstitial pneumonia (NSIP), sarcoidosis, asbestosis, ILD related to occupational exposure, progressive fibrotic ILD, idiopathic interstitial pneumonia (IIP), connective tissue disease-related interstitial pneumonia (CTD-ILD), rheumatoid arthritis-related ILD, scleroderma-related ILD, or exogenous alveolitis. (C) Chronic kidney disease (CKD), where optionally, the CKD is complement glomerulopathy, membranous glomerulopathy, polycystic kidney disease, IgA nephropathy, focal segmental glomerulosclerosis (FSGS), or Alport syndrome. (D) Including fibrosis, where optionally, the fibrosis is pulmonary fibrosis, renal fibrosis, hepatic fibrosis, ocular fibrosis, cardiac fibrosis, or systemic sclerosis. Here, optionally, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF) or progressive fibrotic interstitial lung disease (PF-ILD), or is secondary to a systemic inflammatory disease, where optionally, the systemic inflammatory disease is rheumatoid arthritis, scleroderma, lupus, idiopathic fibrotic alveolitis, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, chronic asthma, silicosis, asbestos-induced pulmonary or pleural fibrosis, acute lung injury or acute respiratory distress, and where optionally, the renal fibrosis is related to diabetic kidney disease. (E) Liver disease, where optionally, the liver disease includes (i) hepatic fibrosis and / or (ii) non-alcoholic fatty liver disease (NAFLD) and / or (iii) steatosis and / or (iv) non-alcoholic steatohepatitis (NASH) and / or (v) cirrhosis (where optionally, the cirrhosis is compensated cirrhosis or decompensated cirrhosis), and / or (vi) hepatocellular carcinoma (HCC), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), or portal hypertension. Pharmaceutical composition.

9. The pharmaceutical composition according to claim 8, characterized in that the pharmaceutical composition is administered in combination with an additional therapeutic agent.

10. The pharmaceutical composition according to claim 9, wherein the additional therapeutic agent is 1, 2, 3, or 4 additional therapeutic agents.

11. The pharmaceutical composition according to claim 9, wherein the additional therapeutic agent comprises an acetyl-CoA carboxylase (ACC) inhibitor, an apoptosis signal-regulating kinase (ASK-1) inhibitor, a farnesoid X receptor (FXR) agonist, fish oil, a glucagon-like peptide-1 receptor agonist, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, or a TGFβ antagonist, wherein optionally, the ACC inhibitor is fildesostat, or the ASK1 inhibitor is selonsertib, or the FXR agonist is cilofexor, or the PPARα agonist is a fibrate, or the fish oil is ethyl eicosapentaenoate, or the GLP-1 receptor agonist is liraglutide or semaglutide, or the TGFβ antagonist is an anti-TGFβ1 specific antibody or a TGFβ receptor, or the additional therapeutic agent comprises fildesostat and cilofexor, or the additional therapeutic agent comprises fildesostat and liraglutide or semaglutide, or the additional therapeutic agent comprises a fibrate or ethyl eicosapentaenoate, or the additional therapeutic agent comprises cilofexor and liraglutide or semaglutide, Pharmaceutical composition.

12. The additional therapeutic agent is a VEGFR inhibitor, FGFR inhibitor, PDGFR inhibitor, autotaxin inhibitor, GPR84 agonist, PASK inhibitor, CFTR agonist, JAK1 inhibitor, ADAMTS5 inhibitor, TOL2 / 3 inhibitor, CTGF inhibitor, soluble PTX2, anti-galectin-3 antibody, integrin-α Ｖ -β ６ / α Ｖ -β １ antagonist, JNK1 inhibitor, mineralocorticoid receptor antagonist, Nrf2 activator, chemase inhibitor, PDE inhibitor, NOX1 / 4 inhibitor, leukotriene / thromboxane receptor antagonist, SLC22A12 inhibitor, sGC inhibitor, or xanthine oxidase inhibitor, or the additional therapeutic agent is selected from the group consisting of nintedanib, pirfenidone, pembrolizumab, PRM-151, GB-0139, PLN-74809, CC-90001, finerenone, BAY1142524, PCS-499, cetnarib, SER150, RDEA3170, praliciguat, TMX-049, GLPG1690, GLPG1205, GLPG1972, GLPG4059, GLPG2737, GLPG3970, and filgotinib. The pharmaceutical composition according to claim 9.

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