Compounds and compositions for treating conditions associated with LPA receptor activity

Abstract

The present disclosure provides LPA antagonists and pharmaceutical compositions comprising the compounds disclosed herein. Methods for treating LPA-related diseases, disorders, and conditions are also provided.

Description

Cross - Reference to Related Applications

[0001] This application claims the benefit of International Patent Application No. PCT / CN2022 / 134099, filed on November 24, 2022, the content of which is hereby incorporated herein by reference in its entirety. Technical Field

[0002] The present disclosure provides LPA antagonists and pharmaceutical compositions comprising the compounds disclosed herein. Also provided are methods for treating LPA - related diseases, disorders, and conditions. Background Art

[0003] A variety of lipid mediators, including eicosanoids and platelet - activating factor (PAF), are generated by the activity of phospholipases from cell membranes. Lysophospholipids are a class of membrane - derived bioactive lipid mediators and include lysophosphatidic acid (LPA). LPA is not a single molecular entity but a collection of endogenous structural variants with fatty acids of different lengths and saturations. LPA affects cell functions including cell proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. These functions influence many biological processes including neurogenesis, angiogenesis, wound healing, immunity, and tumorigenesis. LPA has a role as a bio - effector molecule and has a wide range of physiological effects (such as but not limited to effects on blood pressure, platelet activation, and smooth muscle contraction), as well as a variety of cellular effects, including cell growth, cell rounding, neurite retraction, and actin stress fiber formation and cell migration. The effects of LPA are mainly receptor - mediated. Activation of LPA receptors (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) with LPA mediates a series of downstream signal transduction cascades. Summary of the Invention

[0004] Antagonistic LPA receptors, such as the LPA1 receptor, can be used to treat a variety of disorders, including fibrosis such as pulmonary fibrosis, hepatic fibrosis, renal fibrosis, arterial fibrosis, and systemic sclerosis, and diseases caused thereby (e.g., pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis (IPF)), hepatic fibrosis (including non - alcoholic steatohepatitis (NASH)), renal fibrosis (such as diabetic nephropathy), systemic sclerosis - scleroderma, etc.), COVID - 19, chronic obstructive pulmonary disease (COPD), neuroinflammation, or multiple sclerosis. This application describes LPA antagonists and pharmaceutical compositions comprising the compounds disclosed herein. Also provided are methods for treating LPA - related diseases, disorders, and conditions.

[0005] In one embodiment, the present disclosure provides a compound of Formula I: or a pharmaceutically acceptable salt or solvate thereof, wherein: A is C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each C of A 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1 substituents; L 1 is a bond, -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -, C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene or C 1-3 heteroalkylene; wherein L 1 's C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene or C 1-3 heteroalkylene is independently optionally substituted by one to five substituents independently selected from C 1-9 alkyl, halo, hydroxy and cyano; L 2 is a bond, C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene or C 1-3 heteroalkylene; wherein L 2 's C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene or C 1-3 heteroalkylene is independently optionally substituted by one to five substituents independently selected from C 1-9 alkyl, halo, hydroxy and cyano; X 1 is N or CR 3 ; X 2 is N or CR 5 ; X 3 is N or CR 7 ; X 6 is N or CR 6 ; X 4 is O or CHR 11 ; provided that when A is C 1-6 alkyl, then X 4 is O; Y 2 、Y 3 and Y6 One of them is N, and Y 2 , Y 3 and Y 6 and the others are each independently CR 13 ; n is 0, 1 or 2; R 1 and R 2 are each independently C 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10 cycloalkyl or heterocyclic group; wherein each C of R 1 and R 2 alkyl, C 1-9 alkenyl, C 2-9 alkynyl, C 2-9 cycloalkyl or heterocyclic group is independently optionally substituted by one to five Z 3-10 ; 1 substituted; Or R 1 and R 2 together with the atoms to which they are attached form a C 3-10 cycloalkyl or heterocyclic group; wherein the C 3-10 cycloalkyl or heterocyclic group is optionally substituted by one to five Z 1 ; R 3 is hydrogen, halogen, cyano, nitro, -OH, -SH, -NH2, -NH-C 1-5 alkyl, -N(C 1-5 alkyl)2, -S-C 1-5 alkyl, C 1-5 alkoxy, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or 3-5 membered heterocyclic group; wherein the -NH-C of R 3 alkyl, -N(C 1-5 alkyl)2, -S-C 1-5 alkyl, C 1-5 alkoxy, C 1-5 alkyl, C 1-5 alkenyl, C 2-5 alkynyl, C 2-5 cycloalkyl or 3-5 membered heterocyclic group is independently optionally substituted by one to five substituents independently selected from halogen, hydroxy and cyano; 3-5 substituted; R 4 is halogen, cyano, nitro, -OR 14 , -N(R 14 )2, -SR 14, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclic group; wherein R 4 's C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halo, hydroxy, C 1-5 alkoxy, and cyano; Or R 3 and R 4 together with the atoms to which they are attached form a cycloalkyl, aryl, heterocyclic, or heteroaryl group; wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally substituted with one to five substituents independently selected from halo, hydroxy, and cyano; R 5 is hydrogen, halo, cyano, nitro, -OR 15 , -N(R 15 )2, -SR 15 , -C(O)R 15 , -C(O)OR 15 , C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, 3- to 5-membered heterocyclic, or 5-membered heteroaryl group; wherein R 5 's C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, 3- to 5-membered heterocyclic, or 5-membered heteroaryl group is independently optionally substituted with one to five Z 1 substituents; R 6 is hydrogen, halo, cyano, nitro, -OR 16 , -N(R 16 )2, -SR 16 , C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclic group; wherein R 6 's C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halo, hydroxy, and cyano; R7 is hydrogen, a halogenated group, a cyano group, a nitro group, -OH, -SH, -NH2, -NH-C 1-5 alkyl, -N(C 1-5 alkyl)2, -S-C 1-5 alkyl, C 1-5 alkoxy, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group; wherein R 7 of -NH-C 1-5 alkyl, -N(C 1-5 alkyl)2, -S-C 1-5 alkyl, C 1-5 alkoxy, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halogenated groups, hydroxyl groups, and cyano groups; or R 6 and R 7 together with the atoms to which they are attached form a cycloalkyl group, an aryl group, a heterocyclic group, or a heteroaryl group; wherein the cycloalkyl group, aryl group, heterocyclic group, or heteroaryl group is optionally substituted with one to five substituents independently selected from halogenated groups, hydroxyl groups, and cyano groups; R 8 is hydrogen, C 1-9 alkyl, a halogenated group, a hydroxyl group, or a cyano group; each R 9 is independently hydrogen, C 1-9 alkyl, a halogenated group, a hydroxyl group, or a cyano group; R 10 is hydrogen, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group; wherein R 10 of C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halogenated groups, hydroxyl groups, and cyano groups; R 11 is hydrogen, C 1-9 alkyl, an oxo group, a halogenated group, a hydroxyl group, or a cyano group; each R 13 is independently hydrogen, a halogenated group, a cyano group, a nitro group, -OH, -SH, -NH2, -NH-C1-9 alkyl, -N(C 1-9 alkyl)2, -S-C 1-9 alkyl, C 1-9 alkoxy, C 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group; wherein each -NH-C 13 alkyl, -N(C 1-9 alkyl)2, -S-C 1-9 alkyl, C 1-9 alkoxy, C 1-9 alkyl, C 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halo, hydroxy, and cyano; R 14 is hydrogen, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group; wherein the C 14 alkyl, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halo, hydroxy, and cyano; R 15 is hydrogen, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group; wherein the C 15 alkyl, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halo, hydroxy, and cyano; R 16 is hydrogen, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group; wherein the C 16 alkyl, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C3-5 The cycloalkyl or 3- to 5-membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halo, hydroxy, and cyano; Each Z 1 is independently halo, cyano, nitro, oxo, C 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -L-H, -L-C 1-9 alkyl, -L-C 2-9 alkenyl, -L-C 2-9 alkynyl, -L-C 3-10 cycloalkyl, -L-heterocyclic group, -L-aryl or -L-heteroaryl; wherein each C 1 of Z 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted with one to five Z 1a substituents; Each L is independently -O-, -S-, -NR 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -, -NR 20 C(O)-, -OC(O)NR 20 -, -NR 20 C(O)O-, -NR 20 C(O)NR 21 -, -S(O)-, -S(O)2-, -S(O)NR 20 -, -S(O)2NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR 20 S(O)NR 21 -, or -NR 20 S(O)2NR 21 -; Each R 20 and R 21 is independently hydrogen, C 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C 20 of R 21 and R 1-9 alkyl, C 2-9 alkenyl, C2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted with one to five Z 1a ; or R 20 and R 21 together with the atoms to which they are attached form a heterocyclic group independently optionally substituted with one to five Z 1a ; and each Z 1a is independently a halogen group, hydroxyl group, cyano group, nitro group, oxo group, -SH, -NH2, -NH-C 1-9 alkyl, -N(C 1-9 alkyl)2, -S-C 1-9 alkyl, C 1-9 alkoxy, C 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each -NH-C 1a alkyl, -N(C 1-9 alkyl)2, -S-C 1-9 alkyl, C 1-9 alkoxy, C 1-9 alkyl, C 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted with one to five substituents independently selected from C 1-9 alkyl, oxo group, halogen group, hydroxyl group and cyano group.

[0006] In one embodiment, there is provided a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, there is provided a compound of Table 2 or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers thereof.

[0007] Also provided herein are pharmaceutical compositions comprising a compound of Table 1 or Table 2 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.

[0008] Also provided herein is a method for treating or preventing an LPA-related disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Table 1 or Table 2 or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition thereof. In some embodiments, the LPA-related disease is an LPA1-related disease such as, but not limited to, fibrosis, transplant rejection, cancer, osteoporosis or inflammatory disorders.

[0009] In some embodiments, the LPA-related disease is fibrosis, transplant rejection, cancer, osteoporosis, or an inflammatory disorder. In certain embodiments of these embodiments, the fibrosis is pulmonary, hepatic, renal, cardiac, dermal, ocular, or pancreatic fibrosis. In certain embodiments, the cancer is cancer of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gallbladder, genitalia, genitourinary tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral mucosa or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testis, or thyroid.

[0010] In some embodiments, the LPA-related disease is idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, systemic sclerosis, COVID-19, chronic obstructive pulmonary disease (COPD), neuroinflammation, or multiple sclerosis.

[0011] Also provided herein are methods for treating or preventing fibrosis in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Table 1 or Table 2 or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof.

[0012] In some embodiments, the fibrosis is idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), chronic kidney disease, diabetic kidney disease, and systemic sclerosis. For example, the fibrosis can be IPF. Detailed Description Definitions

[0013] The following description sets forth exemplary embodiments of the technology of the present invention. However, it should be recognized that such description is not intended as a limitation on the scope of the present disclosure, but rather is provided as a description of exemplary embodiments.

[0014] As used in this specification, the following words, phrases, and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0015] A dash (“-”) not located between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -C(O)NH2 is attached through the carbon atom. Dashes at the front or end of a chemical group are for convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy or dashed line drawn through a bond in a structure indicates the designated 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 or stereochemistry.

[0016] The prefix "C" u-v " indicates that the following group has u to v carbon atoms. For example, "C" 1-6 "alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0017] As used herein, the term "about" a value or parameter includes (and describes) embodiments that relate to that value or parameter itself. In certain embodiments, the term "about" includes ±10% of the indicated amount. In other embodiments, the term "about" includes ±5% of the indicated amount. In certain other embodiments, the term "about" includes ±1% of the indicated amount. Additionally, the term "about X" includes a description of "X". Further, unless the context clearly dictates otherwise, the singular forms "a / an" and "the" include plural referents. Thus, for example, reference to "a compound" includes multiple such compounds, and reference to "the assay" includes reference to one or more assays known to those skilled in the art and their equivalents.

[0018] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 12 carbon atoms (i.e., C 1-12 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl) or 1 to 4 carbon atoms (i.e., C 1-4 alkyl). Examples of alkyl include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by a chemical name or identified by a molecular formula, all positional isomers having that number of carbons can be encompassed; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0019] "Alkenyl" refers to such an alkyl that contains at least one (e.g., 1 - 3 or 1) carbon-carbon double bond and has from 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 12 carbon atoms (i.e., C 2-12 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6(alkenyl) or from 2 to 4 carbon atoms (i.e., C 2-4 (alkenyl). Examples of alkenyl include, for example, vinyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0020] "Alkynyl" refers to such alkyl groups that contain at least one (e.g., 1-3 or 1) carbon-carbon triple bond and have from 2 to 20 carbon atoms (i.e., C 2-20 (alkynyl), from 2 to 12 carbon atoms (i.e., C 2-12 (alkynyl), from 2 to 8 carbon atoms (i.e., C 2-8 (alkynyl), from 2 to 6 carbon atoms (i.e., C 2-6 (alkynyl) or from 2 to 4 carbon atoms (i.e., C 2-4 (alkynyl). The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0021] Certain common alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may also be referred to as "alkylene" groups (or "alkylenyl" groups), "arylene" groups (or "arylenyl" groups), respectively.

[0022] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy, and 1,2-dimethylbutoxy.

[0023] "Haloalkyl" refers to a straight-chain or branched-chain alkyl as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen. For example, when the residue is substituted by more than one halogen, it can be referred to by using a prefix corresponding to the number of attached halogen moieties. Dihaloalkyl and trihaloalkyl refer to an alkyl substituted by two ("di") or three ("tri") halo groups, which may or may not be the same halogen. Examples of haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0024] "Haloalkoxy" refers to an alkoxy as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.

[0025] "Hydroxyalkyl" refers to an alkyl as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a hydroxy group.

[0026] "Alkylthio" refers to the group "alkyl-S-".

[0027] "Acyl" refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl, or heteroaryl; as defined herein, each of which may be optionally substituted. Examples of acyl groups include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0028] "Amido" refers to the "C-amido" group (which refers to the group -C(O)NR y R z ) and the "N-amido" group (which refers to the group -NR y C(O)R z ), where R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl, or heteroaryl; as defined herein, each of which may be optionally substituted, or R y and R z together form a cycloalkyl or heterocycloalkyl; as defined herein, each of which may be optionally substituted.

[0029] "Amino" refers to the group -NR y R z , where R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl, or heteroaryl; as defined herein, each of which may be optionally substituted.

[0030] "Amidino" refers to -C(NR y )(NR z 2), where R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl, or heteroaryl; as defined herein, each of which may be optionally substituted.

[0031] "Aryl" refers to an aromatic carbocyclic group having a monocyclic (e.g., monocyclic) or polycyclic (e.g., bicyclic or tricyclic) structure, including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbocyclic atoms (i.e., C 6-12 aryl), or 6 to 10 carbocyclic atoms (i.e., C 6-10aryl). Examples of aryl include, for example, phenyl, naphthyl, fluorenyl, and anthracenyl. However, aryl does not in any way encompass or overlap with heteroaryl as defined below. If one or more aryl groups are fused to a heteroaryl, the resulting ring system is heteroaryl, regardless of the point of attachment. If one or more aryl groups are fused to a heterocyclic group, the resulting ring system is heterocyclic, regardless of the point of attachment. If one or more aryl groups are fused to a cycloalkyl, the resulting ring system is cycloalkyl, regardless of the point of attachment.

[0032] "Carbamoyl" refers to an "O-carbamoyl" group, which refers to -O-C(O)NR y R z group; and an "N-carbamoyl" group, which refers to -NR y C(O)OR z group, where R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; as defined herein, each of which may be optionally substituted.

[0033] "Carboxylate ester" or "ester" refers to both -OC(O)R x and -C(O)OR x where R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; as defined herein, each of which may be optionally substituted.

[0034] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl having a single ring or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl (i.e., a cyclic group having at least one double bond) and a carbocyclic fused ring system having at least one sp 3 carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., C 3-14 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 3-6cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. In addition, the term cycloalkyl is intended to cover any non-aromatic ring that can be fused to an aryl ring, regardless of its attachment to the rest of the molecule. In addition, when there are two substitution positions on the same carbon atom, cycloalkyl also includes "spirocycloalkyl", such as spiro[2.5]octyl, spiro[4.5]decyl, or spiro[5.5]undecyl.

[0035] "Imino" refers to the group -C(NR y )R z , where R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; as defined herein, each of which may optionally be substituted.

[0036] "Halogen" or "halo" refers to an atom occupying Group VIIA of the periodic table, such as fluorine, chlorine, bromine or iodine.

[0037] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatom groups. The term "heteroalkyl" includes straight or branched saturated chains having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may independently be replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, etc., where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclic, each of which may optionally be substituted. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3 and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl or heteroaryl, each of which may optionally be substituted. As used herein, heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom.

[0038] "Heteroalkylene" refers to a divalent heteroalkyl group. The "heteroalkylene" group must have at least one carbon and at least one heteroatom group within the chain. The term "heteroalkylene" includes straight or branched saturated chains having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may independently be replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR y-, -O-, -S-, -S(O)-, -S(O)2-, etc., where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; as defined herein, each of which may optionally be substituted. Examples of heteroalkylene include, for example, -CH2OCH2-, -CH(CH3)OCH2-, -CH2CH2OCH2-, -OCH2-, -CH(CH3)O-, -CH2CH2O-, -CH2CH2OCH2CH2OCH2-, -CH2CH2OCH2CH2O-, -CH2SCH2-, -CH(CH3)SCH2-, -CH2CH2SCH2-, -CH2CH2SCH2CH2SCH2-, -SCH2-, -CH(CH3)S-, -CH2CH2S-, -CH2CH2SCH2CH2S-, -CH2S(O)2CH2-, -CH(CH3)S(O)2CH2-, -CH2CH2S(O)2CH2-, -CH2CH2S(O)2CH2CH2OCH2-, -CH2NR y CH2-, -CH(CH3)NR y CH2-, -CH2CH2NR y CH2-, -CH2CH2NR y CH2CH2NR y CH2-, etc., where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted, as defined herein. As used herein, heteroalkylene includes 1 to 10 carbon atoms, 1 to 8 carbon atoms or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom. As used herein, the term "heteroalkylene" does not include groups such as amides or other functional groups having an oxo group on one or more carbon atoms.

[0039] "Heteroaryl" refers to an aromatic group having a single ring or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C 1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12 heteroaryl) or 3 to 8 carbocyclic atoms (i.e., C 3-8heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom, said ring heteroatoms being independently selected from nitrogen, oxygen and sulfur. In certain cases, the heteroaryl includes a 5- to 10-membered ring system, a 5- to 7-membered ring system or a 5- to 6-membered ring system, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom, said ring heteroatoms being independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzoxazolyl, benzothienyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothienyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, tetrazolyl and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thienyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl and imidazo[1,5-a]pyridinyl, wherein the heteroaryl can be attached via any ring of the fused system. Any aromatic ring having a single or multiple fused rings containing at least one heteroatom is considered a heteroaryl, regardless of the attachment to the rest of the molecule (i.e., via any one of the fused rings). Heteroaryl does not encompass aryl as defined above or overlap with aryl as defined above.

[0040] "heterocyclyl" means a saturated or partially unsaturated cyclic alkyl group in which one or more ring heteroatoms are independently selected from nitrogen, oxygen and sulfur. The term "heterocyclyl" includes heterocyclenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups and spiroheterocyclyl groups. The heterocyclyl can be monocyclic or polycyclic, where the polycyclic can be fused, bridged or spirocyclic, and can include one or more (e.g., 1 to 3) oxo(=O) or N-oxides (-O -) moiety. Any non-aromatic ring or fused ring system containing at least one heteroatom and a non-aromatic ring is considered a heterocyclic group, regardless of the connection to the rest of the molecule. For example, fused ring systems such as decahydroquinazolinyl, 1,2,3,4-tetrahydroquinazolinyl, and 5,6,7,8-tetrahydroquinazolinyl are heterocyclic groups regardless of the connection (i.e., can be attached through a carbon atom or a heteroatom). In addition, the term heterocyclic group is intended to cover any non-aromatic ring containing at least one heteroatom, which ring can be fused to a cycloalkyl, aryl, or heteroaryl ring, regardless of the attachment to the rest of the molecule. As used herein, a heterocyclic group has 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclic group), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclic group), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclic group), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclic group), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclic group), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclic group), or 3 to 6 ring carbon atoms (i.e., C 3-6(heterocyclic group); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, the ring heteroatoms being independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclic groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranone, benzofuranone, dioxolyl, dihydropyranyl, hydropyranyl, thieno[1,3]dithianyl, decahydroisoquinolinyl, furanone, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidinone, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiomorpholinyl, thioxomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. When there are two substitution positions on the same carbon atom, the term "heterocyclic group" also includes "spiroheterocyclic group". Examples of spiroheterocyclic rings include, for example, bicyclic ring systems and tricyclic ring systems, such as oxabicyclo[2.2.2]octyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, and 6-oxa-1-azaspiro[3.3]heptyl. Examples of fused heterocyclic rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclic group can be attached via any ring of the fused system.

[0041] "Sulfonyl" means the group -S(O)2R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroalkyl, or heteroaryl; as defined herein, each of which may optionally be substituted. Examples of sulfonyl groups are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0042] "Alkylsulfonyl" means the group -S(O)2R, where R is alkyl.

[0043] "Alkylsulfinyl" means the group -S(O)R, where R is alkyl.

[0044] The term "optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and the description includes the case where the event or circumstance occurs and the case where the event or circumstance does not occur. In addition, the term "optionally substituted" means that any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on a specified atom or group may or may not be replaced by a moiety other than hydrogen.

[0045] As used herein, the term "compound" means any and all stereoisomers, geometric isomers, tautomers, and isotope-enriched analogs (e.g., deuterated analogs) of the depicted structure. Unless otherwise stated, a compound identified herein by name or structure as a specific tautomeric form is intended to include other tautomeric forms.

[0046] Some of the compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, a compound containing an amide may exist in equilibrium with an imino acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between the tautomers, one of ordinary skill in the art will understand the compound to include both the amide and imino acid tautomers. Thus, a compound containing an amide should be understood to include its imino acid tautomers. Similarly, a compound containing an imino acid should be understood to include its amide tautomers.

[0047] Any compound or structure obtained herein is also intended to represent both the unlabeled form and the isotope-labeled form of the compound. These forms of the compound may also be referred to as "isotope-enriched analogs". An isotope-labeled compound has the structure depicted herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 I. A variety of isotope-labeled compounds incorporated into the present disclosure, for example, incorporating radioactive isotopes such as 3 H and 14compounds of (C). Such isotopically labeled compounds can be used in metabolic studies, reaction kinetics studies, detection or imaging techniques (such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including determination of drug or substrate tissue distribution), or in the radioactive treatment of patients.

[0048] The term “isotope-enriched analog” includes “deuterated analogs” of the compounds described herein, in which one or more hydrogens (such as hydrogens on carbon atoms) are replaced by deuterium. These compounds exhibit increased metabolic resistance and can therefore be used to increase the half-life of any compound when administered to mammals (especially humans). 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 using starting materials in which one or more hydrogens have been replaced by deuterium.

[0049] The deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, related to distribution, metabolism and excretion (ADME). Replacement with a heavier isotope such as deuterium can provide certain therapeutic advantages due to higher metabolic stability, such as an extended in vivo half-life, reduced dose requirements and / or improved therapeutic index. 18 F, 3 H, 11 The C-labeled compounds can be used in PET or SPECT or other imaging studies. The isotopically labeled compounds and prodrugs of the present disclosure can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents, by carrying out the procedures disclosed in the schemes or in the Examples and Preparations described below. It should be understood that deuterium is considered a substituent in the compounds described herein in this context.

[0050] The concentration of such heavier isotopes (especially deuterium) can be defined by an isotope enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as “H” or “hydrogen,” the position is understood to have the hydrogen with its natural abundance isotope composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0051] In many cases, due to the presence of amino and / or carboxyl groups or groups similar thereto, the compounds of the present disclosure are capable of forming acidic and / or basic salts.

[0052] Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0053] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts formed with inorganic acids and salts formed with organic acids. Additionally, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, addition salts (especially pharmaceutically acceptable addition salts) can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize a variety of synthetic methods useful for preparing non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic acids and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic bases and organic bases. By way of example only, salts derived from inorganic bases include sodium salts, potassium salts, lithium salts, aluminum salts, ammonium salts, calcium salts and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of NH3 or primary, secondary, tertiary amines, such as salts derived from N-containing heterocycles, N-containing heteroaryls or amines of the formula N(R N )3 (e.g., HN + (R N )3 or (alkyl)N + (R N )3), where each R N is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl, each of which is optionally substituted, such as by one or more (e.g., 1-5 or 1-3) substituents (e.g., halo group, cyano group, hydroxyl group, amino group, alkyl group, alkenyl group, alkynyl group, haloalkyl group, alkoxy group or haloalkoxy group). By way of example only, specific examples of suitable amines include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, etc.

[0054] The term "substituted" means that any one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents that are not hydrogen, provided that the normal valence of the specified atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxy, carboxyester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclic, hydroxy, hydrazino, imino, oxo, nitro, alkanesulfinyl, sulfonic acid, alkanesulfonyl, thiocyanate, thiol, thione, or combinations thereof. In some embodiments, the one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxy, carboxyester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, hydroxyalkyl, haloalkoxy, haloalkoxyalkyl, heteroalkyl, heteroaryl, heterocyclic, hydroxy, hydrazino, imino, imido, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, thione, or combinations thereof.

[0055] Polymers or similar indefinite structures obtained by defining substituents with an unlimited number of additional substituents (e.g., a substituted aryl having a substituted alkyl, the substituted alkyl itself being substituted by a substituted aryl, the substituted aryl being further substituted by a substituted heteroalkyl, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of consecutive substitutions in the compounds described herein is three. For example, the consecutive substitution of an aryl substituted by two other substituted aryls is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definitions are not intended to include non-permitted substitution patterns (e.g., a methyl substituted by 5 fluorines or a heteroaryl having two adjacent oxygen ring atoms). Such non-permitted substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" may describe other chemical groups as defined herein. Unless otherwise stated, when a group is described as optionally substituted, any substituent of the group itself is unsubstituted. For example, in some embodiments, the term "substituted alkyl" means an alkyl having one or more substituents, the one or more substituents including hydroxy, halo, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted by halo, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituent may be further substituted by halo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclic, aryl, or heteroaryl, each of which is unsubstituted.

[0056] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for a pharmaceutically active substance is well known in the art. Such conventional media or agents are considered for use in therapeutic compositions unless any of them are incompatible with the active ingredient. Supplementary active ingredients can also be incorporated into the compositions.

[0057] A "solvate" is formed by the interaction of a solvent with a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0058] As used herein, the term "LPA-related disease" means a disease, disorder or condition including but not limited to those in which activation of at least one LPA receptor by LPA contributes to the symptoms or progression of the disease, disorder or condition. These diseases, disorders or conditions can be caused by one or more of genetic, iatrogenic, immunologic, infectious, metabolic, neoplastic, toxic, surgical and / or traumatic etiologies. Thus, inhibiting the signaling of one or more lysophosphatidic acid (LPA) receptors (e.g., LPA1, LPA2, LPA3, LPA4, LPA5 or LPA6 receptors) can alter the course and / or symptoms and / or progression of the disease, disorder or condition. In some embodiments, the LPA-related disease is an LPA1-related disease, in which modulating LPA1 receptor signaling can alter the pathology and / or symptoms and / or progression of the disease, disorder or condition.

[0059] As used herein, the term "fibrosis" or "fibrotic disorder" refers to a condition associated with abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased fibroblast recruitment, including but not limited to fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract.

[0060] As used herein, the term "pharmaceutically acceptable" indicates that a compound or its salt or composition is chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the subject being treated therewith.

[0061] The term "administration" or "administering" refers to a method of giving a dose of a compound or pharmaceutical composition to a vertebrate or invertebrate (including a mammal, bird, fish or amphibian). The method of administration can vary depending on a variety of factors such as the components of the pharmaceutical composition, the site of the disease and the severity of the disease.

[0062] As used herein, the term "effective amount" or "effective dose" or "pharmaceutically effective amount" or "therapeutically effective amount" means an amount of a chemical entity (e.g., a compound of formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) administered that will, to some extent, alleviate one or more symptoms of the disease or disorder being treated and may include curing the disease. "Curing" means that the symptoms of the active disease are eliminated. Outcomes include a reduction and / or alleviation of the signs, symptoms, or causes of the disease and / or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound as disclosed herein required to provide a clinically significant reduction in the symptoms of the disease. The appropriate "effective" amount in any individual case is determined using any suitable technique, such as dose escalation studies. In some embodiments, a "therapeutically effective amount" of a compound as provided herein means an amount of the compound that is effective as a monotherapy or in combination therapy.

[0063] The term "excipient" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In some embodiments, a component is "pharmaceutically acceptable" in the sense that it is compatible with the other ingredients of the pharmaceutical formulation and suitable for contact with the tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st Edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th Edition; Edited by Rowe et al.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd Edition; Edited by Ash and Ash; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd Edition; Edited by Gibson; CRC Press LLC: Boca Raton, FL, 2009.

[0064] The term "pharmaceutical composition" refers to a mixture of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, as provided herein, with other chemical components (collectively referred to herein as "excipients") such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickening agents. The pharmaceutical composition facilitates the administration of the compound to an organism. There are various techniques for administering compounds in the art, including but not limited to rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0065] In the context of treating a disease, disorder, or condition, the terms "treat", "treating", and "treatment" are intended to include alleviating or eradicating the disorder, disease, or condition or one or more symptoms associated with the disorder, disease, or condition; or slowing the progression, spread, or worsening of the disease, disorder, or condition or one or more of its symptoms.

[0066] As used herein, the term "prevent" is to completely or partially prevent the onset, recurrence, or spread of a disease or condition or its symptoms as described herein.

[0067] As used herein, the terms "subject", "patient", or "individual" are used interchangeably and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the term refers to a subject in need of or desiring a diagnosis, prognosis, or therapy, particularly a mammalian subject. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibits at least one symptom of a disease, disorder, or condition to be treated and / or prevented.

[0068] The terms "treatment regimen" and "dosage regimen" are used interchangeably to refer to the dosage and timing of administration of each therapeutic agent in a combination.

[0069] As used herein, the term "drug combination" refers to a pharmaceutical treatment resulting from the mixing or combination of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.

[0070] As used herein, the term "combination therapy" refers to a dosage regimen of two different therapeutic active agents (i.e., the components or combination partners of the combination), where the therapeutic active agents are administered together or separately in a manner prescribed by a healthcare provider or in accordance with a regulatory body as defined herein.

[0071] As used herein, the term "modulate", "modulating", or "modulation" refers to regulating or adjusting (e.g., increasing or decreasing) and can include, for example, agonism, partial agonism, or antagonism. Compound

[0072] This document provides compounds that are LPA antagonists. In some embodiments, compounds of Formula I are provided: or a pharmaceutically acceptable salt or solvate thereof, wherein: A is C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each C of A 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1 substituents; L 1 is a bond, -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -, C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene or C 1-3 heteroalkylene; wherein the C of L 1 alkylene, C 1-3 alkenylene, C 2-3 alkynylene or C 2-3 heteroalkylene is independently optionally substituted by one to five substituents independently selected from C 1-3 alkyl, halo, hydroxy and cyano; L 2 is a bond, C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene or C 1-3 heteroalkylene; wherein the C of L 2 alkylene, C 1-3 alkenylene, C 2-3 alkynylene or C 2-3 heteroalkylene is independently optionally substituted by one to five substituents independently selected from C 1-3 alkyl, halo, hydroxy and cyano; X 1-9 is N or CR 1 ; X 3 is N or CR 2 ; X 5 is N or CR 3 ; X 7 is N or CR 6 ; X 6 is N or CR 4 ; X 11 is O or CHR; provided that when A is C 1-6 alkyl, then X 4 is O; Y 2 、Y 3 and Y 6 one of which is N, and Y 2 、Y 3 and Y 6 are each independently CR 13 ; n is 0, 1 or 2; R 1 and R 2 are each independently C 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10 cycloalkyl or heterocyclic group; wherein each C 1 of R 2 alkyl, C 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10 cycloalkyl or heterocyclic group is independently optionally substituted with one to five Z 1 substituents; or R 1 and R 2 together with the atoms to which they are attached form a C 3-10 cycloalkyl or heterocyclic group; wherein the C 3-10 cycloalkyl or heterocyclic group is optionally substituted with one to five Z 1 substituents; R 3 is hydrogen, halo, cyano, nitro, -OH, -SH, -NH2, -NH-C 1-5 alkyl, -N(C 1-5 alkyl)2, -S-C 1-5 alkyl, C 1-5 alkoxy, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclic group; wherein the -NH-C 3 alkyl, -N(C 1-5 alkyl)2, -S-C 1-5 alkyl, C 1-5 alkoxy, C 1-5 alkyl, C 1-5 alkenyl, C 2-5 alkynyl, C 2-5 cycloalkyl or 3- to 5-membered heterocyclic group of R 3-5 is independently optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; R 4 is a halogen group, a cyano group, a nitro group, -OR 14 , -N(R 14 )2, -SR 14 , C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group; wherein the C 4 alkyl, C 1-5 alkenyl, C 2-5 alkynyl, C 2-5 cycloalkyl or a 3- to 5-membered heterocyclic group is independently optionally substituted by one to five substituents independently selected from halogen groups, hydroxyl groups, C 3-5 alkoxy groups and cyano groups; 1-5 or R 3 and R 4 together with the atoms to which they are attached form a cycloalkyl group, an aryl group, a heterocyclic group or a heteroaryl group; wherein the cycloalkyl group, aryl group, heterocyclic group or heteroaryl group is optionally substituted by one to five substituents independently selected from halogen groups, hydroxyl groups and cyano groups; R 5 is hydrogen, a halogen group, a cyano group, a nitro group, -OR 15 , -N(R 15 )2, -SR 15 , -C(O)R 15 , -C(O)OR 15 , C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, a 3- to 5-membered heterocyclic group or a 5-membered heteroaryl group; wherein the C 5 alkyl, C 1-5 alkenyl, C 2-5 alkynyl, C 2-5 cycloalkyl, a 3- to 5-membered heterocyclic group or a 5-membered heteroaryl group is independently optionally substituted by one to five Z 3-5 substituents; 1 R 6 is hydrogen, a halogen group, a cyano group, a nitro group, -OR 16 , -N(R 16 )2, -SR 16 , C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group; wherein the C 6 alkyl, C 1-5 alkenyl, C 2-5 alkynyl, C​​2-5 Alkynyl, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; R 7 is hydrogen, halo, cyano, nitro, -OH, -SH, -NH2, -NH-C 1-5 alkyl, -N(C 1-5 alkyl)2, -S-C 1-5 alkyl, C 1-5 alkoxy, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or 3-5 membered heterocyclic group; wherein R 7 of -NH-C 1-5 alkyl, -N(C 1-5 alkyl)2, -S-C 1-5 alkyl, C 1-5 alkoxy, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; Or R 6 and R 7 together with the atom to which they are attached form a cycloalkyl, aryl, heterocyclic or heteroaryl group; wherein the cycloalkyl, aryl, heterocyclic or heteroaryl group is optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; R 8 is hydrogen, C 1-9 alkyl, halo, hydroxy or cyano; Each R 9 is independently hydrogen, C 1-9 alkyl, halo, hydroxy or cyano; R 10 is hydrogen, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or 3-5 membered heterocyclic group; wherein R 10 of C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; R 11 is hydrogen, C 1-9an alkyl group, an oxo group, a halogenated group, a hydroxyl group or a cyano group; each R 13 is independently hydrogen, a halogenated group, a cyano group, a nitro group, -OH, -SH, -NH2, -NH-C 1-9 alkyl group, -N(C 1-9 alkyl)2, -S-C 1-9 alkyl group, C 1-9 alkoxy group, C 1-9 alkyl group, C 2-9 alkenyl group, C 2-9 alkynyl group, C 3-6 cycloalkyl group or a 3- to 6-membered heterocyclic group; wherein each 13 -NH-C 1-9 alkyl group, -N(C 1-9 alkyl)2, -S-C 1-9 alkyl group, C 1-9 alkoxy group, C 1-9 alkyl group, C 2-9 alkenyl group, C 2-9 alkynyl group, C 3-6 cycloalkyl group or a 3- to 6-membered heterocyclic group is independently optionally substituted by one to five substituents independently selected from halogenated groups, hydroxyl groups and cyano groups; R 14 is hydrogen, C 1-5 alkyl group, C 2-5 alkenyl group, C 2-5 alkynyl group, C 3-5 cycloalkyl group or a 3- to 5-membered heterocyclic group; wherein each 14 C 1-5 alkyl group, C 2-5 alkenyl group, C 2-5 alkynyl group, C 3-5 cycloalkyl group or a 3- to 5-membered heterocyclic group is independently optionally substituted by one to five substituents independently selected from halogenated groups, hydroxyl groups and cyano groups; R 15 is hydrogen, C 1-5 alkyl group, C 2-5 alkenyl group, C 2-5 alkynyl group, C 3-5 cycloalkyl group or a 3- to 5-membered heterocyclic group; wherein each 15 C 1-5 alkyl group, C 2-5 alkenyl group, C 2-5 alkynyl group, C 3-5 cycloalkyl group or a 3- to 5-membered heterocyclic group is independently optionally substituted by one to five substituents independently selected from halogenated groups, hydroxyl groups and cyano groups; R 16 is hydrogen, C 1-5 alkyl group, C 2-5 alkenyl group, C 2-5 alkynyl group, C 3-5a cycloalkyl group or a 3- to 5-membered heterocyclic group; wherein R 16 of C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl group or 3- to 5-membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; each Z 1 is independently halo, cyano, nitro, oxo, C 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -L-H, -L-C 1-9 alkyl, -L-C 2-9 alkenyl, -L-C 2-9 alkynyl, -L-C 3-10 cycloalkyl, -L-heterocyclic, -L-aryl or -L-heteroaryl; wherein each C 1 of Z 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently optionally substituted with one to five Z 1a substituents; each L is independently -O-, -S-, -NR 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -, -NR 20 C(O)-, -OC(O)NR 20 -, -NR 20 C(O)O-, -NR 20 C(O)NR 21 -, -S(O)-, -S(O)2-, -S(O)NR 20 -, -S(O)2NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR 20 S(O)NR 21 -, or -NR 20 S(O)2NR 21 -; each R 20 and R 21 is independently hydrogen, C 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10a cycloalkyl, heterocyclic, aryl or heteroaryl group; wherein R 20 and R 21 each C 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently optionally substituted with one to five Z 1a substituents; or R 20 and R 21 together with the atoms to which they are attached form a heterocyclic group that is independently optionally substituted with one to five Z 1a substituents; and each Z 1a is independently a halo group, hydroxy group, cyano group, nitro group, oxo group, -SH, -NH2, -NH-C 1-9 alkyl, -N(C 1-9 alkyl)2, -S-C 1-9 alkyl, C 1-9 alkoxy, C 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10 cycloalkyl, heterocyclic, aryl or heteroaryl; wherein each -NH-C 1a alkyl, -N(C 1-9 alkyl)2, -S-C 1-9 alkyl, C 1-9 alkoxy, C 1-9 alkyl, C 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10 cycloalkyl, heterocyclic, aryl or heteroaryl of Z 1-9 is independently optionally substituted with one to five substituents independently selected from C

[0073] In some embodiments, a compound of formula IA is provided: or a pharmaceutically acceptable salt or solvate thereof, wherein A, R 1 , R 2 , R 4 , R 8 , R 9 , R 13 , X 1 , X 2 , X 3 , X 4 , X 6 , n, L 1 and L 2 are each independently as defined herein.

[0074] In some embodiments, a compound of formula IB is provided: or a pharmaceutically acceptable salt or solvate thereof, wherein A, R 1 、R 2 、R 4 、R 8 、R 9 、R 13 、X 1 、X 2 、X 3 、X 4 、X 6 、n, L 1 and L 2 are each independently as defined herein.

[0075] In some embodiments, a compound of formula IC is provided: or a pharmaceutically acceptable salt or solvate thereof, wherein A, R 1 、R 2 、R 4 、R 8 、R 9 、R 13 、X 1 、X 2 、X 3 、X 4 、X 6 、n, L 1 and L 2 are each independently as defined herein.

[0076] In some embodiments, X 4 is O. In some embodiments, X 4 is O; and A is C 1-6 alkyl.

[0077] In some embodiments, A is C 3-10 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each C 3-10 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl of ring A is independently optionally substituted with one to five Z 1 substituents. In some embodiments, A is C 3-10 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0078] In some embodiments, A is C 1 cycloalkyl optionally substituted with one to five Z 3-10 substituents. In some embodiments, A is C 3-10Naphthenyl.

[0079] In some embodiments, A is a heterocyclic group optionally substituted with one to five Z 1 In some embodiments, A is a heterocyclic group. In some embodiments, A is a 5- to 10-membered heterocyclic group optionally substituted with one to five Z 1 substituted.

[0080] In some embodiments, A is an aryl group optionally substituted with one to five Z 1 In some embodiments, A is an aryl group optionally substituted with one to five Z 1 substituted phenyl.

[0081] In some embodiments, A is a heteroaryl group optionally substituted with one to five Z 1 In some embodiments, A is a heteroaryl group optionally substituted with one to five Z 1 substituted 5- to 10-membered heteroaryl group. In some embodiments, A is a heteroaryl group optionally substituted with one to five Z 1 substituted 5- to 6-membered heteroaryl group.

[0082] In some embodiments, A is C 1-6 alkyl or C 3-10 naphthenyl.

[0083] In some embodiments, L 1 is a bond, -O-, -NR 10 -, C 1-3 alkylene or C 1-3 heteroalkylene. In some embodiments, L 1 is a bond. In some embodiments, L 1 is -O-, -NR 10 -, C 1-3 alkylene or C 1-3 heteroalkylene. In some embodiments, L 1 is -O- or -NR 10 -. In some embodiments, L 1 is -O- or -NH-. In some embodiments, L 1 is C 1-3 alkylene or C 1-3 heteroalkylene. In some embodiments, L 1 is -O-. In some embodiments, L 1 is -NR 10 -. In some embodiments, L 1 is -NH-. In some embodiments, L 1 is C 1-3 alkylene. In some embodiments, L 1is -CH2-. In some embodiments, L 1 is C 1-3 heteroalkylene. In some embodiments, L 1 is -O-CH2-. In some embodiments, L 1 is -NHCH2-.

[0084] In some embodiments, L 2 is a bond, C 1-3 alkylene or C 1-3 heteroalkylene. In some embodiments, L 2 is C 1-3 alkylene. In some embodiments, L 2 is -CH2-. In some embodiments, L 2 is C 1-3 heteroalkylene. In some embodiments, L 2 is -O-CH2-. In some embodiments, L 2 is -NHCH2-. In some embodiments, L 2 is a bond.

[0085] In some embodiments, L 1 is -O- or -NR 10 -, and L 2 is a bond or -CH2-. In some embodiments, L 1 is -O- or -NR 10 -, and L 2 is a bond. In some embodiments, L 1 is -O- or -NH-, and L 2 is a bond or -CH2-. In some embodiments, L 1 is -O- or -NH-, and L 2 is a bond.

[0086] In some embodiments, R 1 and R 2 together with the atoms to which they are attached form a C 3-10 cycloalkyl, the C 3-10 cycloalkyl being optionally substituted with one to five Z 1 substituents. In some embodiments, R 1 and R 2 together with the atoms to which they are attached form a C 3-6 cycloalkyl, the C 3-6 cycloalkyl being optionally substituted with one to five Z 1 substituents. In some embodiments, R 1 and R 2 together with the atoms to which they are attached form a C 3-10cycloalkyl, said C 3-10 The cycloalkyl is optionally substituted by one to five halogen atoms. In some embodiments, R 1 and R 2 together with the atoms to which they are attached form a C 3-6 cycloalkyl, said C 3-6 cycloalkyl is optionally substituted by one to five halogen atoms.

[0087] In some embodiments, R 1 and R 2 together with the atoms to which they are attached form a heterocyclic group, said heterocyclic group is optionally substituted by one to five Z 1 substituents. In some embodiments, R 1 and R 2 together with the atoms to which they are attached form a heterocyclic group.

[0088] In some embodiments, R 1 and R 2 are each independently C 1-9 alkyl, or R 1 and R 2 together with the atoms to which they are attached form a C 3-10 cycloalkyl or heterocyclic group; wherein each alkyl, cycloalkyl or heterocyclic group is independently optionally substituted by one to five Z 1 substituents.

[0089] In some embodiments, R 1 and R 2 are each independently C 1-9 alkyl, or R 1 and R 2 together with the atoms to which they are attached form a C 3-10 cycloalkyl or heterocyclic group; wherein each alkyl, cycloalkyl or heterocyclic group is independently optionally substituted by one to five halogen atoms.

[0090] In some embodiments, R 1 and R 2 are each independently C 1-9 alkyl; wherein each alkyl is independently optionally substituted by one to five halogen atoms.

[0091] In some embodiments, R 1 and R 2 together with the atoms to which they are attached form a C 3-10 cycloalkyl or heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally substituted by one to five halogen atoms.

[0092] In some embodiments, each R 13 is independently hydrogen or C 1-9Alkyl. In some embodiments, each R 13 is independently hydrogen or methyl. In some embodiments, each R 13 is hydrogen. In some embodiments, one R 13 is hydrogen and one R 13 is C 1-9 alkyl. In some embodiments, one R 13 is hydrogen and one R 13 is methyl.

[0093] In some embodiments, there is provided a compound of formula ID: or a pharmaceutically acceptable salt or solvate thereof, wherein A, R 4 、R 8 、R 9 、X 1 、X 2 、X 3 、X 4 、X 6 、n, L 1 and L 2 are each independently as defined herein; p is 0, 1 or 2; q is 0, 1 or 2; X 5 is absent, or is O, NR 17 or C(R 18 )2; R 17 is hydrogen, C 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -C(O)R 20 、-C(O)OR 20 、-C(O)NR 20 、-S(O)R 20 、-S(O)2R 20 、-S(O)NR 20 R 21 or -S(O)2NR 20 R 21 ; wherein each C 17 of R 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted with one to five Z 1a ; and each R 18Independently is hydrogen or Z 1 .

[0094] In some embodiments, X 4 is -CH2- or O. In some embodiments, X 4 is O. In some embodiments, X 4 is -CH2-.

[0095] In some embodiments, R 8 is hydrogen.

[0096] In some embodiments, R 17 is hydrogen.

[0097] In some embodiments, each R 18 is independently hydrogen or a halo group.

[0098] In some embodiments, n is 0. In some embodiments, n is 1.

[0099] In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1.

[0100] In some embodiments, q is 0 or 1. In some embodiments, q is 0. In some embodiments, q is 1.

[0101] In some embodiments, p and q are each independently 0 or 1. In some embodiments, p and q are each independently 0 or 1; and X 5 is absent, or is O or CF2.

[0102] In some embodiments, X 4 is -CH2- or O; R 8 is hydrogen; and n is 0.

[0103] In some embodiments, L 1 is -O- or -NR 10 -; L 2 is a bond or -CH2-; X 4 is -CH2- or O; R 8 is hydrogen; and n is 0.

[0104] In some embodiments, there is provided a compound of formula IE: or a pharmaceutically acceptable salt or solvate thereof, wherein A, R 4 , X 1 , X 2 , X 3 , X 5 , X 6, p and q are each independently as defined herein;

[0105] In some embodiments, X 1 is CR 3 . In some embodiments, X 1 is CR 3 ; and R 3 is hydrogen, a halo group, or a C 1-5 alkyl group optionally substituted with one to five substituents independently selected from halo groups, hydroxyl groups, and cyano groups. In some embodiments, X 1 is CR 3 ; and R 3 is hydrogen, a halo group, or a C 1-5 alkyl group optionally substituted with one to five halo groups. In some embodiments, X 1 is CR 3 ; and R 3 is hydrogen, fluorine, chlorine, methyl, or difluoromethyl.

[0106] In some embodiments, X 2 is N. In some embodiments, X 2 is CR 5 . In some embodiments, X 2 is N or CR 5 ; and R 5 is hydrogen or C 1-5 alkyl. In some embodiments, X 2 is N or CR 5 ; and R 5 is hydrogen or methyl. In some embodiments, X 2 is CR 5 ; and R 5 is hydrogen or C 1-5 alkyl. In some embodiments, X 2 is CR 5 ; and R 5 is hydrogen or methyl.

[0107] In some embodiments, X 3 is CR 7 . In some embodiments, X 3 is CR 7 ; and R 7 is hydrogen or a halo group.

[0108] In some embodiments, X 5 is absent, or is O or CF2. In some embodiments, X 5 is absent. In some embodiments, X 5 is O. In some embodiments, X 5 is CF2.

[0109] In some embodiments, X 6 is CR 6 。In some embodiments, X 6 is CR 6 ; and R 6 is hydrogen or -OR 16 。In some embodiments, X 6 is CR 6 ; and R 6 is hydrogen or C 1-5 alkoxy. In some embodiments, X 6 is CR 6 ; and R 6 is hydrogen or methoxy.

[0110] In some embodiments, the moiety is:

[0111] In some embodiments, the moiety is

[0112] In some embodiments, the moiety is

[0113] In some embodiments, X 1 is CR 3 ; and R 3 is hydrogen, a halo group, or a C 1-5 alkyl group optionally substituted with one to five substituents independently selected from halo groups, hydroxy groups, and cyano groups. In some embodiments, R 3 is hydrogen, a halo group, or a C 1-5 alkyl group optionally substituted with one to five halo groups.

[0114] In some embodiments, R 5 is hydrogen, -C(O)-C 1-5 alkyl, or C 1-5 alkyl. In some embodiments, R 5 is hydrogen or C 1-5 alkyl. In some embodiments, R 5 is hydrogen or methyl.

[0115] In some embodiments, R 6 is hydrogen or C 1-5 alkoxy. In some embodiments, R 6 is hydrogen or methoxy.

[0116] In some embodiments, R 7is hydrogen, a halogenated group or C 1-5 alkyl, wherein C 1-5 alkyl is optionally substituted with one to five halogenated groups.

[0117] In some embodiments, R 4 is C 1-5 alkoxy or -O-C 3-10 cycloalkyl.

[0118] In some embodiments of Formula I: A is C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; L 1 is a bond, -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -, C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene or C 1-3 heteroalkylene; L 2 is a bond, C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene or C 1-3 heteroalkylene; X 1 is N or CR 3 ; X 2 is N or CR 5 ; X 3 is N or CR 7 ; X 6 is N or CR 6 ; X 4 is O or CHR 11 ; provided that when A is C 1-6 alkyl, then X 4 is O; Y 2 , Y 3 and Y 6 one of them is N, and Y 2 , Y 3 and Y 6 the others are each independently CR 13 ; n is 0, 1 or 2; R 1 and R 2 are each independently C 1-9 alkyl, C 2-9Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl or heterocyclic group; Or R 1 And R 2 Together with the atoms to which they are attached form a C 3-10 Cycloalkyl or heterocyclic group; wherein the C 3-10 Cycloalkyl or heterocyclic group is optionally substituted with one to five halogenated groups; R 3 Is hydrogen, a halogenated group, a cyano group, a nitro group, -OH, -SH, -NH2, -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -S-C 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl or 3- to 5-membered heterocyclic group; wherein R 3 Of -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -S-C 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl or 3- to 5-membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halogenated groups, hydroxy groups, and cyano groups; R 4 Is a halogenated group, a cyano group, a nitro group, -OR 14 , -N(R 14 )2, -SR 14 , C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl or 3- to 5-membered heterocyclic group; wherein R 4 Of C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl or 3- to 5-membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halogenated groups, hydroxy groups, C 1-5 Alkoxy, and cyano groups; Or R 3 And R 4together with the atoms to which they are attached form a cycloalkyl, aryl, heterocyclyl or heteroaryl; wherein the cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; R 5 is hydrogen, halide, cyano, nitro, -OR 15 、-N(R 15 )2. -SR 15 、-C(O)R 15 、-C(O)OR 15 , C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl, 3-5 membered heterocyclyl or 5 membered heteroaryl; wherein R 5 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl, 3-5 membered heterocyclyl or 5 membered heteroaryl are independently optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; R 6 is hydrogen, halide, cyano, nitro, -OR 16 、-N(R 16 )2. -SR 16 , C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclic group; wherein R 6 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclyl is optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; R 7 It is hydrogen, halide, cyano, nitro, -OH, -SH, -NH2, -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclic group; wherein R 7 -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC1-5 alkyl, C 1-5 alkoxy, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 a cycloalkyl or 3- to 5-membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halo, hydroxy, and cyano; or R 6 and R 7 together with the atom to which they are attached form a cycloalkyl, aryl, heterocyclic, or heteroaryl group; wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally substituted with one to five substituents independently selected from halo, hydroxy, and cyano; R 8 is hydrogen, C 1-9 alkyl, halo, hydroxy, or cyano; each R 9 is independently hydrogen, C 1-9 alkyl, halo, hydroxy, or cyano; R 10 is hydrogen, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclic group; R 11 is hydrogen, C 1-9 alkyl, oxo, halo, hydroxy, or cyano; each R 13 is independently hydrogen, halo, cyano, nitro, -OH, -SH, -NH2, -NH-C 1-9 alkyl, -N(C 1-9 alkyl)2, -S-C 1-9 alkyl, C 1-9 alkoxy, C 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-6 cycloalkyl or 3- to 6-membered heterocyclic group; wherein each -NH-C 13 alkyl, -N(C 1-9 alkyl)2, -S-C 1-9 alkyl, C 1-9 alkyl, C 1-9 alkoxy, C 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-6 a cycloalkyl or 3- to 6-membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halo, hydroxy, and cyano; R 14 is hydrogen, C1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclic group; wherein R 14 of C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halo, hydroxy, and cyano; R 15 is hydrogen, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclic group; wherein R 15 of C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halo, hydroxy, and cyano; and R 16 is hydrogen, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclic group; wherein R 16 of C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halo, hydroxy, and cyano.

[0119] In some embodiments, there is provided a compound selected from Table 1 or a pharmaceutically acceptable salt or solvate thereof: Table 1

[0120] The compounds of formula I provided herein encompass the stereochemical forms of said compounds, e.g., optical isomers (such as enantiomers, diastereomers, and mixtures thereof, e.g., mixtures of enantiomers and / or diastereomers, including racemic mixtures, as well as equimolar or non-equimolar mixtures of individual enantiomers and / or diastereomers). All stereochemical forms are contemplated in the present disclosure. Unless otherwise indicated, when the disclosed compounds are named or described in structure without specifying stereochemistry and have one or more chiral centers, it is to be understood that all possible stereoisomers of said compounds are represented. Representative stereochemical forms are provided throughout the specification, including but not limited to those described in Table 2. In some embodiments, a compound selected from Table 2 or a pharmaceutically acceptable salt or solvate thereof is provided: Table 2

[0121] The compounds of formula I include their pharmaceutically acceptable salts. Additionally, the compounds of formula I also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts and which can be used as intermediates for the preparation and / or purification of the compounds of formula I and / or for the separation of enantiomers of the compounds of formula I. Non-limiting examples of pharmaceutically acceptable salts of the compounds of formula I include trifluoroacetate salts.

[0122] It should further be understood that the compounds of formula I or their salts can be isolated in the form of solvates, and accordingly, any such solvates are included within the scope of the present disclosure. For example, the compounds of formula I and their salts can exist in non-solvated form as well as in solvated form with pharmaceutically acceptable solvents (such as water, ethanol, etc.). Therapeutic Methods and Uses

[0123] The methods described herein can be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, such as within an animal or human body. In this context, the methods described herein can be used therapeutically in an individual. "Ex vivo" means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples (including fluid or tissue samples obtained from an individual). Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used ex vivo to determine the optimal schedule and / or dosage of administration of the compounds of the present disclosure for a given indication, cell type, individual, and other parameters. Information collected from such uses can be used for experimental purposes or in the clinic to set in vivo treatment regimens. Other ex vivo uses to which the compounds and compositions described herein are applicable are described below or will be apparent to those skilled in the art. Selected compounds can be further characterized to examine safety or tolerable doses in human or non-human subjects. Such characterization can be examined using methods well known to those skilled in the art.

[0124] A compound or a pharmaceutically acceptable salt or solvate thereof, as provided herein, or a pharmaceutical composition of such a compound can be used as an inhibitor of one or more LPA receptors. As further described herein, compounds that antagonize LPA receptors can be used for the prevention and / or treatment of diseases, such as a variety of diseases including, for example, fibrosis (e.g., renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis, systemic sclerosis), urinary system diseases, cancer-related diseases, proliferative diseases, inflammatory / immune system diseases, diseases caused by secretory dysfunction, brain-related diseases, and chronic diseases.

[0125] In some embodiments, the present disclosure provides methods for treating a subject (e.g., a human) having a disease, disorder, or condition in which inhibition of one or more LPA receptors (i.e., LPA-related diseases) is beneficial for treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, the methods provided herein can include or further include treating one or more conditions, comorbidities, or sequelae associated with any one or more of the conditions provided herein.

[0126] The present disclosure provides a method for treating an LPA-related disease, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein (e.g., a compound of formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition as disclosed herein.

[0127] In some embodiments, LPA-related diseases include, but are not limited to, treating fibrosis of organs (e.g., liver, kidney, lung, heart, and skin), liver diseases (acute hepatitis, chronic hepatitis, liver fibrosis, cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), hepatic hypofunction, hepatic blood flow disorders, etc.), cell proliferative diseases (e.g., cancer, including solid tumors, solid tumor metastases, angiofibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, and chronic lymphocytic leukemia (CLL), and invasive metastasis of cancer cells), inflammatory diseases (e.g., psoriasis, nephropathy, and pneumonia), gastrointestinal diseases (e.g., irritable bowel syndrome (TBS), inflammatory bowel disease (IBD), and abnormal pancreatic secretion), kidney diseases, urinary tract-related diseases (e.g., symptoms related to benign prostatic hyperplasia or neurogenic bladder disease), spinal tumors, hernia of intervertebral disk, spinal stenosis, symptoms derived from diabetes, lower urinary tract diseases (e.g., lower urinary tract obstruction, inflammatory diseases of the lower urinary tract, dysuria, and frequent urination), pancreatic diseases, abnormal angiogenesis-related diseases (e.g., arterial embolism), scleroderma, brain-related diseases (e.g., cerebral infarction and cerebral hemorrhage), neuropathic pain, peripheral neuropathy, eye diseases (e.g., age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, and glaucoma filtration surgery scarring).

[0128] In some embodiments, provided herein are methods for treating or preventing fibrosis, the methods comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition as disclosed herein. For example, the methods can include treating kidney fibrosis, lung fibrosis, liver fibrosis, arterial fibrosis, or systemic sclerosis. In some embodiments, provided herein are methods for treating lung fibrosis (e.g., idiopathic pulmonary fibrosis (IPF)), the methods comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition as provided herein.

[0129] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulae or pharmaceutically acceptable salts or solvates thereof) or pharmaceutical compositions as provided herein are used for treating or preventing fibrosis in a subject. For example, the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulae or pharmaceutically acceptable salts or solvates thereof) or pharmaceutical compositions as provided herein can be used to treat fibrosis of an organ or tissue in a subject. In some embodiments, provided herein is a method for preventing a fibrotic disorder in a subject, the method comprising administering to a subject at risk of developing one or more fibrotic disorders a therapeutically effective amount of the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulae or pharmaceutically acceptable salts or solvates thereof) or pharmaceutical compositions as provided herein. For example, a subject may be exposed to one or more environmental conditions known to increase the risk of fibrosis of an organ or tissue. In some embodiments, the subject is exposed to one or more environmental conditions known to increase the risk of pulmonary, hepatic, or renal fibrosis. In some embodiments, the subject has a genetic susceptibility to developing fibrosis of an organ or tissue. In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulae or pharmaceutically acceptable salts or solvates thereof) or pharmaceutical compositions as provided herein are administered to a subject to prevent or minimize scarring after injury. For example, the injury can include surgery.

[0130] Exemplary diseases, disorders or conditions involving fibrosis include, but are not limited to: lung diseases associated with fibrosis (e.g., idiopathic pulmonary fibrosis); iatrogenic drug-induced, occupational / environmental-induced fibrosis (farmer's lung); granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis); collagen vascular diseases (scleroderma and others); pulmonary alveolar proteinosis; Langerhans cell granulomatosis; lymphangioleiomyomatosis; genetic diseases (e.g., Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders and familial interstitial lung disease); 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, bleomycin-induced pulmonary fibrosis, chronic asthma, silicosis, asbestos-induced pulmonary or pleural fibrosis, acute lung injury, acute respiratory distress syndrome (ARDS) and acute respiratory distress (including that induced by bacterial pneumonia, trauma, viral pneumonia, ventilator, non-pulmonary sepsis and aspiration).Chronic kidney diseases associated with injury / fibrosis, kidney fibrosis (renal fibrosis), glomerulonephritis secondary to systemic inflammatory diseases (such as lupus and scleroderma, tubulointerstitial fibrosis, glomerulonephritis, glomerulosclerosis, focal segmental, diabetes, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allograft and Alport syndrome); dermatological disorders, intestinal fibrosis (e.g., scleroderma and radiation-induced intestinal fibrosis); liver fibrosis, such as cirrhosis, alcohol-induced liver fibrosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), toxic / drug-induced liver fibrosis (e.g., hemochromatosis), bile duct injury, primary biliary cirrhosis, infection or virus-induced fibrosis (e.g., chronic HCV infection), inflammatory / immune disorders and autoimmune hepatitis; head and neck fibrosis, such as corneal scarring (e.g., LASIK (laser-assisted in situ keratomileusis), corneal transplantation and trabeculectomy); hypertrophic scar, Dupuytren disease, dermal fibrosis, cutaneous scleroderma, keloid (e.g., burn-induced or post-operative); and other fibrotic diseases, such as sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, chronic lymphocytic leukemia, tumor metastasis, organ transplant rejection (e.g., bronchiolitis obliterans), endometriosis, neonatal respiratory distress syndrome and neuropathic pain, fibromyalgia, mixed connective tissue disease and Peyronie's disease.

[0131] The present disclosure provides a method for improving the pulmonary function of a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein. In some embodiments, the subject has been diagnosed with pulmonary fibrosis. In some embodiments, the compound disclosed herein (e.g., a compound of formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or the pharmaceutical composition provided herein is used to treat idiopathic pulmonary fibrosis of the subject. In some embodiments, the compound disclosed herein (e.g., a compound of formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or the pharmaceutical composition provided herein is used to treat usual interstitial pneumonia of the subject.

[0132] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) or the pharmaceutical compositions provided herein are used to treat a subject with diffuse parenchymal interstitial lung disease, such as iatrogenic drug-induced, occupational / environmental-induced fibrosis (farmer's lung), granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases (scleroderma and others), alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, genetic diseases (e.g., Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, and familial interstitial lung disease).

[0133] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) or the pharmaceutical compositions provided herein are used to treat post-transplant fibrosis associated with chronic rejection in a subject, such as bronchiolitis obliterans after lung transplantation.

[0134] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) or the pharmaceutical compositions provided herein are used to treat skin fibrosis in a subject, such as cutaneous scleroderma, Dupuytren's contracture, and keloids.

[0135] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) or the pharmaceutical compositions provided herein are used to treat liver fibrosis with or without cirrhosis in a subject. For example, toxicity / drug-induced (hemochromatosis), alcoholic liver disease, viral hepatitis (hepatitis B virus, hepatitis C virus, HCV), non-alcoholic liver disease (NAFLD, NASH), and metabolic and autoimmune diseases.

[0136] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) or the pharmaceutical compositions provided herein are used to treat kidney fibrosis in a subject (e.g., tubulointerstitial fibrosis and glomerulosclerosis).

[0137] Further examples of diseases, disorders, or conditions provided herein include atherosclerosis, thrombosis, heart disease, vasculitis, scar tissue formation, restenosis, phlebitis, COPD (chronic obstructive pulmonary disease), pulmonary hypertension, pulmonary fibrosis, pulmonary inflammation, intestinal adhesions, bladder fibrosis and cystitis, nasal passage fibrosis, sinusitis, neutrophil-mediated inflammation, and fibroblast-mediated fibrosis.

[0138] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or the pharmaceutical compositions provided herein can be used to treat one or more symptoms of COVID-19.

[0139] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or the pharmaceutical compositions provided herein can be used to treat chronic obstructive pulmonary disease (COPD).

[0140] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or the pharmaceutical compositions provided herein can be used to treat neuroinflammation.

[0141] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or the pharmaceutical compositions provided herein can be used to treat multiple sclerosis.

[0142] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or the pharmaceutical compositions provided herein are administered to a subject having or prone to having organ or tissue fibrosis in combination with one or more other agents for treating fibrosis. In some embodiments, the one or more agents include corticosteroids, immunosuppressants, B cell antagonists, and uteroglobin.

[0143] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or the pharmaceutical compositions provided herein are used to treat dermatological disorders of a subject. Such dermatological disorders include, but are not limited to, proliferative or inflammatory disorders of the skin such as atopic dermatitis, bullous disorders, collagenoses, psoriasis, scleroderma, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea, wound healing, scars, hypertrophic scars, keloids, Kawasaki disease, rosacea, Sjogren-Larsso syndrome, or urticaria. In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) are used to treat systemic sclerosis.

[0144] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or a subformula thereof or a pharmaceutically acceptable salt or solvate thereof) are used to treat or prevent inflammation in a subject. For example, the compounds disclosed herein (e.g., compounds of Formula I or a subformula thereof or a pharmaceutically acceptable salt or solvate thereof) are used to treat or prevent an inflammatory / immune disorder in a subject.

[0145] Examples of inflammatory / immune disorders include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle diseases, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, eczema, allogeneic or xenogeneic (organ, bone marrow, stem cells, and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory diseases, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's thyroiditis and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic recurrent hepatitis, primary biliary cirrhosis, allergic conjunctivitis, and atopic dermatitis.

[0146] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or a subformula thereof or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein is used to treat pain in a subject. In some embodiments, the pain is acute pain or chronic pain. In some embodiments, the pain is neuropathic pain.

[0147] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or a subformula thereof or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein is used to treat fibromyalgia. Fibromyalgia is thought to originate from the formation of fibrous scar tissue in contractile muscles (voluntary muscles). Fibrosis binds tissue and inhibits blood flow, leading to pain.

[0148] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) or the pharmaceutical compositions provided herein are used for treating cancer. In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) or the pharmaceutical compositions provided herein are used for treating malignant and benign proliferative diseases. In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) or the pharmaceutical compositions provided herein are used for preventing or reducing the proliferation of tumor cells, invasion and metastasis of cancer, pleural mesothelioma (Yamada, Cancer Sci., 2008, 99(8), 1603-1610) or peritoneal mesothelioma, cancer pain, bone metastatic cancer (Boucharaba et al., J Clin. Invest., 2004, 114(12), 1714-1725; Boucharaba et al., Proc. Natl. Acad. Sci., 2006, 103(25) 9643-9648). Provided herein is a method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) or a pharmaceutical composition provided herein. In some embodiments, the method provided herein further comprises administering a second therapeutic agent, wherein the second therapeutic agent is an anti-cancer agent.

[0149] As used herein, the term “cancer” refers to the abnormal growth of cells that tend to proliferate in an uncontrolled manner and in some cases metastasize (spread). Types of cancer include, but are not limited to, solid tumors (such as those of the bladder, intestine, brain, breast, endometrium, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (thyroid), prostate, skin (melanoma or basal cell carcinoma)) or hematologic malignancies (such as leukemia) at any disease stage with or without metastasis.

[0150] Additional non-limiting examples of cancers include 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 tumors, breast cancer, bronchial tumor, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, embryonal tumor, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumor, eye cancer, retinoblastoma, gallbladder cancer, gastric / stomach cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor (endocrine pancreas), Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, cutaneous T-cell lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, cancer, oropharyngeal cancer, osteosarcoma, bone malignant fibrous histiocytoma, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid carcinoma, penile cancer, pharyngeal cancer, mid-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, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome, skin cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach / gastric cancer, supratentorial primitive neuroectodermal tumor, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor.

[0151] In some embodiments, provided herein is a method of treating an allergic disorder in a subject, the method comprising administering a therapeutically effective amount of a compound disclosed herein as provided herein (e.g., a compound of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the compounds disclosed herein (e.g., a compound of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) can be used to treat a respiratory disease, disorder or condition in a subject. For example, the compounds disclosed herein (e.g., a compound of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) can treat asthma (e.g., chronic asthma) in a subject.

[0152] As used herein, the term "respiratory disease" refers to a disease that affects organs involved in respiration, such as the nose, throat, larynx, eustachian tube, trachea, bronchi, lungs, associated muscles (e.g., the diaphragm and intercostal) and nerves. Non-limiting examples of respiratory diseases include asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, childhood-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease (including chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or airway inflammation and cystic fibrosis, and hypoxia).

[0153] As used herein, the term "asthma" refers to any pulmonary disorder characterized by a change in pulmonary airflow associated with airway narrowing due to any cause (intrinsic, extrinsic or both; allergic or non-allergic). The term asthma can be used with one or more adjectives to indicate the cause.

[0154] Further provided herein is a method for treating or preventing chronic obstructive pulmonary disease in a subject, the method comprising administering a therapeutically effective amount of a compound disclosed herein as provided herein (e.g., a compound of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof). Examples of chronic obstructive pulmonary disease include, but are not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or airway inflammation and cystic fibrosis.

[0155] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) are used to treat or prevent a neurological disorder in a subject. As used herein, the term "neurological disorder" refers to a condition that alters the structure or function of the brain, spinal cord, or peripheral nervous system, including but not limited to Alzheimer's disease, brain edema, cerebral ischemia, stroke, multiple sclerosis, neuropathy, Parkinson's disease, conditions found after blunt or surgical trauma (including postoperative cognitive dysfunction and spinal cord or brainstem injury); and neurological disorders (such as degenerative disc disease and sciatica).

[0156] In some embodiments, provided herein is a method for treating or preventing a CNS disorder in a subject. Non-limiting examples of CNS disorders include multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, postoperative cognitive dysfunction, migraine, peripheral neuropathy / neuropathic pain, spinal cord injury, brain edema, and head injury.

[0157] Also provided herein are methods for treating or preventing cardiovascular diseases in a subject. As used herein, the term "cardiovascular disease" refers to a disease that affects the heart or blood vessels or both, including but not limited to: arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbance; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysms; vasculitis, stroke; peripheral occlusive arterial disease of the limbs, organs, or tissues; post-ischemic reperfusion injury of the brain, heart, or other organs or tissues; endotoxin shock, surgical shock, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including vasoconstriction associated with migraine); vascular abnormalities, inflammation, dysfunction confined to a single organ or tissue. For example, provided herein are methods for treating or preventing vasoconstriction, atherosclerosis and its sequelae, myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis, and stroke, the methods comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof).

[0158] In some embodiments, provided herein is a method for reducing cardiac reperfusion injury after myocardial ischemia and / or endotoxin shock, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof).

[0159] The present invention further provides methods for reducing vasoconstriction in a subject, the methods comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof). For example, the present invention provides methods for reducing blood pressure in a subject or preventing an increase in blood pressure in a subject, the methods comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof).

[0160] The ability of a test compound to act as an LPA receptor inhibitor can be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as LPA receptor inhibitors can be determined in vitro, in vivo, or in cell lines.

[0161] For example, Chinese hamster ovary cells overexpressing human LPA1 can be plated overnight (15,000 cells / well) in DMEM / F12 medium in a microplate. After overnight incubation, the cells are loaded with a calcium indicator dye and incubated at 37 °C for 30 minutes. Then the cells are equilibrated to room temperature for 30 minutes before the assay. The test compound dissolved in DMSO is transferred to a multi-well non-binding surface plate and diluted to a final concentration of 0.5% DMSO with assay buffer (e.g., IX HBSS with calcium / magnesium, 20 mM HEPES, and 0.1% fatty acid-free BSA). The diluted compound is added to the cells at a final concentration ranging from 0.08 nM to 5 mM, and then incubated at room temperature for 20 min, at which time LPA is added at a final concentration of 10 nM to stimulate the cells. The compound IC 50 value is defined as the concentration of the test compound that inhibits the calcium flux induced by LPA alone by 50%. The IC 50 value can be determined by fitting the data to a four-parameter logistic equation.

[0162] In another example, a compound disclosed herein (e.g., a compound of formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) as provided herein is orally administered to CD-1 female mice 2 hours before LPA challenge. Then, LPA (2 pg / pL) in 0.1% BSA / PBS (0.15 mL) is administered to the mice via the tail vein (IV). Exactly 2 minutes after LPA challenge, the mice are euthanized by decapitation and trunk blood is collected. These samples are centrifuged together and individual 75 μL samples are frozen at -20 °C until histamine assays are performed. Plasma histamine analysis can be performed by standard EIA (enzyme immunoassay) methods. The plasma samples are thawed and diluted 1:30 in 0.1% BSA in PBS. The EIA protocol for histamine analysis as described above can be used for this assay.

[0163] LPA acts as a bioactive molecule and has a wide range of physiological effects (including effects on blood pressure, platelet activation, and smooth muscle contraction), as well as a variety of cellular effects, including cell growth, cell rounding, neurite retraction, and the formation of actin stress fibers and cell migration. These effects are mainly receptor-mediated.

[0164] Activation of LPA receptors (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) by LPA mediates a series of downstream signaling cascades. Non-limiting examples include mitogen-activated protein kinase (MAPK) activation, adenylyl cyclase (AC) inhibition / activation, phospholipase C (PLC) activation / Ca2+ mobilization, arachidonic acid release, Akt / PKB activation, and the activation of small GTPases, Rho, ROCK, Rae, and Ras. Additional pathways affected by LPA receptor activation include, for example, cyclic adenosine monophosphate (cAMP), cell division cycle 42 / GTP-binding protein (Cdc42), proto-oncogene serine / threonine-protein kinase Raf (c-RAF), proto-oncogene tyrosine-protein kinase Src (c-src), extracellular signal-regulated kinase (ERK), focal adhesion kinase (FAK), guanine nucleotide exchange factor (GEF), glycogen synthase kinase 3b (GSK3b), c-jun N-terminal kinase (JNK), MEK, myosin light chain II (MLCII), nuclear factor kB (NF-kB), N-methyl-D-aspartic acid (NMDA) receptor activation, phosphatidylinositol 3-kinase (PBK), protein kinase A (PKA), protein kinase C (PKC), ms-related C3 botulinum toxin substrate 1 (RAC1). Almost all mammalian cells, tissues, and organs co-express several LPA receptor subtypes, indicating that LPA receptors signal in a cooperative manner. LPA1, LPA2, and LPA3 share high amino acid sequence similarity.

[0165] LPA1 (previously known as VZG-l / EDG-2 / mrecl.3) couples to three classes of G proteins (G i / o 、G q and G 12 / 13 ). By activating these G proteins, LPA induces a series of cellular responses through LPA1, including, for example, cell proliferation, serum response element (SRE) activation, mitogen-activated protein kinase (MAPK) activation, adenylyl cyclase (AC) inhibition, phospholipase C (PLC) activation, Ca 2+ mobilization, Akt activation, and Rho activation.

[0166] LPA1 expression was observed in the testis, brain, heart, lung, small intestine, stomach, spleen, thymus, and skeletal muscle of mice. Similarly, LPA1 is expressed in human tissues such as the brain, heart, lung, placenta, colon, small intestine, prostate, testis, ovary, pancreas, spleen, kidney, skeletal muscle, and thymus.

[0167] LPA2 (EDG-4) also couples to three classes of G proteins (G i / o , G q and G 12 / 13 ) to mediate LPA-induced cell signaling. LPA2 expression was observed in the testis, kidney, lung, thymus, spleen, and stomach of adult mice and in the testis, pancreas, prostate, thymus, spleen, and peripheral blood leukocytes of humans. LPA2 expression is upregulated in multiple cancer cell lines, and several human LPA2 transcript variants with mutations in the 3'-untranslated region have been observed.

[0168] LPA3 can mediate pleiotropic LPA-induced signaling, including PLC activation, Ca 2+ mobilization, AC inhibition / activation, and MAPK activation. Overexpression of LPA3 in neuroblastoma cells results in neurite outgrowth. LPA3 expression was observed in the testis, kidney, lung, small intestine, heart, thymus, and brain of adult mice. In humans, it was found in the heart, pancreas, prostate, testis, lung, ovary, and brain (frontal cortex, hippocampus, and amygdala).

[0169] Compared with LPA1, LPA2, and LPA3, LPA4 (p2y9 / GPR23) has a different sequence and is more similar to the platelet-activating factor (PAF) receptor. LPA4 mediates LPA-induced Ca 2+ mobilization and cAMP accumulation, as well as functional coupling to the G protein Gs to activate AC, and coupling to other G proteins. The LPA4 gene is expressed in the ovary, pancreas, thymus, kidney, and skeletal muscle.

[0170] LPA5 (GPR92) is a member of the purinocluster of GPCRs and is most closely related structurally to LPA4. LPA5 is expressed in the heart, placenta, spleen, brain, lung, and intestine of humans. LPA also shows very high expression in the CD8+ lymphocyte compartment of the gastrointestinal tract.

[0171] LPA6 (p2y5) is a member of the purinocluster of GPCRs and is most closely related structurally to LPA4. LPA6 is an LPA receptor that couples to the Gl2 / 13-Rho signaling pathway and is expressed in the inner root sheath of human hair follicles.

[0172] Improvements to any of the above reaction criteria are specifically provided by the methods of the present disclosure. Combination therapy

[0173] In one embodiment, the compounds disclosed herein can be used in combination with one or more additional therapeutic agents that are being used and / or developed for the treatment of the above diseases and disorders.

[0174] The compounds or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions of such compounds as provided herein can be used as inhibitors of one or more LPA receptors. As further described herein, compounds that antagonize LPA receptors can be used for the prevention and / or treatment of diseases, such as a variety of classes of diseases including: for example, fibrosis (e.g., renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis, systemic sclerosis), urinary system diseases, cancer-related diseases, proliferative diseases, inflammatory / immune system diseases, diseases caused by secretory dysfunction, brain-related diseases, and chronic diseases.

[0175] In some embodiments, the present disclosure provides methods for treating a subject (e.g., a human) having a disease, disorder, or condition in which inhibition of one or more LPA receptors (i.e., LPA-related diseases) is beneficial for treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, the methods provided herein can include or further include treating one or more conditions, comorbidities, or sequelae associated with any one or more of the conditions provided herein.

[0176] The present disclosure provides a method for treating an LPA-related disease, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein (e.g., a compound of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition as disclosed herein and one or more additional therapeutic agents.

[0177] In some embodiments, LPA-related diseases include, but are not limited to, treating fibrosis of organs (e.g., liver, kidney, lung, heart, and skin), liver diseases (acute hepatitis, chronic hepatitis, liver fibrosis, cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), hypofunction of the liver, hepatic blood flow disorders, etc.), cell proliferative diseases (e.g., cancer, including solid tumors, solid tumor metastases, angiofibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, and chronic lymphocytic leukemia (CLL), and invasive metastasis of cancer cells), inflammatory diseases (e.g., psoriasis, nephritis, and pneumonia), gastrointestinal diseases (e.g., irritable bowel syndrome (TBS), inflammatory bowel disease (IBD), and abnormal pancreatic secretion), kidney diseases, urinary tract-related diseases (e.g., symptoms related to benign prostatic hyperplasia or neurogenic bladder disease), spinal cord tumors, hernia of intervertebral disk, spinal stenosis, symptoms derived from diabetes, lower urinary tract diseases (e.g., lower urinary tract obstruction, inflammatory diseases of the lower urinary tract, dysuria, and frequent urination), pancreatic diseases, diseases related to abnormal angiogenesis (e.g., arterial embolism), scleroderma, brain-related diseases (e.g., cerebral infarction and cerebral hemorrhage), neuropathic pain, peripheral neuropathy, eye diseases (e.g., age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, and glaucoma filtration surgery scarring).

[0178] In some embodiments, provided herein are methods for treating or preventing fibrosis, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition as disclosed herein and one or more additional therapeutic agents. For example, the methods can include treating kidney fibrosis, lung fibrosis, liver fibrosis, arterial fibrosis, or systemic sclerosis. In some embodiments, provided herein are methods for treating lung fibrosis (e.g., idiopathic pulmonary fibrosis (IPF)), the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition as provided herein and one or more additional therapeutic agents.

[0179] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or the pharmaceutical compositions provided herein, along with one or more additional therapeutic agents, are used for treating or preventing fibrosis in a subject. For example, the compounds disclosed herein (e.g., compounds of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or the pharmaceutical compositions provided herein, along with one or more additional therapeutic agents, can be used to treat fibrosis of an organ or tissue of a subject. In some embodiments, a method for preventing a fibrotic disorder in a subject is provided, the method comprising administering to a subject at risk of developing one or more fibrotic disorders a therapeutically effective amount of the compounds disclosed herein (e.g., compounds of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or the pharmaceutical compositions provided herein, along with one or more additional therapeutic agents. For example, the subject may be exposed to one or more environmental conditions known to increase the risk of fibrosis of an organ or tissue. In some embodiments, the subject is exposed to one or more environmental conditions known to increase the risk of pulmonary, hepatic, or renal fibrosis. In some embodiments, the subject has a genetic susceptibility to developing fibrosis of an organ or tissue. In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or the pharmaceutical compositions provided herein, along with one or more additional therapeutic agents, are administered to the subject to prevent or minimize scarring after injury. For example, the injury can include surgery.

[0180] Exemplary diseases, disorders or conditions involving fibrosis include, but are not limited to: lung diseases associated with fibrosis (e.g., idiopathic pulmonary fibrosis); iatrogenic drug-induced, occupational / environmental-induced fibrosis (farmer's lung); granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis); collagen vascular diseases (scleroderma and others); pulmonary alveolar proteinosis; Langerhans cell granulomatosis; lymphangioleiomyomatosis; genetic diseases (e.g., Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders and familial interstitial lung disease); 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, bleomycin-induced pulmonary fibrosis, chronic asthma, silicosis, asbestos-induced pulmonary or pleural fibrosis, acute lung injury, acute respiratory distress syndrome (ARDS) and acute respiratory distress (including that induced by bacterial pneumonia, trauma, viral pneumonia, ventilator, non-pulmonary sepsis and aspiration).Chronic kidney diseases associated with injury / fibrosis, kidney fibrosis (renal fibrosis), glomerulonephritis secondary to systemic inflammatory diseases (such as lupus and scleroderma, tubulointerstitial fibrosis, glomerulonephritis, glomerulosclerosis, focal segmental, diabetes, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allograft and Alport syndrome); dermatological disorders, intestinal fibrosis (e.g., scleroderma and radiation-induced intestinal fibrosis); liver fibrosis, such as cirrhosis, alcohol-induced liver fibrosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), toxic / drug-induced liver fibrosis (e.g., hemochromatosis), bile duct injury, primary biliary cirrhosis, infection or virus-induced fibrosis (e.g., chronic HCV infection), inflammatory / immune disorders and autoimmune hepatitis; head and neck fibrosis, such as corneal scarring (e.g., LASIK (laser-assisted in situ keratomileusis), corneal transplantation and trabeculectomy); hypertrophic scar, Dupuytren disease, dermal fibrosis, cutaneous scleroderma, keloid (e.g., burn-induced or post-operative); and other fibrotic diseases, such as sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, chronic lymphocytic leukemia, tumor metastasis, organ transplant rejection (e.g., bronchiolitis obliterans), endometriosis, neonatal respiratory distress syndrome and neuropathic pain, fibromyalgia, mixed connective tissue disease and Peyronie's disease.

[0181] The present invention provides a method for improving the lung function of a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein and one or more additional therapeutic agents. In some embodiments, the subject has been diagnosed with pulmonary fibrosis. In some embodiments, the compound disclosed herein (e.g., a compound of formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or the pharmaceutical composition provided herein is used for treating idiopathic pulmonary fibrosis of a subject. In some embodiments, the compound disclosed herein (e.g., a compound of formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or the pharmaceutical composition provided herein and one or more additional therapeutic agents are used for treating usual interstitial pneumonia of a subject.

[0182] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) or pharmaceutical compositions as provided herein and one or more additional therapeutic agents are used to treat a subject with diffuse parenchymal interstitial lung disease, such as iatrogenic drug-induced, occupational / environmental-induced fibrosis (farmer's lung), granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases (scleroderma and others), pulmonary alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, genetic diseases (e.g., Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, and familial interstitial lung disease).

[0183] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) or pharmaceutical compositions as provided herein and one or more additional therapeutic agents are used to treat post-transplant fibrosis associated with chronic rejection in a subject, such as bronchiolitis obliterans after lung transplantation.

[0184] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) or pharmaceutical compositions as provided herein and one or more additional therapeutic agents are used to treat skin fibrosis in a subject, such as cutaneous scleroderma, Dupuytren's contracture, and keloids.

[0185] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) or pharmaceutical compositions as provided herein and one or more additional therapeutic agents are used to treat liver fibrosis with or without cirrhosis in a subject. For example, toxicity / drug-induced (hemochromatosis), alcoholic liver disease, viral hepatitis (hepatitis B virus, hepatitis C virus, HCV), non-alcoholic liver disease (NAFLD, NASH), and metabolic and autoimmune diseases.

[0186] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) or pharmaceutical compositions as provided herein and one or more additional therapeutic agents are used to treat renal fibrosis (e.g., tubulointerstitial fibrosis and glomerulosclerosis) in a subject.

[0187] Further examples of diseases, disorders or conditions provided herein include atherosclerosis, thrombosis, heart disease, vasculitis, scar tissue formation, restenosis, phlebitis, COPD (chronic obstructive pulmonary disease), pulmonary hypertension, pulmonary fibrosis, pulmonary inflammation, intestinal adhesions, bladder fibrosis and cystitis, nasal tract fibrosis, sinusitis, neutrophil-mediated inflammation, and fibroblast-mediated fibrosis.

[0188] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or a sub-formula thereof or pharmaceutically acceptable salts or solvates thereof) or the pharmaceutical compositions provided herein, along with one or more additional therapeutic agents, can be used to treat one or more symptoms of COVID-19.

[0189] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or a sub-formula thereof or pharmaceutically acceptable salts or solvates thereof) or the pharmaceutical compositions provided herein, along with one or more additional therapeutic agents, can be used to treat chronic obstructive pulmonary disease (COPD).

[0190] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or a sub-formula thereof or pharmaceutically acceptable salts or solvates thereof) or the pharmaceutical compositions provided herein, along with one or more additional therapeutic agents, can be used to treat neuroinflammation.

[0191] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or a sub-formula thereof or pharmaceutically acceptable salts or solvates thereof) or the pharmaceutical compositions provided herein, along with one or more additional therapeutic agents, can be used to treat multiple sclerosis.

[0192] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or a sub-formula thereof or pharmaceutically acceptable salts or solvates thereof) or the pharmaceutical compositions provided herein, along with one or more additional therapeutic agents, are administered to a subject having organ or tissue fibrosis or having a predisposition to develop organ or tissue fibrosis, in combination with one or more other agents for treating fibrosis. In some embodiments, the one or more agents include corticosteroids, immunosuppressants, B-cell antagonists, and uteroglobin.

[0193] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or a sub-formula thereof or pharmaceutically acceptable salts or solvates thereof) or pharmaceutical compositions as provided herein and one or more additional therapeutic agents are used to treat a skin disorder in a subject. Such dermatological disorders include, but are not limited to, proliferative or inflammatory disorders of the skin, such as atopic dermatitis, bullous disorders, collagenoses, psoriasis, scleroderma, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea, wound healing, scars, hypertrophic scars, keloids, Kawasaki disease, rosacea, Sjogren-Larsso syndrome, or urticaria. In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or a sub-formula thereof or pharmaceutically acceptable salts or solvates thereof) and one or more additional therapeutic agents are used to treat systemic sclerosis.

[0194] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or a sub-formula thereof or pharmaceutically acceptable salts or solvates thereof) and one or more additional therapeutic agents can be used to treat or prevent inflammation in a subject. For example, the compounds disclosed herein (e.g., compounds of Formula I or a sub-formula thereof or pharmaceutically acceptable salts or solvates thereof) and one or more additional therapeutic agents are used to treat or prevent an inflammatory / immune disorder in a subject.

[0195] Examples of inflammatory / immune disorders include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle diseases, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, eczema, allograft or xenograft (organ, bone marrow, stem cells, and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory diseases, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's thyroiditis and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic recurrent hepatitis, primary biliary cirrhosis, allergic conjunctivitis, and atopic dermatitis.

[0196] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or a sub-formula thereof or pharmaceutically acceptable salts or solvates thereof) or pharmaceutical compositions as provided herein and one or more additional therapeutic agents are used to treat pain in a subject. In some embodiments, the pain is acute pain or chronic pain. In some embodiments, the pain is neuropathic pain.

[0197] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) or the pharmaceutical compositions provided herein, and one or more additional therapeutic agents are used for treating fibromyalgia. Fibromyalgia is thought to originate from the formation of fibrous scar tissue in contractile muscles (voluntary muscles). Fibrosis binds tissues and inhibits blood flow, resulting in pain.

[0198] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) or the pharmaceutical compositions provided herein, and one or more additional therapeutic agents are used for treating cancer. In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) or the pharmaceutical compositions provided herein, and one or more additional therapeutic agents are used for treating malignant and benign proliferative diseases. In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) or the pharmaceutical compositions provided herein, and one or more additional therapeutic agents are used for preventing or reducing the proliferation of tumor cells, cancer invasion and metastasis, pleural mesothelioma (Yamada, Cancer Sci., 2008, 99(8), 1603-1610) or peritoneal mesothelioma, cancer pain, bone metastatic cancer (Boucharaba et al., J Clin. Invest., 2004, 114(12), 1714-1725; Boucharaba et al., Proc. Natl. Acad. Sci., 2006, 103(25) 9643-9648). A method for treating cancer in a subject is provided herein, the method comprising administering to the subject a therapeutically effective amount of the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) or the pharmaceutical compositions provided herein, and one or more additional therapeutic agents. In some embodiments, the method provided herein further comprises administering a second therapeutic agent, wherein the second therapeutic agent is an anti-cancer agent.

[0199] As used herein, the term "cancer" refers to the abnormal growth of cells that tend to proliferate in an uncontrolled manner and, in some cases, metastasize (spread). Types of cancer include, but are not limited to, solid tumors (such as those of the bladder, intestine, brain, breast, endometrium, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (thyroid), prostate, skin (melanoma or basal cell carcinoma)) or hematological tumors (such as leukemia) at any disease stage with or without metastasis.

[0200] Additional non - limiting examples of cancers include 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 tumors, breast cancer, bronchial tumor, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, embryonal tumor, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumor, eye cancer, retinoblastoma, gallbladder cancer, gastric / stomach cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor (endocrine pancreas), Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, liver cancer, non - small cell lung cancer, small cell lung cancer, cutaneous T - cell lymphoma, non - Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, cancer, oropharyngeal cancer, osteosarcoma, bone malignant fibrous histiocytoma, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumor, intermediate differentiation, 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, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome, skin cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach / gastric cancer, supratentorial primitive neuroectodermal tumor, T - cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor.

[0201] In some embodiments, provided herein is a method of treating an allergic disorder in a subject, the method comprising administering a therapeutically effective amount of a compound disclosed herein as provided herein (e.g., a compound of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) and one or more additional therapeutic agents. In some embodiments, the compounds disclosed herein (e.g., a compound of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) and one or more additional therapeutic agents can be used to treat a respiratory disease, disorder, or condition in a subject. For example, the compounds disclosed herein (e.g., a compound of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) and one or more additional therapeutic agents can treat asthma (e.g., chronic asthma) in a subject.

[0202] As used herein, the term "respiratory disease" refers to a disease that affects organs involved in respiration, such as the nose, throat, larynx, eustachian tube, trachea, bronchi, lungs, associated muscles (e.g., the diaphragm and intercostal), and nerves. Non-limiting examples of respiratory diseases include asthma, adult respiratory distress syndrome, and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, childhood-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease (including chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis, and / or airway inflammation and cystic fibrosis, and hypoxia).

[0203] As used herein, the term "asthma" refers to any pulmonary disorder characterized by a change in pulmonary airflow associated with airway narrowing due to any cause (intrinsic, extrinsic, or both; allergic or non-allergic). The term asthma can be used with one or more adjectives to indicate the cause.

[0204] Further provided herein are methods for treating or preventing chronic obstructive pulmonary disease in a subject, the methods comprising administering a therapeutically effective amount of a compound disclosed herein as provided herein (e.g., a compound of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) and one or more additional therapeutic agents. Examples of chronic obstructive pulmonary disease include, but are not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis, and / or airway inflammation, and cystic fibrosis.

[0205] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) and one or more additional therapeutic agents are used to treat or prevent a neurological disorder in a subject. As used herein, the term "neurological disorder" refers to a condition that alters the structure or function of the brain, spinal cord, or peripheral nervous system, including but not limited to Alzheimer's disease, cerebral edema, cerebral ischemia, stroke, multiple sclerosis, neuropathy, Parkinson's disease, conditions found after blunt trauma or surgical trauma (including postoperative cognitive dysfunction and spinal cord or brainstem injury); and neurological disorders (such as degenerative disc disease and sciatica).

[0206] In some embodiments, provided herein is a method for treating or preventing a CNS disorder in a subject. Non-limiting examples of CNS disorders include multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, postoperative cognitive dysfunction, migraine, peripheral neuropathy / neuropathic pain, spinal cord injury, cerebral edema, and head injury.

[0207] Also provided herein are methods for treating or preventing cardiovascular diseases in a subject. As used herein, the term "cardiovascular disease" refers to a disease that affects the heart or blood vessels or both, including but not limited to: arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina pectoris; cardiac rhythm disturbance; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysms; vasculitis, stroke; peripheral obstructive arterial disease of the limbs, organs, or tissues; post-ischemic reperfusion injury of the brain, heart, or other organs or tissues; endotoxin shock, surgical shock, or traumatic shock; hypertension, valvular heart disease, heart failure, blood pressure abnormalities; shock; vasoconstriction (including vasoconstriction associated with migraine); vascular abnormalities, inflammation, and dysfunction limited to a single organ or tissue. For example, provided herein are methods for treating or preventing vasoconstriction, atherosclerosis and its sequelae, myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis, and stroke, the methods comprising administering a therapeutically effective amount of the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) and one or more additional therapeutic agents.

[0208] In some embodiments, provided herein are methods for reducing cardiac reperfusion injury after myocardial ischemia and / or endotoxin shock, the methods comprising administering to a subject in need thereof a therapeutically effective amount of the compounds disclosed herein (e.g., compounds of Formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) and one or more additional therapeutic agents.

[0209] The present invention further provides methods for reducing vasoconstriction in a subject, the methods comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) and one or more additional therapeutic agents. For example, the present invention provides methods for reducing blood pressure or preventing an increase in blood pressure in a subject, the methods comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) and one or more additional therapeutic agents. Pharmaceutical Compositions and Modes of Administration

[0210] The compounds provided herein are generally administered in the form of pharmaceutical compositions.

[0211] When used as a medicine, the compounds disclosed herein (e.g., a compound of formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) (including pharmaceutically acceptable salts or solvates thereof) can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art and can be administered by a variety of routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epidermal, ocular, and mucosal, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of a powder or aerosol, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Oral administration can include dosage forms formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose or can be, for example, by continuous infusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickening agents, etc. may be necessary or desirable.

[0212] The present invention also provides a pharmaceutical composition, which contains a combination of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of formula I or its sub-formula or a pharmaceutically acceptable salt or solvate thereof) as an active ingredient and one or more pharmaceutically acceptable excipients (carriers). For example, a pharmaceutical composition prepared using a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of formula I or its sub-formula or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the composition is suitable for topical administration. In manufacturing the compositions provided herein, typically the active ingredient is admixed with an excipient, diluted with an excipient or enclosed within a carrier which may be in the form of, for example, a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid or liquid material which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments (containing, for example, up to 10% by weight of the active compound), soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is a solid oral formulation. In some embodiments, the composition is formulated as a tablet or a capsule.

[0213] The present invention further provides a pharmaceutical composition containing a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of formula I or its sub-formula or a pharmaceutically acceptable salt or solvate thereof) and a pharmaceutically acceptable excipient. A pharmaceutical composition containing a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of formula I or its sub-formula or a pharmaceutically acceptable salt or solvate thereof) as an active ingredient can be prepared by intimately mixing the compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound in formula I or its sub-formula or a pharmaceutically acceptable salt thereof) with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take many forms, depending on the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition.

[0214] Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0215] Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1 - 3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1 - 2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1 - 2, edited by Lieberman et al.; published by Marcel Dekker, Inc.

[0216] Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS), such as d-α-tocopheryl polyethylene glycol 1000 succinate; surfactants for use in pharmaceutical dosage forms, such as Tweens, poloxamers, or other similar polymeric delivery matrices; serum proteins, such as human serum albumin; buffering substances, such as phosphates, tris, glycine, sorbic acid, potassium sorbate; mixtures of partial glycerides of saturated vegetable fatty acids; water, salts, or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; cellulose-based substances; polyethylene glycol; sodium carboxymethyl cellulose; polyacrylates; waxes; polyethylene-polypropylene block copolymers; and lanolin. Cyclodextrins (such as α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin) or chemically modified derivatives such as hydroxyalkyl cyclodextrins (including 2- and 3-hydroxypropyl-β-cyclodextrin) or other solubilizing derivatives may also be used to enhance the delivery of compounds such as those provided herein. Dosage forms or compositions may be prepared containing chemical entities as provided herein in the range of 0.005% to 100%, with the remainder consisting of non-toxic excipients. The compositions contemplated may contain 0.001% - 100%, in one embodiment 0.1% - 95%, in another embodiment 75% - 85%, in another embodiment 20% - 80% of the chemical entities provided herein. The actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, UK. 2012).

[0217] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula I or a sub-formula thereof, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition as provided herein, can be administered to a subject in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, intra-cervical, intra-nasal, intra-tracheal, enteral, epidural, interstitial, intraperitoneal, intra-arterial, intra-bronchial, intra-capsular, intra-cerebral, intra-cisternal, intra-coronary, intradermal, intra-catheter, intra-duodenal, intradural, intra-epidermal, intra-esophageal, intra-gastric, intra-gingival, intra-ileal, intra-lymphatic, intramedullary, intra-meningeal, intramuscular, intra-ovarian, intra-peritoneal, intra-prostatic, intra-pulmonary, intra-sinus, intra-spinal, intra-synovial, intra-testicular, intrathecal, intra-tubular, intratumoral, intra-uterine, intra-vascular, intravenous, nasal (e.g., intranasal), nasogastric, oral, parenteral, percutaneous, transdural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, and vaginal. In some embodiments, a preferred route of administration is parenteral (e.g., intratumoral).

[0218] In some embodiments, a compound disclosed herein as provided herein (e.g., a compound of Formula I or a sub-formula thereof, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition thereof, can be formulated for parenteral administration, such as by being formulated for injection via an intra-arterial, intrasternal, intracranial, intravenous, intramuscular, subcutaneous, or intraperitoneal route. For example, such compositions can be prepared as injectables, as liquid solutions or suspensions; they can also be prepared in solid forms suitable for the preparation of solutions or suspensions upon addition of a liquid prior to injection; and the formulations can also be emulsions. Given the present disclosure, the preparation of such formulations will be known to those skilled in the art. In some embodiments, parenteral administration is effected using a device. For example, such devices can include needle syringes, microneedle syringes, needleless syringes, and infusion techniques.

[0219] In some embodiments, drug forms suitable for injection include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the form must be sterile and must be fluid to the extent that it can be easily injected. In some embodiments, the form should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0220] In some embodiments, the carrier can also be a solvent or dispersion medium, which contains, for example, water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In some embodiments, for example, by using a coating (such as lecithin), in the case of a dispersion, by maintaining the desired particle size, and by using surfactants, appropriate fluidity can be maintained. In some embodiments, the action of microorganisms can be prevented by a variety of antibacterial and antifungal agents (such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.). In some embodiments, isotonic agents are included, such as sugars or sodium chloride. In some embodiments, the absorption of an injectable composition can be prolonged by using agents that delay absorption (such as aluminum monostearate and gelatin) in the composition.

[0221] In some embodiments, a sterile injectable solution is prepared by incorporating a compound disclosed herein (such as a compound of formula I or its sub-formula, or a pharmaceutically acceptable salt or solvate thereof) into a suitable solvent with the various other ingredients listed above as needed, and then subjecting it to filtration sterilization. In some embodiments, a dispersion is prepared by incorporating a variety of sterile active ingredients into a sterile vehicle, which contains a base dispersion medium and the required other ingredients from those listed above. In some embodiments, sterile powders are used to prepare sterile injectable solutions. In some embodiments, the preparation methods are vacuum drying and freeze-drying techniques, which produce powders of the active ingredient plus any additional desired ingredients from their previously sterile-filtered solutions.

[0222] In some embodiments, pharmaceutically acceptable excipients that can be used in rectal compositions such as gels, creams, enemas, or rectal suppositories include, but are not limited to, any one or more of the following: cocoa butter glycerides, synthetic polymers (such as polyvinylpyrrolidone), PEG (such as PEG ointment), glycerol, glycerol-treated gelatin, hydrogenated vegetable oil, poloxamer, mixtures of polyethylene glycols with polyethylene glycol fatty acid esters of various molecular weights, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, essential oil of vanilla, aerosol, parabens in phenoxyethanol, sodium methylparaben, sodium propylparaben, diethylamine, carbomer, carbopol, methylparaben, polyethylene glycol cetostearyl ether, cocoylcaprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-bisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins (such as vitamins A and E), and potassium acetate.

[0223] In some embodiments, suppositories can be prepared by mixing a compound disclosed herein (e.g., a compound of formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition as provided herein with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, suppository wax, which is solid at ambient temperature but liquid at body temperature and thus melts in the rectum and releases the active compound. In some embodiments, the composition for rectal administration is in the form of an enema.

[0224] In some embodiments, a compound disclosed herein (e.g., a compound of formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition as provided herein is formulated for topical delivery to the digestive tract or GI tract by oral administration (e.g., in solid or liquid dosage forms).

[0225] In some embodiments, solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) is mixed with one or more pharmaceutically acceptable excipients such as sodium citrate or calcium phosphate dibasic and / or the following: a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution blockers such as paraffin wax; f) absorption promoters such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glyceryl monostearate; h) adsorbents such as kaolin and bentonite; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. For example, in the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. In some embodiments, solid compositions of a similar type can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0226] In some embodiments, the pharmaceutical composition will be in the form of unit dosage forms such as pills or tablets, and accordingly, the composition can contain a diluent such as lactose, sucrose, dicalcium phosphate, etc.; a lubricant such as magnesium stearate, etc.; and a binder such as starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives, etc., together with a compound disclosed herein as provided herein (e.g., a compound of formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, powders, marumes, solutions or suspensions (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124 or triglyceride) as another solid dosage form will be encapsulated in a capsule (gelatin or cellulose matrix capsule). In some embodiments, unit dosage forms in which one or more compounds and pharmaceutical compositions or additional active agents are physically separated as provided herein are also contemplated; for example, capsules with granules of each drug (or tablets in capsules); bilayer tablets; two-chamber gel caps, etc. In some embodiments, enteric-coated or delayed-release oral dosage forms are also contemplated.

[0227] In some embodiments, other physiologically acceptable compounds can include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing microbial growth or activity. For example, a variety of preservatives are well known and include, for example, phenol and ascorbic acid.

[0228] In some embodiments, the excipients are sterile and generally free of undesirable substances. For example, these compositions can be sterilized by conventional well-known sterilization techniques. In some embodiments, sterilization is not required for a variety of oral dosage form excipients such as tablets and capsules. For example, the United States Pharmacopeia / National Formulary (USP / NF) standards can be sufficient.

[0229] In some embodiments, the compounds disclosed herein as provided herein (e.g., compounds of formula I or its sub-formulae or pharmaceutically acceptable salts or solvates thereof) or pharmaceutical compositions thereof are formulated for ocular administration. In some embodiments, the ocular composition can include, without limitation, one or more of the following: viscogens (e.g., carboxymethyl cellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., pluronic (triblock copolymer), cyclodextrin); preservatives (e.g., benzalkonium chloride, EDTA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0230] In some embodiments, the compounds disclosed herein as provided herein (e.g., compounds of formula I or its sub-formulae or pharmaceutically acceptable salts or solvates thereof) or pharmaceutical compositions thereof are formulated for topical administration to the skin or mucosa (e.g., transdermal or percutaneous). In some embodiments, the topical composition can include ointments and creams. In some embodiments, an ointment is typically a semi-solid preparation based on petrolatum or other petroleum derivatives. In some embodiments, a cream containing a selected active agent is typically a viscous liquid or semi-solid emulsion, often water-in-oil or oil-in-water. For example, a cream matrix is typically washable and contains an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase, sometimes also referred to as the "internal" phase, is typically composed of petrolatum and fatty alcohols such as cetyl alcohol or stearyl alcohol; although not required, the volume of the aqueous phase typically exceeds that of the oil phase and typically contains a humectant. In some embodiments, the emulsifier in a cream formulation is typically a nonionic, anionic, cationic, or amphoteric surfactant. In some embodiments, like other carriers or vehicles, an ointment matrix should be inert, stable, non-irritating, and non-sensitizing.

[0231] In any of the foregoing embodiments, the pharmaceutical composition as provided herein can include one or more of the following: lipids, bilayer-interlinked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-loaded lipid bilayers.

[0232] In some embodiments, the dosage of the compounds disclosed herein (e.g., a compound of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) is determined based on a variety of factors, including but not limited to the type, age, weight, sex, medical condition of the subject, the severity of the medical condition of the subject, the route of administration, and the activity of the compound or its pharmaceutically acceptable salt or solvate. In some embodiments, the appropriate dosage for a particular situation can be determined by a person skilled in the medical arts. In some embodiments, the total daily dose can be divided into multiple portions and administered in multiple portions throughout the day or by means of a continuous delivery.

[0233] In some embodiments, the compounds disclosed herein (e.g., a compound of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) are administered in a dosage of from about 0.01 to about 1000 mg. For example, from about 0.1 to about 30 mg, from about 10 to about 80 mg, from about 0.5 to about 15 mg, from about 50 mg to about 200 mg, from about 100 mg to about 300 mg, from about 200 to about 400 mg, from about 300 mg to about 500 mg, from about 400 mg to about 600 mg, from about 500 mg to about 800 mg, from about 600 mg to about 900 mg, or from about 700 mg to about 1000 mg. In some embodiments, the dosage is a therapeutically effective amount.

[0234] In some embodiments, the compounds disclosed herein as provided herein (e.g., compounds of formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) are administered at a dose of from about 0.0002 mg / Kg to about 100 mg / Kg (e.g., from about 0.0002 mg / Kg to about 50 mg / Kg; from about 0.0002 mg / Kg to about 25 mg / Kg; from about 0.0002 mg / Kg to about 10 mg / Kg; from about 0.0002 mg / Kg to about 5 mg / Kg; from about 0.0002 mg / Kg to about 1 mg / Kg; from about 0.0002 mg / Kg to about 0.5 mg / Kg; from about 0.0002 mg / Kg to about 0.1 mg / Kg; from about 0.001 mg / Kg to about 50 mg / Kg; from about 0.001 mg / Kg to about 25 mg / Kg; from about 0.001 mg / Kg to about 10 mg / Kg; from about 0.001 mg / Kg to about 5 mg / Kg; from about 0.001 mg / Kg to about 1 mg / Kg; from about 0.001 mg / Kg to about 0.5 mg / Kg; from about 0.001 mg / Kg to about 0.1 mg / Kg; from about 0.01 mg / Kg to about 50 mg / Kg; from about 0.01 mg / Kg to about 25 mg / Kg; from about 0.01 mg / Kg to about 10 mg / Kg; from about 0.01 mg / Kg to about 5 mg / Kg; from about 0.01 mg / Kg to about 1 mg / Kg; from about 0.01 mg / Kg to about 0.5 mg / Kg; from about 0.01 mg / Kg to about 0.1 mg / Kg; from about 0.1 mg / Kg to about 50 mg / Kg; from about 0.1 mg / Kg to about 25 mg / Kg; from about 0.1 mg / Kg to about 10 mg / Kg; from about 0.1 mg / Kg to about 5 mg / Kg; from about 0.1 mg / Kg to about 1 mg / Kg; from about 0.1 mg / Kg to about 0.5 mg / Kg). In some embodiments, the compounds disclosed herein as provided herein (e.g., compounds of formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) are administered at a dose of about 100 mg / Kg.

[0235] In some embodiments, the foregoing doses of the compounds disclosed herein (e.g., compounds of formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or on a non-daily basis (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month).

[0236] In some embodiments, the period of administration of the compounds disclosed herein (e.g., compounds of formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) as provided herein is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In some embodiments, the period of discontinuation of administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In some embodiments, the compounds disclosed herein (e.g., compounds of formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) are administered to a subject for a period of time, followed by a separate period of discontinuation of administration of the compounds disclosed herein or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof). In some embodiments, the compounds disclosed herein (e.g., compounds of formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) are administered for a first period of time, and a second period of time after the first period, wherein administration is discontinued during the second period, followed by a third period of time during which administration of the compounds disclosed herein or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof) is initiated, and then a fourth period of time after the third period, during which administration is discontinued. For example, the period of administration of the compounds disclosed herein (e.g., compounds of formula I or its sub-formulas or pharmaceutically acceptable salts or solvates thereof), followed by the period of discontinuation, is repeated over a determined or undetermined period of time. In some embodiments, the period of administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In some embodiments, the period of discontinuation of administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer.

[0237] In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) is administered orally to a subject one or more times per day (e.g., once a day, twice a day, three times a day, four times a day, or a single daily dose).

[0238] In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) is administered to a subject by parenteral administration one or more times per day (e.g., 1 to 4 times, once a day, twice a day, three times a day, four times a day, or a single daily dose).

[0239] In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a sub-formula thereof or a pharmaceutically acceptable salt or solvate thereof) is administered to a subject by parenteral administration once a week. Synthesis of Compounds

[0240] The compounds of the present disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be understood that unless otherwise specified, other process conditions may also be used when certain process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given. The optimal reaction conditions may vary depending on the reactants or solvents used, but such conditions can be determined by those skilled in the art through routine optimization procedures.

[0241] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing unwanted reactions. Suitable protecting groups for a variety of functional groups and suitable conditions for protecting and deprotecting certain functional groups are well known in the art. For example, many protecting groups are described in T.W. Greene and G.M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York and the references cited therein.

[0242] In addition, the compounds of the present disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or separated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as mixtures enriched in stereoisomers. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0243] Starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), EMKA-Chemie Gmbh & Co. KG (Eching, Germany) or Millipore Sigma (Burlington, Massachusetts, USA). Other starting materials can be prepared by procedures described in standard reference texts or obvious modifications thereof, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991); March's Advanced Organic Chemistry (John Wiley, and Sons, 5th Edition, 2001) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0244] Scheme I illustrates a general method that can be used to synthesize the compounds described herein, where R 1 、R 2 、R 4 、R 8 、R 9 、X 1 、X 2 、X 3 、X 4, X 6 , Y 2 , Y 3 , Y 6 , A, n, L 1 and L 2 Each of and is independently defined herein, LG and LG’ are suitable leaving groups such as a halogen group (e.g., Cl, Br or I), where LG and LG’ are not the same, PG is a suitable carboxyl protecting group (such as an alkyl or benzyl group), and each R 50 is independently an alkyl or substituted alkyl, or two R 50 are linked to form a cyclic borate ester, which may optionally be substituted (e.g., pinacol borate ester). Scheme I

[0245] The compound of formula I is prepared by: first coupling the compound I-1, followed by deprotection to obtain the free acid of formula I, where B is a suitable functional group such as, but not limited to, boric acid or its derivatives (such as borate esters (cyclic or acyclic)), zinc halide or magnesium halide, organotin compounds (such as tributylstannane or trimethylstannane), fluorosulfonyl esters, tin, sodium, hydrogen, etc. Such reactions are commonly used for aromatic functionalization and such reactions are typically carried out in the presence of a suitable catalyst, such as, but not limited to, palladium catalysts including [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, Pd(OAc)2, Pd(PPh3)4, PdCl2(PPh3)2 or tris(dibenzylideneacetone)dipalladium(0), etc.; or copper catalysts such as CuCl or CuI; and, if desired, suitable media, cocatalysts and / or bases known to those skilled in the art using a suitable solvent / solvent mixture. After completion of the reaction, the compound of formula I can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, etc. In certain embodiments, when control of stereochemistry is desired, appropriate control of the reaction conditions and the choice of substituents for the reagents can at least partially determine or maintain the formation of multiple stereoisomers. Compounds I-1 and I-2 can be obtained commercially or synthesized from scratch. For example, as shown in Scheme I above, compound I-1 can be prepared by coupling compound I-3 with compound I-4 under standard nucleophilic aromatic substitution conditions.

[0246] It should be understood that the various substituents of each intermediate (e.g., compounds I-1, I-2, I-3 and I-4) can be modified or added before (as shown in Scheme I) or after the addition of the I-2 moiety. For example, ring A can be appended before or after the steps shown in Scheme I above. The ring A moiety can be coupled with the X 4 precursor under substitution reaction conditions.

[0247] For any compound shown in Scheme I, it should be understood that various derivatives can be provided by interconversion of functional groups at any step. In some embodiments, the various substituents of Formula I-1, I-2, I-3, or I-4 (e.g., R 1 、R 2 、R 4 、R 8 、R 9 、X 1 、X 2 、X 3 、X 4 、X 6 、Y 2 、Y 3 、Y 6 、A, n, L 1 and L 2 ) are as defined herein. However, prior to reaction at any step, derivatization of Compound I, II-1, I-2, I-3, or I-4 and / or further derivatization of the resulting reaction product provides a variety of compounds of Formula I or Formula II. Suitable starting materials and reagents can be purchased or prepared by methods known to those skilled in the art. After each reaction is completed, each of the intermediates or final compounds can be recovered and optionally purified by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, etc. Other modifications of the compounds for implementing the present disclosure are within the scope of those skilled in the art. General Synthesis

[0248] Typical embodiments of the compounds described herein can be synthesized using the general reaction schemes described below. In view of the description herein, it should be clear that the general scheme can be varied by substituting other materials having similar structures for the starting materials to produce correspondingly different products. The following description of the synthesis provides many examples of how the starting materials can be varied to provide the corresponding products. Given the desired product that defines the substituent groups, the necessary starting materials can generally be determined by inspection. The starting materials are generally obtained from commercial sources or synthesized using published methods. To synthesize the compounds that are embodiments of the present disclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. In view of the examples herein, by a simple process of inspection, the identity of the necessary starting materials will generally be made clear by the identity of the final product. Generally, the compounds described herein are typically stable and separable at room temperature and pressure.

[0249] In some embodiments, a method for preparing a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is provided, which comprises reacting a compound of Formula I-1 under conditions sufficient to provide the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof: A compound of formula I-2: wherein R 1 、R 2 、R 4 、R 8 、R 9 、X 1 、X 2 、X 3 、X 4 、X 6 、Y 2 、Y 3 、Y 6 、A, n, L 1 and L 2 each is as defined herein, PG is a suitable carboxyl protecting group, LG is a suitable leaving group, and each R 50 is independently alkyl or substituted alkyl, or two R 50 are linked to form a cyclic borate ester, which may optionally be substituted.

[0250] In some embodiments, the method further comprises a deprotection step after the contacting step. In some embodiments, the conditions include a base. In some embodiments, the conditions include an acid. In some embodiments, the conditions include a temperature of about 50 °C to about 120 °C. In some embodiments, provided herein is a method for preparing compound I-1 or a pharmaceutically acceptable salt or solvate thereof, which comprises reacting a compound of formula I-3: with a compound of formula I-4: wherein R 1 、R 2 、R 4 、R 8 、R 9 、X 1 、X 2 、X 3 、X 4 、X 6 、Y 2 、Y 3 、Y 6 、A, n, L 1 and L 2 each is independently as defined herein, LG and LG' are suitable leaving groups, where LG and LG' are different, and PG is a suitable carboxyl protecting group. Examples

[0251] The following examples are included to illustrate specific embodiments of the present disclosure. Those skilled in the art will understand that the techniques disclosed in the following examples represent techniques that function well in the practice of the present disclosure and can thus be considered to constitute specific modes of its practice. However, according to the present disclosure, those skilled in the art will understand that many changes can be made in the specific embodiments disclosed without departing from the spirit and scope of the present disclosure and still obtain the same or similar results.

[0252] Abbreviations (as used herein):

[0253] General information: All evaporations or concentrations were carried out in vacuo using a rotary evaporator. Analytical samples were dried in vacuo (1 - 5 mmHg) at room temperature. Thin layer chromatography (TLC) was performed on silica gel plates and spots were visualized with ultraviolet light (214 and 254 nm). Purification was carried out using silica gel (100 - 200 mesh) by column and flash chromatography. Solvent systems are reported as mixtures by volume. NMR spectra were recorded on a Bruker 400 or Varian (400 MHz) spectrometer. 1 1H chemical shifts are reported as δ values in ppm, where the deuterated solvent is used as an internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad peak, m = multiplet), coupling constant (Hz), integration. Unless otherwise stated, LCMS spectra were obtained on a SHIMADZU LC20 - MS2020 or an Agilent 1260 series 6125B mass spectrometer or an Agilent 1200 series, 6110 or 6120 mass spectrometer with electrospray ionization. Example A1 4 - ({4 - [(Cyclopentyloxy)methyl] - 5 - (3,5 - dimethoxy - 4 - methylphenyl) - 6 - methylpyridin - 2 - yl}amino)oxane - 4 - carboxylic acid (Compound 101) -2 - yl}amino)oxane - 4 - carboxylic acid (Compound 101)

[0254] Step A (2 - chloro - 6 - methylpyridin - 4 - yl)methanol

[0255] To a solution of methyl 2-chloro-6-methylisonicotinate (10.0 g, 53.9 mmol) in THF (100 mL) at -78 °C was slowly added DIBAL-H (71.8 mL, 107.7 mmol, 1.5 M solution in toluene). The mixture was stirred at 25 °C for 16 h under a N2 atmosphere. The reaction mixture was quenched with H2O (4 mL) and 4 N aqueous NaOH solution (4 mL) at -78 °C, diluted with H2O (4 mL), and extracted with DCM (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (20 g silica gel flash column, eluent with a 0 - 50% EtOAc / PE gradient at 100 mL / min) to afford methyl 2-chloro-6-methylisonicotinate (7.0 g, yield 82%). 1 1H NMR (400 MHz, CDCl3) δ 7.09 (s, 1H), 7.00 (s, 1H), 4.64 (d, J = 1.6 Hz, 2H), 2.45 (s, 3H).

[0256] Step B 4-(Bromomethyl)-2-chloro-6-methylpyridine

[0257] To a solution of (2-chloro-6-methylpyridin-4-yl)methanol (7.0 g, 44.4 mmol) in DCM (100 mL) was added dropwise PBr3 (12.02 g, 44.42 mmol). The mixture was stirred at 25 °C for 2 h under a N2 atmosphere. The reaction mixture was basified to pH = 8 with saturated aqueous NaHCO3 solution. The organic layer was separated, and the aqueous layer was extracted with DCM (50 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (40 g silica gel flash column, eluent with a 0 - 20% EtOAc / PE gradient at 100 mL / min) to afford 4-(bromomethyl)-2-chloro-6-methylpyridine (9.0 g, yield 92%).

[0258] Step C 2-Chloro-4-((cyclopentyloxy)methyl)-6-methylpyridine

[0259] To a solution of 4-(bromomethyl)-2-chloro-6-methylpyridine (4.0 g, 18.1 mmol) and cyclopentanol (1.88 g, 21.8 mmol) in THF (40 mL) was added t-BuOK (3.05 g, 27.2 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated. The residue was diluted with brine (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (10 g silica gel flash column, eluent with a 0 - 9% EtOAc / PE gradient at 50 mL / min) to give 2-chloro-4-((cyclopentyloxy)methyl)-6-methylpyridine (440 mg, yield 11%). 1 H NMR (400 MHz, CDCl3) δ 7.12 (s, 1H), 6.97 (s, 1H), 4.42 (s, 2H), 4.06 - 3.95 (m, 1H), 2.52 (s, 3H), 1.80 - 1.52 (m, 8H).

[0260] Step D N-(4-((cyclopentyloxy)methyl)-6-methylpyridin-2-yl)-1,1-diphenylmethanimine

[0261] To a solution of diphenylmethanimine (389 mg, 2.14 mmol) and 2-chloro-4-((cyclopentyloxy)methyl)-6-methylpyridine (440 mg, 1.95 mmol) in toluene (5 mL) were added t-BuONa (281 mg, 2.92 mmol), BINAP (12.1 mg, 19.5 μmol), and Pd2(dba)3 (89.3 mg, 97.5 μmol). The mixture was stirred at 110 °C for 1 h. The reaction mixture was concentrated. The residue was diluted with brine (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (10 g silica gel flash column, eluent with a 0 - 50% EtOAc / PE gradient at 50 mL / min) to give N-(4-((cyclopentyloxy)methyl)-6-methylpyridin-2-yl)-1,1-diphenylmethanimine (500 mg, yield 69%). LC-MS: m / z 371.0 (M + H) + .

[0262] Step E 4-((cyclopentyloxy)methyl)-6-methylpyridin-2-amine

[0263] To a solution of N-(4-((cyclopentyloxy)methyl)-6-methylpyridin-2-yl)-1,1-diphenylmethanimine (500 mg, 1.35 mmol) in THF (2 mL) was added 2 M HCl (1.35 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was basified to pH = 8 with saturated aqueous NaHCO3 and extracted with EtOAc (50 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (10 g silica gel flash column, eluent with a 0 - 50% EtOAc / PE gradient at 50 mL / min) to afford 4-((cyclopentyloxy)methyl)-6-methylpyridin-2-amine (250 mg, 90% yield). 1 1H NMR (400 MHz, CDCl3) δ 6.40 (s, 1H), 6.27 (s, 1H), 4.34 (brs, 2H), 4.27 (s, 2H), 3.91 - 3.90 (m, 1H), 2.29 (s, 3H), 1.69 - 1.44 (m, 8H).

[0264] Step F 5-Bromo-4-((cyclopentyloxy)methyl)-6-methylpyridin-2-amine

[0265] To a solution of 4-((cyclopentyloxy)methyl)-6-methylpyridin-2-amine (220 mg, 1.07 mmol) in DMF (4 mL) was added NBS (190 mg, 1.07 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated. The residue was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (10 g silica gel flash column, eluent with a 0 - 40% EtOAc / PE gradient at 50 mL / min) to afford 5-bromo-4-(cyclopentyloxymethyl)-6-methyl-pyridin-2-amine (178 mg, 58% yield). LC-MS: m / z 286.3 (M + H) + .

[0266] Step G 4-((cyclopentyloxy)methyl)-5-(3,5-dimethoxy-4-methylphenyl)-6-methylpyridin-2-amine

[0267] To a solution of 5-bromo-4-((cyclopentyloxy)methyl)-6-methylpyridin-2-amine (100 mg, 351 μmol) and 2-(3,5-dimethoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (97.5 mg, 351 μmol) in THF (0.5 mL) and H2O (0.1 mL) was added XPhos Pd G3 (29.7 mg, 35.1 μmol) and Cs2CO3 (229 mg, 701 μmol). The mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated. The residue was diluted with brine (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica chromatography (10 g silica flash column, eluent with a 10%-20% EtOAc / PE gradient at 50 mL / min) to give 4-((cyclopentyloxy)methyl)-5-(3,5-dimethoxy-4-methylphenyl)-6-methylpyridin-2-amine (110 mg, yield 88%). 1 H NMR (400 MHz, CDCl3) δ 6.59 (s, 1H), 6.30 (s, 2H), 4.49 (brs, 2H), 4.08 (s, 2H), 3.85 - 3.79 (m 1H), 3.80 (s, 6H), 2.16 (s, 3H), 2.14 (s, 3H), 1.60 - 1.48 (m, 8H).

[0268] Step H 4-((4-((cyclopentyloxy)methyl)-5-(3,5-dimethoxy-4-methylphenyl)-6-methylpyridin-2-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (Compound 101)

[0269] At 0 °C, NaOH (37.0 mg, 926 μmol), dihydro-2H-pyran-4(3H)-one (61.8 mg, 617 μmol) were added to a solution of 4-((cyclopentyloxy)methyl)-5-(3,5-dimethoxy-4-methylphenyl)-6-methylpyridin-2-amine (110 mg, 309 μmol) in THF (5 mL), and then CHCl3 (111 mg, 926 μmol) was added. The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated. The residue was diluted with water (50 mL), acidified to pH = 6 with 1N HCl, and extracted with EtOAc (50 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150*30 mm, 5 μm; mobile phase A: water (0.05% NH3.H2O + 10 mM NH4HCO3), mobile phase B: CH3CN; flow rate: 40 mL / min; gradient: 25% B to 55% B in 7 min) to obtain 4-((4-((cyclopentyloxy)methyl)-5-(3,5-dimethoxyphenyl)-6-methylpyridin-2-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (5 mg, yield 3.3%). LC-MS: m / z 485.4 (M+H) + 。 1 H NMR (400 MHz, CD3OD) δ 7.08 (s, 1H), 6.44 (s, 2H), 4.18 (s, 2H), 3.96 - 3.89 (m, 1H), 3.82 - 3.76 (m, 8H), 3.77 - 3.71 (m, 2H), 2.44 - 2.30 (m, 2H), 2.24 (s, 3H), 2.11 (s, 3H), 2.00 - 1.88 (m, 2H), 1.71 - 1.53 (m, 8H). Example A2 4-({4-[(Cyclopentyloxy)methyl]-5-(3,5-dimethoxyphenyl)pyridin-2-yl}amino)oxane-4-carboxylic acid (Compound 102)

[0270] Step A 5-Bromo-4-(bromomethyl)-2-chloropyridine

[0271] To a solution of 5-bromo-2-chloro-4-methylpyridine (20.0 g, 96.9 mmol) in CCl4 (200 mL) was added NBS (20.7 g, 116 mmol) and BPO (3.13 g, 9.69 mmol, purity 75%). The mixture was stirred at 80 °C for 16 h. After cooling, the reaction mixture was diluted with H2O (500 mL) and extracted with DCM (300 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (220 g silica gel flash column, eluent with 0 - 5% EtOAc / PE gradient at 100 mL / min) to give 5-bromo-4-(bromomethyl)-2-chloropyridine (5.7 g, yield 21%). LC-MS: m / z 285.9 (M+H) + .

[0272] Step B 5-bromo-2-chloro-4-((cyclopentyloxy)methyl)pyridine

[0273] To a solution of 5-bromo-4-(bromomethyl)-2-chloropyridine (1.0 g, 3.50 mmol) and cyclopentanol (302 mg, 3.50 mmol) in DCM (10 mL) was added AgOTf (1.35 g, 5.26 mmol) and 2,6-di-tert-butylpyridine (1.34 g, 7.01 mmol). The mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with H2O (50 mL) and extracted with DCM (50 mL x3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (10 g silica gel flash column, eluent with 0 - 10% EtOAc / PE gradient at 40 mL / min) to give 5-bromo-2-chloro-4-((cyclopentyloxy)methyl)pyridine (360 mg, yield 35%). LC-MS: m / z 292.0 (M+H) + .

[0274] Step C 2-chloro-4-((cyclopentyloxy)methyl)-5-(3,5-dimethoxy-4-methylphenyl)pyridine

[0275] To a solution of 5-bromo-2-chloro-4-((cyclopentyloxy)methyl)pyridine (200 mg, 688 μmol) and 2-(3,5-dimethoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (191 mg, 688 μmol) in dioxane (3 mL) and H2O (3 mL) was added Pd(dppf)Cl2 (50.4 mg, 68.8 μmol) and Na2CO3 (146 mg, 1.38 mmol). The mixture was stirred at 70 °C for 16 h. The mixture was poured into H2O (30 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica chromatography (4 g silica flash column, eluent with a 0 - 5% EtOAc / PE gradient at 100 mL / min) to afford 2-chloro-4-(cyclopentyloxymethyl)-5-(3,5-dimethoxy-4-methyl-phenyl)pyridine (170 mg, 68% yield). LC-MS: m / z 361.9 (M+H) + .

[0276] Step D 4-((4-((Cyclopentyloxy)methyl)-5-(3,5-dimethoxy-4-methylphenyl)pyridin-2-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (Compound 102)

[0277] To a solution of 2-chloro-4-(cyclopentyloxymethyl)-5-(3,5-dimethoxy-4-methylphenyl)pyridine (90 mg, 249 μmol) and methyl 4-aminotetrahydro-2H-pyran-4-carboxylate (79.2 mg, 497 μmol) in DMA (2 mL) was added CuI (19.0 mg, 99.5 μmol) and DBU (75.7 mg, 497 μmol). The mixture was stirred at 150 °C under Biotage microwave for 2 h. After cooling to room temperature, the mixture was diluted with water (20 mL), acidified to pH = 5 with 1N HCl and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica chromatography (4 g Purified by silica gel flash column with an eluent of 0 - 8% MeOH / DCM gradient at 80 mL / min, and then further purified by preparative HPLC (column: Phenomenex C18 80*40mm*3um; mobile phase A: water (0.05% NH3.H2O + 10 mM NH4HCO3), mobile phase B: CH3CN; flow rate: 40 mL / min; gradient: 30% B to 60% B in 7 min) to obtain 4 - ((4 - ((cyclopentyloxy)methyl)-5-(3,5 - dimethoxy - 4 - methylphenyl)pyridin - 2 - yl)amino)tetrahydro - 2H - pyran - 4 - carboxylic acid (2.36 mg, yield 2.0%).

[0278] LC-MS: m / z 471.2 (M + H) + 。 1 1H NMR (400 MHz, CD3OD) δ 7.82 (s, 1H), 6.98 (s, 1H), 6.51 (s, 2H), 4.35 (s, 2H), 4.04 - 3.92 (m, 1H), 3.81 (s, 6H), 3.80 - 3.76 (m, 4H), 2.35 - 2.23 (m, 2H), 2.13 - 2.04 (m, 5H), 1.75 - 1.50 (m, 8H). Example A3 4 - ((4 - ((cyclopentyloxy)methyl)-5-(3 - cyclopropoxy - 2 - fluoro - 5 - methoxyphenyl)pyridin - 2 - yl)amino)tetrahydro - 2H - pyran - 4 - carboxylic acid (Compound 103)

[0279] Step A2 - (2 - chloroethoxy)-1 - fluoro - 4 - methoxybenzene

[0280] To a solution of 2 - fluoro - 5 - methoxyphenol (5.0 g, 35.18 mmol) in EtOH (40 mL) and H2O (4 mL) was added NaOH (1.41 g, 35.18 mmol). The mixture was stirred at 25 °C for 30 min. Then 1 - bromo - 2 - chloroethane (10.09 g, 70.36 mmol) was added. The mixture was stirred at 70 °C for 12 h. After cooling, the mixture was acidified to pH = 7 with 1N HCl and concentrated. The residue was purified by silica gel column (10% EtOAc / PE) to obtain 2 - (2 - chloroethoxy)-1 - fluoro - 4 - methoxybenzene (4.8 g, yield 66%). LC-MS: m / z 204.7 (M + H) + 。

[0281] Step B 1-Fluoro-4-methoxy-2-(vinyloxy)benzene

[0282] To a solution of 2-(2-chloroethoxy)-1-fluoro-4-methoxybenzene (4.8 g, 23.46 mmol) in THF (40 mL) was added t-BuOK (5.26 g, 46.91 mmol). The mixture was stirred at 25 °C for 16 h. The mixture was acidified to pH = 7 with 1N HCl and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column (2% EtOAc / PE) to give 1-fluoro-4-methoxy-2-(vinyloxy)benzene (3.45 g, 88% yield).

[0283] Step C 2-Cyclopropoxy-1-fluoro-4-methoxybenzene

[0284] To a solution of 1-fluoro-4-methoxy-2-(vinyloxy)benzene (1.5 g, 8.92 mmol) and chloroiodomethane (6.29 g, 35.68 mmol) in DCE (40 mL) at 0 °C was added a 1.0 M solution of diethylzinc in hexane (22.30 mL, 22.3 mmol). The mixture was stirred at 0 °C for 3 h. The mixture was quenched with aqueous NH4Cl solution (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (40 g Silica gel flash column, eluent with a 0-2% EtOAc / PE gradient at 50 mL / min) to give 2-cyclopropoxy-1-fluoro-4-methoxybenzene (1.28 g, 79% yield). 1 1H NMR (400 MHz, DMSO-d6) δ 7.15 (dd, J = 11.2 Hz, 8.8 Hz, 1H), 6.97 (dd, J = 7.2 Hz, 4.0 Hz, 1H), 6.59 - 6.49 (m, 1H), 4.00 - 3.94 (m, 1H), 3.78 (s, 3H), 0.89 - 0.68 (m, 4H).

[0285] Step D 2-(3-Cyclopropoxy-2-fluoro-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0286] To a solution of 2-cyclopropoxy-1-fluoro-4-methoxybenzene (1.28 g, 7.03 mmol) and bis(pinacolato)diboron (1.96 g, 7.73 mmol) in THF (20 mL) was added [Ir(COD)OMe]2 (47 mg, 0.70 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (dtbpy) (38 mg, 0.14 mmol). The mixture was stirred under N2 at 80 °C for 12 h. The reaction mixture was concentrated. The residue was purified by flash silica gel chromatography (40 g silica gel flash column, eluent with a 0 - 2% EtOAc / PE gradient at 50 mL / min) to give 2-(3-cyclopropoxy-2-fluoro-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.46 g, yield 31%). 1 1H NMR (400 MHz, DMSO-d6) δ 6.92 (dd, J = 7.2 Hz, 4.0 Hz, 1H), 6.48 (t, J = 3.2 Hz, 1H), 3.85 - 3.76 (m, 1H), 3.62 (s, 3H), 1.16 (s, 12H), 0.70 - 0.62 (m, 2H), 0.58 - 0.51 (m, 2H).

[0287] 4-((4-((Cyclopentyloxy)methyl)-5-(3-cyclopropoxy-2-fluoro-5-methoxyphenyl)pyridin-2-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (Compound 103) was synthesized according to the procedure for Example A2 (Steps C and D) using 2-(3-cyclopropoxy-2-fluoro-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in Step C and 4-aminotetrahydropyran-4-carboxylic acid in Step D. LC-MS: m / z 501.6 (M+H) + . 1 1H NMR (400 MHz, CD3OD) δ 7.78 (s, 1H), 6.97 (dd, J = 6.8 Hz, 1H), 6.93 (s, 1H), 6.36 (dd, J = 4.8, 3.0 Hz, 1H), 4.25 (s, 2H), 3.95 - 3.87 (m, 2H), 3.85 - 3.77 (m, 7H), 2.30 - 2.23 (m, 2H), 2.16 - 2.12 (m, 2H), 1.72 - 1.58 (m, 6H), 1.57 - 1.48 (m, 2H), 0.89 - 0.75 (m, 4H). Example A4 4-((4-(2-Cyclopropylethyl)-5-(3-ethoxy-2-fluoro-5-methoxy-4-methylphenyl)pyridin-2-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (Compound 108)

[0288] Step A 1-Fluoro-4-methoxy-2-(methoxymethoxy)benzene

[0289] To a solution of 2-fluoro-5-methoxyphenol (3.9 g, 27.4 mmol) in THF (20 mL) was added 60% NaH (1.21 g, 30.2 mmol). The mixture was stirred at 0 °C for 0.5 h. Then bromomethyl methyl ether (2.24 mL, 27.4 mmol) was added. The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by adding H2O (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (40 g silica gel flash column, eluent with 0 - 6% EtOAc / PE gradient at 80 mL / min) to give 1-fluoro-4-methoxy-2-(methoxymethoxy)benzene (5.0 g, yield 98%). LC-MS: m / z 187.1 (M+H) + .

[0290] Step B 1-Fluoro-4-methoxy-2-(methoxymethoxy)-3-methylbenzene

[0291] To a solution of 1-fluoro-4-methoxy-2-(methoxymethoxy)benzene (11.6 g, 62.3 mmol) in THF (100 mL) at -70 °C was added dropwise t-BuLi (95.9 mL, 124.6 mmol, 1.3 M pentane solution). After the addition, the mixture was stirred at -20 °C for 3 h and MeI (7.76 mL, 125 mmol) was added dropwise at -20 °C. The resulting mixture was stirred at -20 °C for 1 h. The mixture was quenched with H2O (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL x 3). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (40 g Silica gel flash column, eluting with 0 - 4% EtOAc / PE gradient at 80 mL / min) to purify to obtain 1-fluoro-4-methoxy-2-(methoxymethoxy)-3-methylbenzene (10.0 g, yield 80%). LC-MS: m / z 201.1 (M+H) + 。

[0292] Step C 6-Fluoro-3-methoxy-2-methylphenol

[0293] To a solution of 1-fluoro-4-methoxy-2-(methoxymethoxy)-3-methylbenzene (10.0 g, 50.0 mmol) in THF (2 mL) was added 6 M aqueous HCl (8.32 mL). The mixture was stirred at 60 °C for 12 h. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to obtain 6-fluoro-3-methoxy-2-methyl-phenol (5.0 g, yield 64%). 1 1H NMR (400 MHz, CDCl3) δ 6.90 - 6.83 (m, 1H), 6.36 - 6.28 (m, 1H), 5.18 (s, 1H), 3.80 (s, 3H), 2.16 (s, 3H).

[0294] Step D 2-Ethoxy-1-fluoro-4-methoxy-3-methylbenzene

[0295] To a solution of 6-fluoro-3-methoxy-2-methyl-phenol (0.5 g, 3.20 mmol) and EtI (499 mg, 3.20 mmol) in DMF (5 mL) was added K2CO3 (885 mg, 6.40 mmol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (4 g silica gel flash column, eluting with 0 - 8% EtOAc / PE gradient at 40 mL / min) to obtain 2-ethoxy-1-fluoro-4-methoxy-3-methylbenzene (0.35 g, yield 59%). 11H NMR (400 MHz, CDCl3) δ 6.88 (dd, J = 10.4, 9.2 Hz, 1H), 6.50 (dd, J = 9.0, 3.8 Hz, 1H), 4.09 (q, J = 7.0 Hz, 2H), 3.81 (s, 3H), 2.17 (s, 3H), 1.40 (t, J = 7.0 Hz, 3H).

[0296] Step E 2-(3-Ethoxy-2-fluoro-5-methoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0297] To a solution of 2-ethoxy-1-fluoro-4-methoxy-3-methylbenzene (0.35 g, 1.90 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (434 mg, 1.71 mmol) in THF (5 mL) was added [Ir(COD)OMe]2 (6.30 mg, 9.50 μmol) and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (dtbpy) (5.10 mg, 19.00 μmol). The mixture was stirred at 80 °C for 48 h. The reaction mixture was concentrated. The residue was purified by flash silica gel chromatography (12 g silica gel flash column, eluent with a 0 - 8% EtOAc / PE gradient at 40 mL / min) to give 2-(3-ethoxy-2-fluoro-5-methoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.27 g, yield 46%). LC-MS: m / z 311.2 (M+H) + .

[0298] Step F 5-Chloro-4-(cyclopropylethynyl)pyridin-2-amine

[0299] To a solution of 4-bromo-5-chloro-pyridin-2-amine (3.0 g, 14.5 mmol) and ethynylcyclopropane (3.00 mL, 36.2 mmol) in MeCN (120 mL) was added Pd(PPh3)2Cl2 (1.02 g, 1.45 mmol), CuI (275 mg, 1.45 mmol) and DIEA (12.6 mL, 72.3 mmol). The mixture was stirred at 90 °C for 12 h. After cooling to room temperature, the mixture was diluted with water (250 mL), acidified to pH = 5 with 1 N aqueous HCl, and extracted with ethyl acetate (80 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to give a residue. The residue was purified by flash silica chromatography (80 g silica flash column, eluent with 0 - 30% EtOAc / PE gradient at 100 mL / min) to give 5-chloro-4-(2-cyclopropylethynyl)pyridin-2-amine (2.5 g, 90% yield). LC-MS: m / z 192.7 (M+H) + .

[0300] Step G 4-((5-chloro-4-(cyclopropylethynyl)pyridin-2-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid

[0301] To a solution of 5-chloro-4-(2-cyclopropylethynyl)pyridin-2-amine (2.5 g, 13.0 mmol) in THF (50 mL) at 0 °C was added NaOH (2.60 g, 64.9 mmol) and tetrahydropyran-4-one (2.60 g, 26.0 mmol, 2.38 mL). After stirring for 10 min, CHCl3 (5.23 mL, 64.9 mmol) was added dropwise. The resulting mixture was stirred at 0 °C for 1 h and at 25 °C for 15 h. Then the mixture was diluted with water (150 mL), acidified to pH = 5 with 1 N aqueous HCl, and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to give a residue. The residue was purified by flash silica chromatography (40 g silica flash column, eluent with 25% - 60% EtOAc / PE gradient at 100 mL / min) to give 4-((5-chloro-4-(cyclopropylethynyl)pyridin-2-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (875 mg, 21% yield). LC-MS: m / z 321.0 (M+H) + .

[0302] Step H 4-((5-chloro-4-(2-cyclopropylethyl)pyridin-2-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid

[0303] To a mixture of 4-[[5-chloro-4-(2-cyclopropylethynyl)-2-pyridinyl]amino]tetrahydro-2H-pyran-4-carboxylic acid (800 mg, 2.49 mmol) in toluene (30 mL) was added PtO2 (170 mg, 748 μmol). After degassing and purging with H2 three times, the resulting mixture was stirred at 25 °C, 15 psi, under H2 atmosphere for 12 h. After filtration, the filtrate was evaporated to give a residue. The residue was purified by flash silica gel chromatography (20 g silica gel flash column, eluent with 0 - 50% EtOAc / PE gradient at 100 mL / min) to afford 4-[[5-chloro-4-(2-cyclopropylethyl)-2-pyridinyl]amino]tetrahydro-2H-pyran-4-carboxylic acid (510 mg, yield 63%). LC-MS: m / z 324.9 (M+H) + 。

[0304] Step I 4-((4-(2-cyclopropylethyl)-5-(3-ethoxy-2-fluoro-5-methoxy-4-methylphenyl)pyridin-2-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid

[0305] To a solution of 4-((5-chloro-4-(2-cyclopropylethyl)pyridin-2-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (200 mg, 616 μmol) and 2-(3-ethoxy-2-fluoro-5-methoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (229 mg, 739 μmol) in THF (3 mL) and H2O (1.5 mL) was added XPhos Pd G3 (52.1 mg, 61.6 μmol) and Cs2CO3 (401 mg, 1.23 mmol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with water (40 mL), acidified to pH = 5 with 1N aqueous HCl, and extracted with ethyl acetate (50 mL x 3). The combined organic layers were evaporated to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica gel quick column, purified with an eluent of 0 - 4% MeOH / DCM gradient at 100 mL / min, and further purified by preparative HPLC (column: Phenomenex C18 80*40mm*3um; mobile phase A: water (0.05% NH3.H2O + 10 mM NH4HCO3), mobile phase B: CH3CN; flow rate: 40 mL / min; gradient: 30% B to 60% B in 7 min) to obtain 4-((4-(2-cyclopropylethyl)-5-(3-ethoxy-2-fluoro-5-methoxy-4-methylphenyl)pyridin-2-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (86.87 mg, yield 28.5%). LC-MS: m / z 473.3 (M+H) + 。 1 H NMR (400 MHz, CD3OD) δ 7.90 (s, 1H), 6.86 (s, 1H), 6.64 (d, J = 5.6 Hz, 1H), 4.21 (q, J = 6.8 Hz, 2H), 3.96 - 3.94 (m, 7H), 2.74 - 2.70 (m, 2H), 2.70 - 2.41 (m, 2H), 2.32 (s, 3H), 2.25 - 2.21 (m, 2H), 1.53 (q, J = 7.2 Hz, 1H), 1.51 - 1.46 (m, 2H), 0.75 - 0.73 (m, 1H), 0.51 - 0.46 (m, 2H), 0.04 - 0.01 (m, 2H).

[0306] The compounds in Table 1 were synthesized using appropriate starting materials and a similar procedure described in the above examples. Biological Assay In Vitro LPA1 Calcium Flux Antagonist Assay - Bioduro Protocol

[0307] CHO-K1 cells overexpressing human LPA1 and G15a were seeded at a total volume of 20 μL (15,000 cells / well) into Matrigel pre-coated 384-well plates (Corning-3764) and incubated at 37 °C. After overnight incubation, the cells were serum-starved for 4 h. The assay was performed in dye loading buffer containing 1x Fluo-8 AM (AAT Bioquest, 21080) and 2.5 mM probenecid (Thermo Fisher, 36400) in HBSS / 20 mM Hepes. After cell starvation, the medium was replaced with 20 μL of dye loading buffer and incubated at 37 °C for 30 min. Then, 5 μL of 5X compound titrated in dye loading buffer was added to the cells and incubated for 30 min, followed by LPA stimulation at EC80. Calcium mobilization was measured on a FLIPR Tetra (MDS). For LPA EC80 determination, the starved cells were incubated with 20 μL of dye loading buffer for 1 h, then 5 μL of 5X LPA titrated in dye loading buffer was added to the cells. The calcium signal induced by LPA was monitored on a FLIPR.

[0308] The percent inhibition was calculated using the following formula: % Inhibition = 100% x (1 - (Average RFU of test sample - Average RFU of DMSO) / (Average RFU of LPA control - Average RFU of DMSO)).

[0309] Table B1 shows the bioactivity of the compounds in an in vitro LPA1 calcium flux antagonist assay - Bioduro protocol. The activities of the test compounds are provided in Table B1 below. Table B1

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt or solvate thereof, wherein: A is C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C of A 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1 substituted; L 1 is a bond, -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -, C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene or C 1-3 heteroalkylene; wherein L 1 's C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene or C 1-3 heteroalkylene is independently optionally substituted with one to five substituents independently selected from C 1-9 alkyl, halo, hydroxy and cyano; L 2 is a key, C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene or C 1-3 heteroalkylene; wherein L 2 of C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene or C 1-3 heteroalkylene is independently optionally substituted with one to five substituents independently selected from C 1-9 alkyl, halo, hydroxy and cyano; X 1 is N or CR 3 ; X 2 is N or CR 5 ; X 3 is N or CR 7 ; X 6 is N or CR 6 ; X 4 is O or CHR 11 ; provided that when A is C 1-6 alkyl, then X 4 is O; Y 2 , Y 3 and Y 6 One of them is N, and Y 2 , Y 3 and Y 6 The others are independently CR 13 ; n is 0, 1 or 2; R 1 and R 2 each independently is C 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10 cycloalkyl or heterocyclic group; wherein each C 1 of R 2 and R 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10 cycloalkyl or heterocyclic group is independently optionally substituted with one to five Z 1 substituents; or R 1 and R 2 together with the atoms to which they are attached form a C 3-10 cycloalkyl or heterocyclic group; wherein said C 3-10 cycloalkyl or heterocyclic group is optionally substituted by one to five Z 1 substituents; R 3 is hydrogen, a halogen group, a cyano group, a nitro group, -OH, -SH, -NH2, -NH-C 1-5 alkyl, -N(C 1-5 alkyl)2, -S-C 1-5 alkyl, C 1-5 alkoxy, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group; wherein R 3 of -NH-C 1-5 alkyl, -N(C 1-5 alkyl)2, -S-C 1-5 alkyl, C 1-5 alkoxy, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen groups, hydroxyl groups, and cyano groups; R 4 is a halogen group, a cyano group, a nitro group, -OR 14 , -N(R 14 )2, -SR 14 , C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group; wherein the C 4 alkyl, C 1-5 alkenyl, C 2-5 alkynyl, C 2-5 cycloalkyl or 3- to 5-membered heterocyclic group of R 3-5 is independently optionally substituted with one to five substituents independently selected from halogen groups, hydroxyl groups, C 1-5 alkoxy groups and cyano groups; or R 3 and R 4 together with the atoms to which they are attached form a cycloalkyl, aryl, heterocyclic or heteroaryl group; wherein the cycloalkyl, aryl, heterocyclic or heteroaryl group is optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; R 5 is hydrogen, a halogen group, a cyano group, a nitro group, -OR 15 , -N(R 15 )2, -SR 15 , -C(O)R 15 , -C(O)OR 15 , C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, a 3- to 5-membered heterocyclic group or a 5-membered heteroaryl group; wherein the C 5 alkyl, C 1-5 alkenyl, C 2-5 alkynyl, C 2-5 cycloalkyl, a 3- to 5-membered heterocyclic group or a 5-membered heteroaryl group of R 3-5 is independently optionally substituted by one to five Z 1 ; R 6 is hydrogen, a halogen group, a cyano group, a nitro group, -OR 16 , -N(R 16 )2, -SR 16 , C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group; wherein the C 6 alkyl, C 1-5 alkenyl, C 2-5 alkynyl, C 2-5 alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclic group is independently optionally substituted by one to five substituents independently selected from halogen groups, hydroxyl groups and cyano groups; R 7 is hydrogen, a halogen group, a cyano group, a nitro group, -OH, -SH, -NH2, -NH-C 1-5 alkyl, -N(C 1-5 alkyl)2, -S-C 1-5 alkyl, C 1-5 alkoxy, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group; wherein the -NH-C 7 alkyl, -N(C 1-5 alkyl)2, -S-C 1-5 alkyl, C 1-5 alkoxy, C 1-5 alkyl, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group is independently optionally substituted by one to five substituents independently selected from halogen groups, hydroxy groups, and cyano groups; or R 6 and R 7 together with the atoms to which they are attached form a cycloalkyl, aryl, heterocyclic or heteroaryl group; wherein the cycloalkyl, aryl, heterocyclic or heteroaryl group is optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; R 8 is hydrogen, C 1-9 alkyl, halo, hydroxy or cyano; Each R 9 is independently hydrogen, C 1-9 alkyl, halo, hydroxy or cyano; R 10 is hydrogen, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group; wherein R 10 of C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; R 11 is hydrogen, C 1-9 alkyl, oxo group, halogenated group, hydroxyl group or cyano group; Each R 13 are independently hydrogen, halo, cyano, nitro, -OH, -SH, -NH2, -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-6 Cycloalkyl or 3 to 6 membered heterocyclic group; wherein R 13 Each -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-6 Cycloalkyl or 3 to 6 membered heterocyclyl is independently optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; R 14 is hydrogen, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group; wherein R 14 of C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halo, hydroxy, and cyano; R 15 is hydrogen, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group; wherein R 15 of C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halo, hydroxy, and cyano; R 16 is hydrogen, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group; wherein R 16 of C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl or a 3- to 5-membered heterocyclic group is independently optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; Each Z 1 is independently a halogen group, a cyano group, a nitro group, an oxo group, C 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -L-H, -L-C 1-9 alkyl, -L-C 2-9 alkenyl, -L-C 2-9 alkynyl, -L-C 3-10 cycloalkyl, -L-heterocyclic group, -L-aryl or -L-heteroaryl; wherein each C 1 of Z 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1a substituents; Each L is independently -O-, -S-, -NR 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -, -NR 20 C(O)-, -OC(O)NR 20 -, -NR 20 C(O)O-, -NR 20 C(O)NR 21 -, -S(O)-, -S(O)2-, -S(O)NR 20 -, -S(O)2NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR 20 S(O)NR 21 - or -NR 20 S(O)2NR 21 -; Each R 20 and R 21 is independently hydrogen, C 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C 20 of R 21 and R 1-9 alkyl, C 2-9 alkenyl, C 2-9 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted with one to five Z 1a ; or R 20 and R 21 together with the atoms to which they are attached form a heterocyclic group that is independently optionally substituted with one to five Z 1a ; and Each Z 1a are independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein Z 1a Each -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one to five independently selected 1-9 The substituents of the alkyl, oxo, halo, hydroxy and cyano groups are substituted.

2. The compound according to claim 1, said compound being represented by formula IA:

3. The compound according to claim 1, said compound being represented by formula IB:

4. The compound according to claim 1, said compound being represented by formula IC:

5. A compound according to any one of the preceding claims, wherein X 4 is O; and A is C 1-6 alkyl.

6. The compound according to any one of the preceding claims, wherein A is C 3-10 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and each C of ring A 3-10 cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently optionally substituted with one to five Z 1 substituents.

7. A compound according to any one of the preceding claims, wherein A is a C cycloalkyl optionally substituted with one to five Z 1 cycloalkyl 3-10 which is optionally substituted with one to five Z.

8. A compound according to any one of the preceding claims, wherein L 1 is a bond, -O-, -NR 10 -, C 1-3 alkylene or C 1-3 heteroalkylene.

9. A compound according to any one of the preceding claims, wherein L 1 is -O- or -NH-.

10. The compound according to any one of the preceding claims, wherein L 2 is a bond.

11. A compound according to any one of the preceding claims, wherein R 1 and R 2 together with the atoms to which they are attached form a C 3-10 cycloalkyl, the C 3-10 cycloalkyl being optionally substituted by one to five Z 1 substituents.

12. The compound according to any one of claims 1-10, wherein R 1 and R 2 together with the atoms to which they are attached form a heterocyclic group, which heterocyclic group is optionally substituted with one to five Z 1 substituents.

13. A compound according to any one of the preceding claims, wherein each R 13 is independently hydrogen or C 1-9 alkyl.

14. The compound according to claim 1, said compound being represented by formula ID: wherein: p is 0, 1 or 2; q is 0, 1 or 2; X 5 is absent, or is O, NR 17 or C(R 18 )2; R 17 It is hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 、-C(O)OR 20 、-C(O)NR 20 、-S(O)R 20 、-S(O)2R 20 、-S(O)NR 20 R 21 or -S(O)2NR 20 R 21 ; where R 17 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1a replace; and Each R 18 is independently hydrogen or Z 1 .

15. The compound according to any one of the preceding claims, wherein X 4 is O.

16. The compound according to any one of the preceding claims, wherein R 8 is hydrogen.

17. The compound according to any one of the preceding claims, wherein n is 0.

18. The compound according to claim 14, said compound being represented by formula IE:

19. The compound according to any one of the preceding claims, wherein X 1 is CR 3 .

20. The compound according to any one of the preceding claims, wherein X 2 is CR 5 .

21. The compound according to any one of the preceding claims, wherein X 3 is CR 7 .

22. The compound according to any one of the preceding claims, wherein X 6 is CR 6 .

23. The compound according to any one of the preceding claims, wherein the moiety is:

24. The compound according to any one of the preceding claims, wherein said moiety is:

25. The compound according to any one of the preceding claims, wherein R 3 is hydrogen, a halogenated group or C 1-5 alkyl, wherein the C 1-5 alkyl is optionally substituted with one to five halogenated groups.

26. The compound according to any one of the preceding claims, wherein R 5 is hydrogen, -C(O)-C 1-5 alkyl or C 1-5 alkyl.

27. A compound according to any one of the preceding claims, wherein R 6 is hydrogen or C 1-5 alkoxy.

28. The compound according to any one of the preceding claims, wherein R 7 is hydrogen, a halogenated group or C 1-5 alkyl, wherein the C 1-5 alkyl is optionally substituted with one to five halogenated groups.

29. The compound according to any one of the preceding claims, wherein R 4 is C 1-5 alkoxy or -O-C 3-10 cycloalkyl.

30. A compound selected from Table 1 or Table 2 or a pharmaceutically acceptable salt or solvate thereof.

31. A pharmaceutical composition comprising the compound according to any one of the preceding claims or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.

32. A method for treating an LPA-related disease, disorder or condition, said method comprising administering to a patient in need thereof an effective amount of the compound according to any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 31.

33. The method according to claim 32, wherein the LPA-related disease, disorder or condition is an LPA1-related disease.

34. The method according to claim 32 or 33, wherein the LPA-related disease, disorder or condition is fibrosis, transplant rejection, cancer, osteoporosis or an inflammatory disorder.

35. The method according to claim 34, wherein the fibrosis is pulmonary fibrosis, liver fibrosis, renal fibrosis, cardiac fibrosis, skin fibrosis, ocular fibrosis or pancreatic fibrosis.

36. The method according to claim 34, wherein the cancer is cancer of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gallbladder, genitalia, genitourinary tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral mucosa, nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testis or thyroid.

37. The method according to claim 32 or 33, wherein the LPA-related disease, disorder or condition is idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, systemic sclerosis, COVID-19, chronic obstructive pulmonary disease (COPD), neuroinflammation or multiple sclerosis.

38. A method for preparing the compound of formula I according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, said method comprising reacting a compound of formula I-1: with a compound of formula I-2: wherein PG is a suitable carboxyl protecting group, LG is a suitable leaving group, and each R 50 is independently alkyl or substituted alkyl, or two Rs 50 are linked to form a cyclic borate ester, which cyclic borate ester may optionally be substituted.

39. The method according to claim 38, wherein the method further comprises a deprotection step after said contacting.

40. A method for preparing a compound of formula I-1 as claimed in claim 38 or a pharmaceutically acceptable salt or solvate thereof, the method comprising reacting a compound of formula I-3: with a compound of formula I-4: wherein LG and LG' are suitable leaving groups, wherein LG and LG' are different, and PG is a suitable carboxyl protecting group.

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