Compounds and compositions for treating conditions associated with LPA receptor activity

Abstract

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

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of International Patent Application PCT / CN2022 / 134099, filed November 24, 2022, the contents of which are incorporated herein by reference in their entirety.

[0002] Field The present invention relates to LPA antagonists and pharmaceutical compositions comprising the compounds disclosed herein. Methods for treating LPA-related diseases, disorders, and conditions are also provided. [Background technology]

[0003] background Various lipid mediators, including eicosanoids and platelet-activating factor (PAF), are generated from cell membranes by the activity of phospholipases. Lysophospholipids, one class of these membrane-derived bioactive lipid mediators, include lysophosphatidic acid (LPA). LPA is not a single molecular entity but a collection of endogenous structural variants of fatty acids of various lengths and degrees of saturation. LPA influences cellular functions, including cell proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. These functions influence many biological processes, including neurogenesis, angiogenesis, wound healing, immunity, and carcinogenesis. LPA acts as a biological effector molecule, exerting diverse physiological effects, including, but not limited to, effects on blood pressure, platelet activation, and smooth muscle contraction, as well as diverse cellular effects, including cell proliferation, cell rounding, neurite retraction, actin stress fiber formation, and cell migration. The effects of LPA are primarily receptor-mediated. Activation of LPA receptors (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) by LPA mediates a series of downstream signaling cascades. Summary of the Invention [Problem to be solved by the invention]

[0004] overview Antagonizing LPA receptors (e.g., LPA1 receptors) can be useful in treating a variety of disorders, including fibrosis and thus diseases caused by fibrosis, such as pulmonary fibrosis, liver fibrosis, renal fibrosis, arterial fibrosis, and systemic sclerosis (e.g., pulmonary fibrosis, e.g., idiopathic pulmonary fibrosis (IPF), liver fibrosis including nonalcoholic steatohepatitis (NASH), renal fibrosis such as diabetic nephropathy, systemic sclerosis-scleroderma, etc.), COVID-19, chronic obstructive pulmonary disease (COPD), neuroinflammation, or multiple sclerosis. This specification describes LPA antagonists, as well as pharmaceutical compositions comprising the compounds disclosed herein. Methods for treating LPA-related diseases, disorders, and conditions are also provided. [Means for solving the problem]

[0005] In one embodiment, the present invention provides a compound of formula I: [ka] [During the ceremony, A is C 1-6 Alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1-6 Alkyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally independently has 1 to 5 Z 1 is replaced by; 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; 1 C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene or C 1-3 The heteroalkylene optionally independently represents C 1-9 substituted with 1 to 5 substituents independently selected from 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; 2 C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene or C 1-3 The heteroalkylene optionally independently represents C 1-9 substituted with 1 to 5 substituents independently selected from alkyl, halo, hydroxy, and cyano; X 1 is N or CR 3 and; X 2 is N or CR 5 and; X 3 is N or CR 7 and; X 6 is N or CR 6 and; X 4 is O or CHR 11 where A is C 1-6 If it is alkyl, then X 4 is O; Y 2 , Y 3 and Y 6 One of them is N and the other is Y 2 , Y 3 and Y 6 The rest are each independently CR 13 and; 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 heterocyclyl; where R 1 and R 2 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9Alkynyl, C 3-10 The cycloalkyl or heterocyclyl optionally independently has 1 to 5 Z 1 is replaced by; or R 1 and R 2 are combined with the atoms to which they are bonded to form C 3-10 Forms a cycloalkyl or heterocyclyl; 3-10 The cycloalkyl or heterocyclyl optionally has 1 to 5 Z 1 is replaced by; R 3 are hydrogen, halo, 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- to 5-membered heterocyclyl; where R 3 -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 the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 4 are halo, 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 heterocyclyl; where R 4 C 1-5 Alkyl, C 2-5 Alkenyl, C2-5 Alkynyl, C 3-5 The cycloalkyl or 3- to 5-membered heterocyclyl is optionally independently selected from halo, hydroxy, C 1-5 substituted with 1 to 5 substituents independently selected from alkoxy and cyano; or R 3 and R 4 together with the atom to which they are attached form a cycloalkyl, aryl, heterocyclyl, or heteroaryl; wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with 1 to 5 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 heterocyclyl, or 5-membered heteroaryl; where R 5 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 The cycloalkyl, 3- to 5-membered heterocyclyl, or 5-membered heteroaryl may optionally independently be substituted with 1 to 5 Z 1 is replaced by; 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 heterocyclyl; where R 6 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 7 are hydrogen, halo, 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- to 5-membered heterocyclyl; where R 7 -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 the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 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, heterocyclyl, or heteroaryl; wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 8 is hydrogen, C 1-9 alkyl, halo, hydroxy, or cyano; Each R 9 are 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 3-5cycloalkyl or 3- to 5-membered heterocyclyl; where R 10 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 11 is hydrogen, C 1-9 alkyl, oxo, halo, hydroxy, or cyano; 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 heterocyclyl; where R 13 Each of -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 the cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted with 1 to 5 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 3- to 5-membered heterocyclyl; where R 14 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 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 heterocyclyl; where R 15 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 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 3- to 5-membered heterocyclyl; where R 16 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; each Z 1 are independently halo, cyano, nitro, oxo, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LH, -LC 1-9 Alkyl, -LC 2-9 Alkenyl, -LC 2-9 Alkynyl, -LC 3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; 1 Each C 1-9 Alkyl, C 2-9Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally independently has 1 to 5 Z 1a is replaced by; Each L is independently -O-, -S-, or -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)NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR 20 S(O)NR 21 -or-NR 20 S(O)NR 21 - and; Each R 20 and R 21 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 20 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl and R 21 optionally independently represent 1 to 5 Z 1a or R 20 and R 21 may independently optionally be 1 to 5 Z together with the atom to which they are attached. 1a forming a heterocyclyl substituted with each Z 1aare 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; 1a Each of -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 are independently optionally C 1-9 and substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy, and cyano. or a pharmaceutically acceptable salt or solvate thereof.

[0006] In certain embodiments, provided are compounds of Table 1, or pharmaceutically acceptable salts or solvates thereof. In certain embodiments, provided are compounds of Table 2, or pharmaceutically acceptable salts, solvates, stereoisomers, or mixtures of stereoisomers thereof.

[0007] Also provided herein is a pharmaceutical composition 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, 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 certain embodiments, the LPA-related disease is an LPA1-related disease, such as, but not limited to, fibrosis, transplant rejection, cancer, osteoporosis, or an inflammatory disorder.

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

[0010] In certain embodiments, the LPA-associated 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 is a method for treating or preventing fibrosis in a subject in need thereof, 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 nephropathy and systemic sclerosis.For example, the fibrosis can be IPF. DETAILED DESCRIPTION OF THE INVENTION

[0013] Detailed Description definition The following description sets forth exemplary embodiments of the present technology, however, it should be recognized that such description is not intended to broaden the scope of the present invention, but rather is provided as a description of exemplary embodiments.

[0014] As used herein, the following words, phrases and symbols are intended to have the meanings indicated, unless the context of common usage dictates otherwise.

[0015] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment of a substituent. For example, -C(O)NH2 is attached through the carbon atom. Dashes at the beginning or end of a chemical group are for convenience; a chemical group may be written with or without one or more dashes without loss of normal meaning. A wavy or dashed line drawn across a line in a structure indicates a particular point of attachment of a group. Unless chemically or structurally necessary, no directionality or stereochemistry is indicated or implied by the order in which chemical groups are written or named.

[0016] 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 from 1 to 6 carbon atoms.

[0017] Reference herein to "about" a value or parameter includes (and describes) embodiments relating to that value or parameter itself. In certain embodiments, the term "about" includes the recited amount ±10%. In other embodiments, the term "about" includes the recited amount ±5%. In certain other embodiments, the term "about" includes the recited amount ±1%. Also, the term "about X" includes reference to "X". Additionally, singular references include plural referents unless the context clearly requires otherwise. Thus, for example, reference to a "compound" includes a plurality of such compounds, and reference to an "assay" includes one or more assays and equivalents thereof known to those of skill in the art.

[0018] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to a group having 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 Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl 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 included; 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 an alkyl group containing at least one (e.g., 1 to 3 or 1) carbon-carbon double bond and having 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 2 to 4 carbon atoms (i.e., C 2-4 Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0020] "Alkynyl" refers to an alkyl group containing at least one (e.g., 1 to 3 or 1) carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), 2 to 12 carbon atoms (i.e., C 2-12 alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl) or 2 to 4 carbon atoms (i.e., C 2-4 The term "alkynyl" refers to an alkyl group having one triple bond and one double bond.

[0021] Certain commonly used 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" or "alkylenyl" groups, "arylene" or "arylenyl" groups, respectively.

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

[0023] "Haloalkyl" refers to an unbranched or branched alkyl group, as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms have been replaced with halogen. For example, when a residue is substituted with more than one halogen, it can be referred to by a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, which may, but not necessarily, 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, and the like.

[0024] "Haloalkoxy" refers to an alkoxy group, as defined above, in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms have been replaced with halogen.

[0025] "Hydroxyalkyl" refers to an alkyl group, as defined above, in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms have been replaced with hydroxy groups.

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

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

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

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

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

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

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

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

[0034] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having a single ring or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" refers to cycloalkenyl groups (i.e., cyclic groups having at least one double bond) and at least one sp 3As used herein, cycloalkyl includes carbocyclic fused ring systems (i.e., at least one non-aromatic ring) having 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl) or 3 to 6 ring carbon atoms (i.e., C 3-6 cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Furthermore, the term cycloalkyl is intended to encompass any non-aromatic ring that can be fused to an aryl ring, regardless of the point of attachment to the rest of the molecule. Still further, cycloalkyl also includes "spirocycloalkyl," when there are two positions for substitution on the same carbon atom, such as spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

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

[0036] "Halogen" or "halo" refers to atoms occupying Group VIIA of the Periodic Table of the Elements, such as fluoro, chloro, bromo, or iodo.

[0037] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. By way of example, one, two, or three carbon atoms can be independently replaced with the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)-, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted. Examples of heteroalkyl groups include -OCH, -CHOCH, -SCH, -CHSCH, -NRCH, and -CHNRCH (where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which is optionally 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. A "heteroalkylene" group can have at least one carbon and at least one heteroatom group within the chain. The term "heteroalkylene" includes unbranched or branched saturated chains containing carbon and heteroatoms. For example, one, two, or three carbon atoms can be independently replaced with the same or different heteroatom groups. A heteroatom group can be -NR y -, -O-, -S-, -S(O)-, -S(O)2-, etc. (where R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which is optionally substituted as defined herein. Examples of heteroalkylene groups 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)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, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which is optionally substituted as defined herein. As used herein, heteroalkylene includes groups having up 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 amide or other functional groups having oxo present at one or more carbon atoms.

[0039] "Heteroaryl" refers to an aromatic group having a single ring or multiple condensed rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to an aromatic group having 1 to 20 ring carbon atoms (i.e., C 1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12heteroaryl) or 3 to 8 carbon ring atoms (i.e., C 3-8 Heteroaryl) 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 independently selected from nitrogen, oxygen, and sulfur. In some cases, heteroaryl includes 5- to 10-membered, 5- to 7-membered, or 5- to 6-membered ring systems, each having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothienyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, and isoquinolyl. , isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 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 may be attached via any ring of the fused system). Aromatic rings having one or more fused rings containing at least one heteroatom are considered heteroaryl, regardless of the point of attachment to the rest of the molecule (i.e., via any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0040] "Heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be monocyclic or multicyclic, where the multicyclic rings may be fused, bridged, or spiro, and may contain one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O - ) moiety. Any non-aromatic ring or fused ring system containing at least one heteroatom and one non-aromatic ring is considered heterocyclyl, regardless of the point of attachment 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 heterocyclyl, regardless of the point of attachment (i.e., they may be attached via a carbon atom or a heteroatom). Furthermore, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, aryl, or heteroaryl ring, regardless of the point of attachment to the rest of the molecule. As used herein, heterocyclyl refers to a ring having 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclyl) or 3 to 6 ring carbon atoms (i.e., C 3-6and 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 independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindoline, and the like.

[0033] The term "heterocyclyl" includes "spiroheterocyclyl" when there are two positions for substitution on the same carbon atom. Examples of spiro-heterocyclyl rings include bicyclic and tricyclic ring systems such as, for example, oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl (wherein the heterocyclyl may be attached via either ring of the fused system).

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

[0042] "Alkylsulfonyl" refers to the group -S(O)R where R is alkyl.

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

[0044] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not occur. Also, the term "optionally substituted" refers to the fact that any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms of the specified atom or group may or may not be replaced with a non-hydrogen moiety.

[0045] As used herein, the term "compound" is intended to include any and all stereoisomers, geometric isomers, tautomers, and isotopically enriched analogs (e.g., deuterated analogs) of the depicted structures. A compound identified by name or structure as one particular tautomeric form is intended to include other tautomeric forms unless otherwise specified.

[0046] Some compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that the compound includes both amide and imidic acid tautomers. Thus, amide-containing compounds are understood to include imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include amide tautomers.

[0047] Any compound or structure depicted herein is also intended to include unlabeled and isotopically labeled forms of the compound. These forms of the compound may also be referred to as "isotopically enriched analogs." Isotopically labeled compounds have structures described herein except that one or more atoms are replaced with an atom 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, e.g., 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. Various isotopically labeled compounds of the present invention, such as 3 H and 14 Those incorporating a radioactive isotope, such as C. Such isotopically labeled compounds may be useful in metabolism studies including drug or substrate tissue distribution assays, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) or radioactive treatment of patients.

[0048] The term "isotopically enriched analog" includes "deuterated analogs" of compounds described herein in which one or more hydrogens, such as hydrogens on carbon atoms, have been replaced with deuterium. Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of a compound when administered to mammals, particularly humans. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds can be synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogens have been replaced with deuterium.

[0049] Deuterium-labeled or substituted therapeutic compounds of the present invention may exhibit improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavy isotopes such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F, 3 H, 11 C-labeled compounds may be useful for PET or SPECT or other imaging studies. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by practicing the procedures disclosed in the following schemes or in the Examples and Preparations, substituting readily available isotopically labeled reagents for non-isotopically labeled reagents. It is understood that deuterium in this context is considered a substituent of the compounds described herein.

[0050] The concentration of such heavy isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present invention, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen of natural abundance isotopic composition. Thus, in the compounds of the present invention, any atom specifically designated as deuterium (D) means deuterium.

[0051] In many cases, the compounds of this invention are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0052] Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other substances that are useful in the manufacture of pharmaceutical compositions suitable for animal 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 with inorganic acids and organic acids. Furthermore, if a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional methods for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. 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-toluene-sulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include salts of NH or primary, secondary, and tertiary amines, such as those derived from N-containing heterocycles, N-containing heteroaryls, or compounds of the formula N(R N ) 3 amines (e.g., HN + (R N )3 or (alkyl)N + (R N )3) (where each R Nare independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with one or more (e.g., 1 to 5 or 1 to 3) substituents (e.g., halo, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy). Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0054] The term "substituted" means that any one or more hydrogen atoms on the specified atom or group are replaced with one or more non-hydrogen substituents, 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, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonate, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. In certain embodiments, the one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, acyl, amino, amido, amidino, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, hydroxyalkyl, haloalkoxy, haloalkoxyalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, imido, oxo, nitro, sulfinyl, sulfonate, sulfonyl, thiocyanate, thiol, thione, or a combination thereof.

[0055] Polymers or similar undefined structures arrived at by the addition of unlimited further substituents to a defined substituent (e.g., a substituted aryl with a substituted alkyl, where the alkyl is itself substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is the limit for ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., a methyl substituted with five fluorines or a heteroaryl group having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those of skill in the art. When used to modify a chemical group, the term "substituted" can describe other chemical groups as defined herein. Unless otherwise specified, when a group is described as optionally substituted, any substituents of the group are themselves unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, one or more substituents can be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituent can be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0056] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable additive" 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 pharmaceutically active substances is well known in the art. Except as long as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0057] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of the 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" includes, but is not limited to, diseases, disorders, or conditions in which the activation of at least one LPA receptor by LPA contributes to the symptomatology or progression of the disease, disorder, or condition. These diseases, disorders, or conditions can be caused by one or more of genetic, iatrogenic, immunological, infectious, metabolic, oncological, toxic, surgical, and / or traumatic etiologies. Thus, inhibition of one or more lysophosphatidic acid (LPA) receptor (e.g., LPA1, LPA2, LPA3, LPA4, LPA5, or LPA6 receptor) signaling can alter the pathology 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 modulation of LPA1 receptor signaling alters 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 recruitment of fibroblasts, 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 gastrointestinal 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 other ingredients contained in the formulation and / or the subject being treated therewith.

[0061] The terms "administration" or "administering" refer to a method of providing a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, bird, fish, or amphibian. The method of administration varies depending on various 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 dosage" or "pharmaceutically effective amount" or "therapeutically effective amount" refers to a sufficient amount of an administered chemical entity (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) to relieve to some extent one or more symptoms of a disease or condition, and may include curing the disease. "Cure" means that symptoms of active disease are no longer present. Results include reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to clinically significantly reduce disease symptoms. An appropriate "effective" amount in any individual case can be determined using any suitable technique, such as a dose escalation study. In certain embodiments, a "therapeutically effective amount" of a compound provided herein refers to an amount of the compound that is effective as a monotherapy or combination therapy.

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

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

[0065] The terms "treatment" and "treating" in the context of a disease, disorder, or condition are meant to include the alleviation or elimination of a disorder, disease, or condition or one or more symptoms associated with a disorder, disease, or condition; or the slowing of the progression, spread, or worsening of a disease, disorder, or condition, or one or more of its symptoms.

[0066] As used herein, the term "prevention" refers to the complete or partial prevention of the onset, recurrence or spread of a disease or condition described herein or its symptoms.

[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, particularly a mammalian subject, for whom diagnosis, prognosis, or treatment is desired or required. In some embodiments, the subject is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of the disease, disorder, or condition to be treated and / or prevented.

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

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

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

[0071] As used herein, the term "modulation" or "modulate" refers to regulation or adjustment (e.g., increase or decrease), and can include, for example, agonism, partial agonism, or antagonism.

[0072] compound Provided herein are compounds that are LPA antagonists. In some embodiments, provided are compounds of Formula I: [ka] [During the ceremony, A is C 1-6 Alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1-6 Alkyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally independently has 1 to 5 Z 1 is replaced by; 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; 1 C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene or C 1-3 The heteroalkylene optionally independently represents C 1-9 substituted with 1 to 5 substituents independently selected from 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; 2 C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene or C 1-3The heteroalkylene optionally independently represents C 1-9 substituted with 1 to 5 substituents independently selected from alkyl, halo, hydroxy, and cyano; X 1 is N or CR 3 and; X 2 is N or CR 5 and; X 3 is N or CR 7 and; X 6 is N or CR 6 and; X 4 is O or CHR 11 where A is C 1-6 If it is alkyl, then X 4 is O; Y 2 , Y 3 and Y 6 One of them is N and the other is Y 2 , Y 3 and Y 6 The rest are each independently CR 13 and; 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 heterocyclyl; where R 1 and R 2 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl or heterocyclyl optionally independently has 1 to 5 Z 1 is replaced by; or R 1 and R 2 are combined with the atoms to which they are bonded to form C 3-10 Forms a cycloalkyl or heterocyclyl; 3-10The cycloalkyl or heterocyclyl optionally has 1 to 5 Z 1 is replaced by; R 3 are hydrogen, halo, 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- to 5-membered heterocyclyl; where R 3 -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 the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 4 are halo, 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 heterocyclyl; where R 4 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 The cycloalkyl or 3- to 5-membered heterocyclyl is optionally independently selected from halo, hydroxy, C 1-5 substituted with 1 to 5 substituents independently selected from alkoxy and cyano; or R 3 and R 4together with the atom to which they are attached form a cycloalkyl, aryl, heterocyclyl, or heteroaryl; wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with 1 to 5 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 heterocyclyl, or 5-membered heteroaryl; where R 5 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 The cycloalkyl, 3- to 5-membered heterocyclyl, or 5-membered heteroaryl may optionally independently be substituted with 1 to 5 Z 1 is replaced by; 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 heterocyclyl; where R 6 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 7 are hydrogen, halo, cyano, nitro, -OH, -SH, -NH2, -NH-C 1-5 Alkyl, -N(C 1-5Alkyl)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- to 5-membered heterocyclyl; where R 7 -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 the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 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, heterocyclyl, or heteroaryl; wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 8 is hydrogen, C 1-9 alkyl, halo, hydroxy, or cyano; Each R 9 are 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 heterocyclyl; where R 10 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 11 is hydrogen, C 1-9 alkyl, oxo, halo, hydroxy, or cyano; 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 heterocyclyl; where R 13 Each of -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 the cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted with 1 to 5 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 3- to 5-membered heterocyclyl; where R 14 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 15 is hydrogen, C 1-5 Alkyl, C2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 15 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 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 3- to 5-membered heterocyclyl; where R 16 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; each Z 1 are independently halo, cyano, nitro, oxo, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LH, -LC 1-9 Alkyl, -LC 2-9 Alkenyl, -LC 2-9 Alkynyl, -LC 3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; 1 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally independently has 1 to 5 Z 1a is replaced by; Each L is independently -O-, -S-, or -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)NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR 20 S(O)NR 21 -or-NR 20 S(O)NR 21 - and; Each R 20 and R 21 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 20 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl and R 21 optionally independently represent 1 to 5 Z 1a or R 20 and R 21 may independently optionally be 1 to 5 Z together with the atom to which they are attached. 1a forming a heterocyclyl substituted with 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, C2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1a Each of -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 optionally independently represent C 1-9 and substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy, and cyano. or a pharmaceutically acceptable salt or solvate thereof.

[0073] In some embodiments, a compound of formula IA: [ka] [In the formula, 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. or a pharmaceutically acceptable salt or solvate thereof.

[0074] In some embodiments, a compound of formula IB: [ka] [In the formula, A, R 1 , R 2 , R 4 , R 8 , R9 , R 13 , X 1 , X 2 , X 3 , X 4 , X 6 , n, L 1 and L 2 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0075] In certain embodiments, a compound of formula IC: [ka] [In the formula, 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. or a pharmaceutically acceptable salt or solvate thereof.

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

[0077] In some embodiments, A is C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C of ring A 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally independently has 1 to 5 Z 1 In some embodiments, A is substituted with C 3-10 It is cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0078] In some embodiments, A optionally contains 1 to 5 Z 1 C is replaced by 3-10 In some embodiments, A is C 3-10 It is cycloalkyl.

[0079] In some embodiments, A optionally contains 1 to 5 Z 1 In some embodiments, A is heterocyclyl substituted with 1 to 5 Z. In some embodiments, A is heterocyclyl substituted with 1 to 5 Z. 1 is a 5- to 10-membered heterocyclyl substituted with

[0080] In some embodiments, A optionally contains 1 to 5 Z 1 In some embodiments, A is optionally aryl substituted with 1 to 5 Z 1 is phenyl substituted with

[0081] In some embodiments, A optionally contains 1 to 5 Z 1 In some embodiments, A is heteroaryl optionally substituted with 1 to 5 Z 1 In some embodiments, A is optionally substituted with 1 to 5 Z 1 is a 5- to 6-membered heteroaryl substituted with

[0082] In some embodiments, A is C 1-6 Alkyl or C 3-10 It is cycloalkyl.

[0083] In one embodiment, L 1 is a bond, -O-, -NR 10 -, C 1-3 Alkylene or C 1-3 In certain embodiments, L is heteroalkylene. 1 is a bond. In some embodiments, L 1 -O-, -NR 10 -, C 1-3Alkylene or C 1-3 In certain embodiments, L is heteroalkylene. 1 is -O- or -NR 10 In one embodiment, L 1 is —O— or —NH—. In some embodiments, L 1 is C 1-3 Alkylene or C 1-3 In certain embodiments, L is heteroalkylene. 1 is —O—. In some embodiments, L 1 Ha-NR 10 In one embodiment, L 1 is -NH-. In some embodiments, L 1 is C 1-3 In some embodiments, L is alkylene. 1 is —CH—. In some embodiments, L 1 is C 1-3 In certain embodiments, L is heteroalkylene. 1 is —O—CH—. In some embodiments, L 1 is -NHCH2-.

[0084] In one embodiment, L 2 is a bond, C 1-3 Alkylene or C 1-3 In certain embodiments, L is heteroalkylene. 2 is C 1-3 In some embodiments, L is alkylene. 2 is —CH—. In some embodiments, L 2 is C 1-3 In certain embodiments, L is heteroalkylene. 2 is —O—CH—. In some embodiments, L 2 is -NHCH2-. In some embodiments, L 2 is a bond.

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

[0086] In some embodiments, R 1 and R 2 are optionally C together with the atoms to which they are attached. 3-10 Cycloalkyl-substituted C 3-10 In some embodiments, R 1 and R 2 are optionally C together with the atoms to which they are attached. 3-6 Cycloalkyl-substituted C 3-6 In some embodiments, R 1 and R 2 are optionally C together with the atoms to which they are attached. 3-10 Cycloalkyl-substituted C 3-10 In some embodiments, R 1 and R 2 are optionally C together with the atoms to which they are attached. 3-6 Cycloalkyl-substituted C 3-6 Forms a cycloalkyl.

[0087] In some embodiments, R 1 and R 2 together with the atoms to which they are attached, optionally 1 to 5 Z 1 In certain embodiments, R 1 and R 2 together with the atoms to which they are attached form a heterocyclyl.

[0088] In some embodiments, R 1 and R 2 are each independently C 1-9 alkyl or R 1 and R 2 are combined with the atoms to which they are bonded to form C 3-10 cycloalkyl or heterocyclyl; wherein each alkyl, cycloalkyl, or heterocyclyl independently optionally contains 1 to 5 Z 1 is replaced by .

[0089] In some embodiments, R 1 and R 2 are each independently C 1-9 alkyl or R 1 and R 2 are combined with the atoms to which they are bonded to form C 3-10 and forming a cycloalkyl or heterocyclyl; wherein each alkyl, cycloalkyl, or heterocyclyl is independently optionally substituted with 1 to 5 halo.

[0090] In some embodiments, R 1 and R 2 are each independently C 1-9 alkyl; where each alkyl is independently optionally substituted with 1 to 5 halo.

[0091] In some embodiments, R 1 and R 2 are combined with the atoms to which they are bonded to form C 3-10 It forms a cycloalkyl or heterocyclyl; wherein the cycloalkyl or heterocyclyl is optionally substituted with 1 to 5 halo.

[0092] In certain embodiments, each R 13 are independently hydrogen or C 1-9 In certain embodiments, each R 13 is independently hydrogen or methyl. In certain embodiments, each R 13is hydrogen. In some embodiments, one R 13 is hydrogen, and the other R 13 is C 1-9 In some embodiments, one R 13 is hydrogen, and the other R 13 is methyl.

[0093] In some embodiments, the compound of formula ID: [ka] [In the formula, 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, 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, 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)NR 20 R 21 where R 17 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10The cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally independently has 1 to 5 Z 1a is substituted with; and Each R 18 are independently hydrogen or Z 1 It is. or a pharmaceutically acceptable salt or solvate thereof.

[0094] In some embodiments, X 4 is —CH— 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 certain embodiments, each R 18 are independently hydrogen or halo.

[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 certain embodiments, q is 0 or 1. In certain embodiments, q is 0. In certain 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, O or CF2.

[0102] In some embodiments, X4 is -CH2- or O; R 8 is hydrogen; and n is 0.

[0103] In some embodiments, L 1 is -O- or -NR 10 -And;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, the compound of formula IE: [ka] [In the formula, A, R 4 , X 1 , X 2 , X 3 , X 5 , X 6 , p and q are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0105] In some embodiments, X 1 is CR 3 In one embodiment, X 1 is CR 3 and R 3 is hydrogen, halo, or C optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; 1-5 In some embodiments, X is alkyl. 1 is CR 3 and R 3 is hydrogen, halo, or C optionally substituted with 1 to 5 halo 1-5 In some embodiments, X is alkyl. 1 is CR 3 and R 3 is hydrogen, fluoro, chloro, methyl or difluoromethyl.

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

[0107] In some embodiments, X 3 is CR 7 In one embodiment, X 3 is CR 7 and R 7 is hydrogen or halo.

[0108] In some embodiments, X 5 is absent, O, or CF. 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 one embodiment, X 6 is CR 6 and R 6 is hydrogen or -OR 16 In some embodiments, X 6 is CR 6 and R 6is hydrogen or C 1-5 In some embodiments, X is alkoxy. 6 is CR 6 and R 6 is hydrogen or methoxy.

[0110] In one embodiment, the moiety [ka] teeth: [ka] is.

[0111] In one embodiment, the moiety [ka] teeth [ka] is.

[0112] In one embodiment, the moiety [ka] teeth [ka] is.

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

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

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

[0116] In some embodiments, R 7 is hydrogen, halo or C 1-5 alkyl, where C 1-5 The alkyl is optionally substituted with 1 to 5 halo.

[0117] In some embodiments, R 4 is C 1-5 Alkoxy or -OC 3-10 It is cycloalkyl.

[0118] In some embodiments of Formula I: A is C 1-6 Alkyl, C 3-10 is cycloalkyl, heterocyclyl, 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 is heteroalkylene; L 2 is a bond, C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene or C 1-3 is heteroalkylene; X 1 is N or CR 3 and; X 2 is N or CR 5 and; X 3 is N or CR 7 and; X 6 is N or CR 6 and; X 4 is O or CHR 11 where A is C 1-6 If it is alkyl, then X 4 is O; Y 2 , Y 3 and Y 6 One of them is N and the other is Y 2 , Y 3 and Y 6 The rest are each independently CR 13 and; 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 is cycloalkyl or heterocyclyl; or R 1 and R 2 are combined with the atoms to which they are bonded to form C 3-10 forms a cycloalkyl or heterocyclyl; where R 3 C 3-10 the cycloalkyl or heterocyclyl is optionally substituted with 1 to 5 halo; R 3 are hydrogen, halo, 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- to 5-membered heterocyclyl;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 the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 4 are halo, 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 heterocyclyl; where R 4 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 The cycloalkyl or 3- to 5-membered heterocyclyl is optionally independently selected from halo, hydroxy, C 1-5 substituted with 1 to 5 substituents independently selected from alkoxy and cyano; or R 3 and R 4 together with the atom to which they are attached form a cycloalkyl, aryl, heterocyclyl, or heteroaryl; wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with 1 to 5 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 3-5cycloalkyl, 3- to 5-membered heterocyclyl, or 5-membered heteroaryl; where R 5 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl, 3- to 5-membered heterocyclyl, or 5-membered heteroaryl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; 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 heterocyclyl; where R 6 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 7 are hydrogen, halo, 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- to 5-membered heterocyclyl; where R 7 -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 3-5the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 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, heterocyclyl, or heteroaryl; wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 8 is hydrogen, C 1-9 alkyl, halo, hydroxy, or cyano; Each R 9 are 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 heterocyclyl; R 11 is hydrogen, C 1-9 alkyl, oxo, halo, hydroxy, or cyano; 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 heterocyclyl; where R 13 Each of -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, C2-9 Alkynyl, C 3-6 the cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted with 1 to 5 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 3- to 5-membered heterocyclyl; where R 14 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 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 heterocyclyl; where R 15 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 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 heterocyclyl; where R 16 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 The cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano.

[0119] In certain embodiments, a compound selected from Table 1, or a pharmaceutically acceptable salt or solvate thereof, is provided. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9]

[0120] The compounds of Formula I provided herein include stereochemical forms of the compounds, e.g., optical isomers, e.g., enantiomers, diastereomers, and mixtures thereof, e.g., racemic mixtures and mixtures of enantiomers and / or diastereomers, including equal or unequal mixtures of individual enantiomers and / or diastereomers. All stereochemical forms are contemplated by the present invention. Unless otherwise specified, when a disclosed compound is named or described by a structure in which the stereochemistry is not specified and has one or more chiral centers, it is considered to represent all possible stereoisomers of the compound. Representative stereochemical forms, including, but not limited to, those set forth in Table 2, are provided throughout the specification. In certain embodiments, provided is a compound selected from Table 2, or a pharmaceutically acceptable salt or solvate thereof. [Table 10]

[0121] The compounds of Formula I include pharmaceutically acceptable salts thereof. Additionally, the compounds of Formula I also include other salts of the compounds that are not necessarily pharmaceutically acceptable salts but may be useful as intermediates for the preparation and / or purification of the compounds of Formula I and / or 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 is further recognized that the compounds of Formula I or their salts can be isolated in the form of solvates, and therefore, any such solvates are within the scope of the present invention. For example, the compounds of Formula I and their salts can exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

[0123] Treatment Methods and Uses The methods described herein can be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, such as an animal or human. In this context, the methods described herein can be used therapeutically on an individual. "Ex vivo" means outside 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. Examples of 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 optimal schedules and / or dosages for administration of the compounds of the invention for a given indication, cell type, individual, and other parameters. Information obtained from such use can be used to design in vivo treatment protocols, either experimentally or clinically. Other ex vivo uses for which the compounds and compositions described herein may be suitable are described below or will become apparent to those skilled in the art. Selected compounds may be further characterized and tested for safety or tolerable dosage in human or non-human subjects. Such properties may be tested using methods commonly known to those skilled in the art.

[0124] The compounds provided herein, or their pharmaceutically acceptable salts or solvates, or pharmaceutical compositions of such compounds, are useful as one or more inhibitors of LPA receptors.As further described herein, compounds that antagonize LPA receptors can be useful for the prevention and / or treatment of various types of diseases, including, for example, fibrosis (e.g., renal fibrosis, pulmonary fibrosis, liver fibrosis, arterial fibrosis, systemic sclerosis), urinary tract diseases, carcinoma-related diseases, proliferative diseases, inflammation / immune system diseases, diseases caused by secretory dysfunction, brain-related diseases, and chronic diseases.

[0125] In certain embodiments, the present invention provides methods of treating a subject (e.g., a human) having a disease, disorder, or condition (i.e., an LPA-associated disease) in which inhibition of one or more LPA receptors is beneficial in treating the pathology and / or symptoms and / or progression of the underlying disease, disorder, or condition. In certain embodiments, the methods provided herein can include, or further include, treatment of one or more conditions associated with, coexisting with, or secondary to any one or more of the conditions provided herein.

[0126] Methods for treating an LPA-associated disease are provided, 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 subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition disclosed herein.

[0127] In certain embodiments, the LPA-related disease is fibrosis of organs (e.g., liver, kidney, lung, heart, and skin), liver diseases (acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative disorders, non-alcoholic steatohepatitis (NASH), decreased liver function, impaired hepatic blood flow, etc.), cell proliferative diseases (e.g., solid tumors, solid tumor metastasis, angiofibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, and chronic lymphocytic leukemia (CLL), and cancers including 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 pancreatic secretory dysfunction). These include, but are not limited to, the treatment of conditions such as: urinary tract-related conditions (e.g., symptoms associated with benign prostatic hyperplasia or neurogenic bladder disease), spinal cord tumors, herniated discs, spinal stenosis, symptoms resulting from diabetes, lower urinary tract conditions (e.g., lower urinary tract obstruction, inflammatory diseases of the lower urinary tract, dysuria and frequent urination), pancreatic conditions, conditions associated with abnormal angiogenesis (e.g., arterial occlusion), scleroderma, brain-related conditions (e.g., cerebral infarction and cerebral hemorrhage), neuropathic pain, peripheral neuropathy, and eye conditions (e.g., age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, and glaucoma filtration surgery scars).

[0128] In certain embodiments, provided herein are methods for treating or preventing fibrosis, 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 subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition disclosed herein. For example, the methods may include treating renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis, or systemic sclerosis. In certain embodiments, provided herein are methods for treating pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis (IPF)), 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 subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein.

[0129] In some embodiments, a compound disclosed herein (e.g., a compound 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 or prevent fibrosis in a subject. For example, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein can be used to treat organ or tissue fibrosis in a subject. In some embodiments, a method of preventing a fibrotic condition in a subject is provided herein, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein to a subject at risk of developing one or more fibrotic conditions. For example, the subject may be exposed to one or more environmental conditions known to increase the risk of organ or tissue fibrosis. In some embodiments, the subject is exposed to one or more environmental conditions known to increase the risk of lung, liver, or kidney fibrosis. In some embodiments, the subject has a genetic predisposition to developing organ or tissue fibrosis. In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein is administered to a subject to prevent or minimize scarring after injury. For example, the injury may include surgery.

[0130] Examples of diseases, disorders, or conditions involving fibrosis include 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, and genetic disorders (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, idiopathic interstitial pneumonia, 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 bacterial pneumonia-induced, trauma-induced, viral pneumonia-induced, ventilator-induced, non-pulmonary sepsis-induced and aspiration-induced); chronic lung injury / fibrosis-associated Glomerulonephritis secondary to systemic inflammatory diseases such as nephropathy, renal fibrosis (renal fibrosis), 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, e.g., cirrhosis, alcohol-induced liver fibrosis, non-alcoholic steatohepatitis (NASH), non-alcoholic steatohepatitis (NASH), fatty liver disease (NAFLD), toxic / drug-induced liver fibrosis (e.g., hemochromatosis), bile duct injury, primary biliary cirrhosis, infectious or virally induced liver fibrosis (e.g., chronic HCV infection), inflammatory / immune disorders and autoimmune hepatitis; head and neck fibrosis, e.g., corneal scarring, e.g., LASIK (laser-assisted keratomileusis), corneal transplantation and trabeculectomy; hypertrophic scarring, Dupuytren's disease, skin fibrosis, cutaneous scleroderma, keloids, e.g., burn-induced or surgical;and other fibrotic diseases, including, but not limited to, sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, chronic lymphocytic leukemia, tumor metastasis, transplanted organ rejection (e.g., bronchiolitis obliterans), endometriosis, neonatal respiratory distress syndrome and neuropathic pain, fibromyalgia, mixed connective tissue disease, and Peyronie's disease;

[0131] Provided are methods for improving pulmonary function in a subject, 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 subformula 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, a compound disclosed herein (e.g., a compound 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 idiopathic pulmonary fibrosis in a subject. In some embodiments, a compound disclosed herein (e.g., a compound 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 common interstitial pneumonia in a subject.

[0132] In certain embodiments, a compound disclosed herein (e.g., a compound 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 generalized parenchymal interstitial lung diseases in a subject, such as iatrogenic drug-induced, occupational / environmentally 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 diseases).

[0133] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein is useful for treating post-transplant fibrosis associated with chronic rejection in a subject, such as bronchiolitis obliterans after lung transplantation.

[0134] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein is useful for treating cutaneous fibrosis, such as cutaneous scleroderma, Dupuytren's disease, and keloids, in a subject.

[0135] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its subformulas, or pharmaceutically acceptable salts or solvates thereof) or pharmaceutical compositions provided herein are useful for treating liver fibrosis with or without cirrhosis in subjects, such as toxic / 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 certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein is useful for treating renal fibrosis (e.g., tubulointerstitial fibrosis and glomerulosclerosis) in a subject.

[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 fibrosis, sinusitis, neutrophil-mediated inflammation, and fibroblast-mediated fibrosis.

[0138] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein is useful for treating one or more symptoms of COVID-19.

[0139] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein is useful for treating chronic obstructive pulmonary disease (COPD).

[0140] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein is useful for treating neuroinflammation.

[0141] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein is useful for treating multiple sclerosis.

[0142] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein is administered to a subject having organ or tissue fibrosis or predisposed to developing organ or tissue fibrosis in combination with one or more other agents used to treat fibrosis. In certain embodiments, the one or more agents include a corticosteroid, an immunosuppressant, a B-cell antagonist, and a uteroglobin.

[0143] In some embodiments, a compound disclosed herein (e.g., a compound 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 a dermatological disorder in a subject. Such dermatological disorders include, but are not limited to, atopic dermatitis, bullous disorders, collagen diseases, psoriasis, scleroderma, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) is used to treat systemic sclerosis.

[0144] In certain embodiments, the compounds disclosed herein (e.g., compounds of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) are useful for treating or preventing 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) can be 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, allo- or xenotransplant (organ, bone marrow, stem cells and other cells and tissue) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory diseases, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopic dermatitis.

[0146] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its subformulas, or pharmaceutically acceptable salts or solvates thereof) or pharmaceutical compositions provided herein 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.

[0147] In some embodiments, a compound disclosed herein (e.g., a compound 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 result from the formation of fibrous scar tissue in contractile (voluntary) muscles. Fibrosis binds to tissue, blocking blood flow and causing pain.

[0148] In certain embodiments, a compound disclosed herein (e.g., a compound 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 cancer. In certain embodiments, a compound disclosed herein (e.g., a compound 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 malignant and benign proliferative diseases. In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein is used to prevent or reduce the growth of tumor cells, invasion, and metastasis of carcinoma, pleural mesothelioma (Yamada, Cancer Sci., 2008, 99(8), 1603-1610) or peritoneal mesothelioma, cancer pain, and bone metastasis (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, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein. In certain embodiments, the methods provided herein further comprise administering a second therapeutic agent, wherein the second therapeutic agent is an anti-cancer agent.

[0149] As used herein, the term "cancer" refers to an abnormal growth of cells that tend to grow in an uncontrolled manner and, in some cases, metastasize (spread). Types of cancer include, but are not limited to, solid tumors (e.g., 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 (e.g., leukemia) with or without metastasis, at any stage of disease.

[0150] Further non-limiting examples of cancer include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal region cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumor, brain and spinal cord tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, embryonal tumor, endometrial cancer, upper respiratory tract cancer, and urinary tract cancer. Ependymoblastoma, Ependymoma, Esophageal cancer, Ewing's sarcoma family of tumors, Eye cancer, Retinoblastoma, Gallbladder cancer, Gastric (stomach) cancer, Gastrointestinal carcinoid tumor, Gastrointestinal stromal tumor (GIST), Gastrointestinal stromal cell tumor, Germ cell tumor, Glioma, Hairy cell leukemia, Head and neck cancer, Hepatocellular (liver) cancer, Hodgkin's lymphoma, Hypopharyngeal cancer, Intraocular melanoma, Islet cell tumor (endocrine pancreas), Kaposi's sarcoma, Kidney cancer, Langerhans cell histiocytosis, Laryngeal cancer, Leukemia, Liver cancer, Non-small cell lung cancer, Small cell Lung cancer, cutaneous T-cell lymphoma, non-Hodgkin's lymphoma, lymphoma, Waldenstrom's macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, oral cancer, myeloid leukemia, multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, carcinoma of the oropharyngeal, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papilloma, parathyroid cancer, penile cancer, pharyngeal cancer, moderately differentiated pineal gland parenchymal tumor, pineoblastoma and supratentorial primitive neuroectoblastoma Includes: follicular tumors, pituitary tumors, plasma cell neoplasms / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sézary syndrome, skin cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric (stomach) cancer, supratentorial cerebellar primitive neuroectodermal tumor, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer and Wilms' tumor.

[0151] In certain embodiments, provided are methods for treating an allergic disorder in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof). In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) is useful for treating a respiratory disease, disorder, or condition in a subject. For example, a compound disclosed herein (e.g., a compound of Formula I or a subformula 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 affecting the organs involved in breathing, such as the nose, pharynx, larynx, Eustachian tube, trachea, bronchi, lungs, associated muscles (e.g., diaphragm and intercostal spaces), 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 disorder of the lung, whatever the cause (intrinsic, extrinsic, or both; allergic or non-allergic), characterized by airway narrowing and associated alterations in pulmonary gas flow. The term asthma may be used with one or more adjectives to indicate the cause.

[0154] Also provided is a method for treating or preventing chronic obstructive pulmonary disease in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) provided herein. 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 certain embodiments, the compounds disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) are useful for treating or preventing a nervous system disorder in a subject. As used herein, the term "nervous system 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, neurological aspects of disorders such as those seen after blunt or surgical trauma (including post-operative cognitive impairment and spinal cord or brainstem injury), and degenerative disc disease and sciatica.

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

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

[0158] In certain embodiments, provided herein are methods for reducing cardiac reperfusion injury following myocardial ischemia and / or endotoxic shock, 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 subformula thereof, or a pharmaceutically acceptable salt or solvate thereof).

[0159] Also provided herein is a method for reducing vasoconstriction in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof). For example, provided herein is a method for lowering or preventing an increase in blood pressure in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a subformula 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 assayed in vitro, in vivo, or in a cell line.

[0161] For example, Chinese hamster ovary cells overexpressing human LPA1 can be seeded overnight (15,000 cells / well) in DMEM / F12 medium in microplates. After overnight incubation, the cells are loaded with a calcium indicator dye for 30 minutes at 37°C. The cells are then equilibrated to room temperature for 30 minutes before assay. Test compounds dissolved in DMSO are transferred to other wells of the non-binding surface plate and diluted to a final concentration of 0.5% DMSO in assay buffer (e.g., IX HBSS supplemented with calcium / magnesium, 20 mM HEPES, and 0.1% fatty acid-free BSA). The diluted compounds are added to the cells at final concentrations ranging from 0.08 nM to 5 mM and then incubated for 20 minutes at room temperature, during which time LPA is added to a final concentration of 10 nM to stimulate the cells. Compound IC 50 The IC value is defined as the concentration of test compound that inhibits 50% of the calcium flux induced by LPA alone. 50 Values ​​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 subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) is orally administered to CD-1 female mice 2 hours before LPA challenge. The mice are then administered 0.15 mL of LPA in 0.1% BSA / PBS (2 pg / pL) via the tail vein (IV). Exactly 2 minutes after LPA challenge, the mice are sacrificed by decapitation, and trunk blood is collected. These samples are pooled and centrifuged, and individual 75 pL samples are frozen at -20°C until histamine assay is performed. Plasma histamine analysis can be performed using standard EIA (enzyme area assay) methods. Plasma samples are thawed and diluted 1:30 with 0.1% BSA in PBS. The previously described EIA protocol for histamine analysis can be used in this assay.

[0163] LPA acts as a biological effector molecule, exerting physiological effects including effects on blood pressure, platelet activation, and smooth muscle contraction, as well as diverse cellular effects including cell proliferation, cell rounding, neurite retraction, actin stress fiber formation, and cell migration, which are primarily 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 / Ca 2+ These include recruitment, arachidonic acid release, Akt / PKB activation and activation of the 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 factors (GEFs), glycogen synthase kinase 3b (GSK3b), c-jun amino-terminal kinase (JNK), MEK, myosin light chain II (MLC II), nuclear factor kB (NF-kB), N-methyl-D-aspartate (NMDA) receptor activation, phosphatidylinositol 3-kinase (PBK), protein kinase A (PKA), protein kinase C (PKC), and ms-related C3 botulinum toxin substrate 1 (RAC1). Nearly 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 called VZG-1 / EDG-2 / mrecl.3) is a G protein of three types: G i / o , G q and G 12 / 13 Through the activation of these G proteins, LPA induces, for example, cell proliferation, serum response element (SRE) activation, mitogen-activated protein kinase (MAPK) activation, adenylyl cyclase (AC) inhibition, phospholipase C (PLC) activation, and Ca 2+ It induces a series of LPA1-mediated cellular responses, including recruitment, Akt activation, and Rho activation.

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

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

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

[0169] LPA4 (p2y9 / GPR23) has a distinct sequence compared to LPA1, LPA2, and LPA3, and shares close similarity with the platelet-activating factor (PAF) receptor. LPA4 mediates LPA-induced Ca2+ activation. 2+ It mediates the functional coupling of the G protein Gs and other G proteins for mobilization and cAMP accumulation and AC activation. The LPA4 gene is expressed in the ovary, pancreas, thymus, kidney, and skeletal muscle.

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

[0171] LPA6 (p2y5) is a member of the purino-cluster of GPCRs and is structurally most closely related to LPA4. LPA6 is an LPA receptor linked to the Gl2 / l3-Rho signaling pathway and is expressed in the inner root sheath of human hair follicles.

[0172] Improvement in any of the above response criteria is specifically provided by the methods of the present invention.

[0173] Combination therapy In certain embodiments, the compounds disclosed herein may be used in combination with one or more additional therapeutic agents used and / or developed for the treatment of the above-mentioned diseases and disorders.

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

[0175] In certain embodiments, the present invention provides methods of treating a subject (e.g., a human) having a disease, disorder, or condition (i.e., an LPA-associated disease) in which inhibition of one or more LPA receptors is beneficial in treating the pathology and / or symptoms and / or progression of the underlying disease, disorder, or condition. In certain embodiments, the methods provided herein can include, or further include, treatment of one or more conditions associated with, coexisting with, or secondary to any one or more of the conditions provided herein.

[0176] Provided herein are methods for treating an LPA-associated disease, 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 subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition disclosed herein and one or more additional therapeutic agents.

[0177] In certain embodiments, the LPA-related disease is fibrosis of organs (e.g., liver, kidney, lung, heart, and skin), liver diseases (acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative disorders, non-alcoholic steatohepatitis (NASH), decreased liver function, impaired hepatic blood flow, etc.), cell proliferative diseases (e.g., solid tumors, solid tumor metastasis, angiofibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, and chronic lymphocytic leukemia (CLL), and cancers including 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 pancreatic secretory dysfunction). These include, but are not limited to, the treatment of conditions such as: urinary tract-related conditions (e.g., symptoms associated with benign prostatic hyperplasia or neurogenic bladder disease), spinal cord tumors, herniated discs, spinal stenosis, symptoms resulting from diabetes, lower urinary tract conditions (e.g., lower urinary tract obstruction, inflammatory diseases of the lower urinary tract, dysuria and frequent urination), pancreatic conditions, conditions associated with abnormal angiogenesis (e.g., arterial occlusion), scleroderma, brain-related conditions (e.g., cerebral infarction and cerebral hemorrhage), neuropathic pain, peripheral neuropathy, and eye conditions (e.g., age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, and glaucoma filtration surgery scars).

[0178] In certain embodiments, provided herein is a method for treating or preventing fibrosis, 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 subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition disclosed herein and one or more additional therapeutic agents. For example, the method may include treatment of renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis, or systemic sclerosis. In certain embodiments, provided herein is a method for treating pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis (IPF)), 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 subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein and one or more additional therapeutic agents.

[0179] In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein and one or more additional therapeutic agents are used to treat or prevent fibrosis in a subject. For example, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein and one or more additional therapeutic agents can be used to treat organ or tissue fibrosis in a subject. In some embodiments, provided herein is a method for preventing a fibrotic condition in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein and one or more additional therapeutic agents to a subject at risk of developing one or more fibrotic conditions. For example, the subject may be exposed to one or more environmental conditions known to increase the risk of organ or tissue fibrosis. In some embodiments, the subject is exposed to one or more environmental conditions known to increase the risk of lung, liver, or kidney fibrosis. In some embodiments, the subject has a genetic predisposition to develop organ or tissue fibrosis.In some embodiments, the compound disclosed herein (for example, the compound of Formula I or its subformula, or its pharmaceutically acceptable salt or solvate) or the pharmaceutical composition provided herein and 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] Examples of diseases, disorders, or conditions involving fibrosis include 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 disorders (e.g., Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, and familial interstitial lung disease). Interstitial lung disease), pulmonary fibrosis secondary to systemic inflammatory diseases such as rheumatoid arthritis, scleroderma, lupus, idiopathic interstitial pneumonia, 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 bacterial pneumonia-induced, trauma-induced, viral pneumonia-induced, ventilator-induced, non-pulmonary sepsis-induced and aspiration-induced).Chronic nephropathy associated with injury / fibrosis, renal fibrosis (nephrofibrosis), 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, e.g., 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 liver fibrosis (e.g., chronic HCV infection), inflammation head and neck fibrosis, e.g., corneal scarring, e.g., LASIK (laser-assisted keratomileusis), corneal transplantation and trabeculectomy; hypertrophic scarring, Dupuytren's disease, dermal fibrosis, cutaneous scleroderma, keloids, e.g., burn-induced or surgical; and other fibrotic diseases, e.g., sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, chronic lymphocytic leukemia, tumor metastasis, transplanted organ rejection (e.g., bronchiolitis obliterans), endometriosis, neonatal respiratory distress syndrome and neuropathic pain, fibromyalgia, mixed connective tissue disease and Peyronie's disease.

[0181] Provided herein is a method for improving pulmonary function in 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 subformula 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, a compound disclosed herein (e.g., a compound 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 idiopathic pulmonary fibrosis in a subject. In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein and one or more additional therapeutic agents is used to treat common interstitial pneumonia in a subject.

[0182] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein and one or more additional therapeutic agents are used to treat generalized parenchymal interstitial lung diseases in a subject, such as iatrogenic drug-induced, occupational / environmentally 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 diseases).

[0183] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein and one or more additional therapeutic agents is useful for treating post-transplant fibrosis associated with chronic rejection in a subject, such as bronchiolitis obliterans after lung transplantation.

[0184] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein and one or more additional therapeutic agents is useful for treating skin fibrosis, such as cutaneous scleroderma, Dupuytren's disease, and keloids, in a subject.

[0185] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its subformulas, or pharmaceutically acceptable salts or solvates thereof) or pharmaceutical compositions provided herein and one or more additional therapeutic agents are useful for treating liver fibrosis with or without cirrhosis in a subject, such as toxic / 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 certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein and one or more additional therapeutic agents is useful for treating 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 fibrosis, sinusitis, neutrophil-mediated inflammation, and fibroblast-mediated fibrosis.

[0188] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein and one or more additional therapeutic agents are useful for treating one or more symptoms of COVID-19.

[0189] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein and one or more additional therapeutic agents are useful for treating chronic obstructive pulmonary disease (COPD).

[0190] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein and one or more additional therapeutic agents are useful for treating neuroinflammation.

[0191] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein and one or more additional therapeutic agents is useful for treating multiple sclerosis.

[0192] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein and one or more additional therapeutic agents are administered to a subject having organ or tissue fibrosis or predisposed to developing organ or tissue fibrosis, along with one or more other agents used to treat fibrosis. In certain embodiments, the one or more agents include a corticosteroid, an immunosuppressant, a B-cell antagonist, and a uteroglobin.

[0193] In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein and one or more additional therapeutic agents are used to treat a dermatological disorder in a subject. Such dermatological disorders include, but are not limited to, atopic dermatitis, bullous disorders, collagen diseases, psoriasis, scleroderma, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) and one or more additional therapeutic agents are used to treat systemic sclerosis.

[0194] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) and one or more additional therapeutic agents are useful for treating or preventing inflammation in a subject. For example, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) and one or more additional therapeutic agents can be 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, allo- or xenotransplant (organ, bone marrow, stem cells and other cells and tissue) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory diseases, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopic dermatitis.

[0196] In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition 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, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein and one or more additional therapeutic agents are used to treat fibromyalgia. Fibromyalgia is thought to result from the formation of fibrous scar tissue in contractile (voluntary) muscles. Fibrosis binds to tissue, blocking blood flow and causing pain.

[0198] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein and one or more additional therapeutic agents are used to treat cancer. In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein and one or more additional therapeutic agents are used to treat malignant and benign proliferative diseases. In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein and one or more additional therapeutic agents are used to prevent or reduce the growth of tumor cells, invasion, and metastasis of carcinoma, pleural mesothelioma (Yamada, Cancer Sci., 2008, 99(8), 1603-1610) or peritoneal mesothelioma, cancer pain, bone metastasis (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 are methods for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a subformula 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 methods provided herein further comprise administering a second therapeutic agent, wherein the second therapeutic agent is an anti-cancer agent.

[0199] As used herein, the term "cancer" refers to an abnormal growth of cells that tend to grow in an uncontrolled manner and, in some cases, metastasize (spread). Types of cancer include, but are not limited to, solid tumors (e.g., 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 (e.g., leukemia) with or without metastasis, at any stage of disease.

[0200] Further non-limiting examples of cancer include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal region cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumor, brain and spinal cord tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, embryonal tumor, endometrial cancer, upper respiratory tract cancer, and urinary tract cancer. Ependymoblastoma, Ependymoma, Esophageal cancer, Ewing's sarcoma family of tumors, Eye cancer, Retinoblastoma, Gallbladder cancer, Gastric (stomach) cancer, Gastrointestinal carcinoid tumor, Gastrointestinal stromal tumor (GIST), Gastrointestinal stromal cell tumor, Germ cell tumor, Glioma, Hairy cell leukemia, Head and neck cancer, Hepatocellular (liver) cancer, Hodgkin's lymphoma, Hypopharyngeal cancer, Intraocular melanoma, Islet cell tumor (endocrine pancreas), Kaposi's sarcoma, Kidney cancer, Langerhans cell histiocytosis, Laryngeal cancer, Leukemia, Liver cancer, Non-small cell lung cancer, Small cell Lung cancer, cutaneous T-cell lymphoma, non-Hodgkin's lymphoma, lymphoma, Waldenstrom's macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, oral cancer, myeloid leukemia, multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, carcinoma of the oropharyngeal, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papilloma, parathyroid cancer, penile cancer, pharyngeal cancer, moderately differentiated pineal gland parenchymal tumor, pineoblastoma and supratentorial primitive neuroectoblastoma Includes: follicular tumors, pituitary tumors, plasma cell neoplasms / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sézary syndrome, skin cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric (stomach) cancer, supratentorial cerebellar primitive neuroectodermal tumor, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer and Wilms' tumor.

[0201] In certain embodiments, provided herein are methods for treating an allergic disorder in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) and one or more additional therapeutic agents. In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) and one or more additional therapeutic agents are useful for treating a respiratory disease, disorder, or condition in a subject. For example, a compound disclosed herein (e.g., a compound of Formula I or a subformula 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 affecting the organs involved in breathing, such as the nose, pharynx, larynx, Eustachian tube, trachea, bronchi, lungs, associated muscles (e.g., diaphragm and intercostal spaces), 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 disorder of the lung, whatever the cause (intrinsic, extrinsic, or both; allergic or non-allergic), characterized by airway narrowing and associated alterations in pulmonary gas flow. The term asthma may be used with one or more adjectives to indicate the cause.

[0204] Also provided herein are methods for treating or preventing chronic obstructive pulmonary disease in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a subformula 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 certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) and one or more additional therapeutic agents are useful for treating or preventing a nervous system disorder in a subject. As used herein, the term "nervous system 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, neurological aspects of disorders such as those seen after blunt or surgical trauma (including post-operative cognitive impairment and spinal cord or brainstem injury), and degenerative disc disease and sciatica.

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

[0207] Also provided herein is a method for treating or preventing cardiovascular disease in a subject. As used herein, the term "cardiovascular disease" refers to diseases that affect the heart or blood vessels, or both, including, but not limited to, arrhythmias (atrial or ventricular, or both); atherosclerosis and its sequelae; angina pectoris; cardiac rhythm disorders; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysms; vasculitis, stroke; peripheral occlusive arteriopathy of limbs, organs, or tissues; post-ischemic reperfusion injury of the brain, heart, or other organs or tissues; endotoxin, surgical or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including that associated with migraine); vascular abnormalities, inflammation, and failure 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, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) and one or more additional therapeutic agents.

[0208] In certain embodiments, provided herein are methods for reducing cardiac reperfusion injury following myocardial ischemia and / or endotoxic shock, 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 subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) and one or more additional therapeutic agents.

[0209] Also provided herein is a method for reducing vasoconstriction in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) and one or more additional therapeutic agents. For example, provided herein is a method for lowering or preventing an increase in blood pressure in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) and one or more additional therapeutic agents.

[0210] Pharmaceutical Compositions and Methods of Administration The compounds provided herein are typically administered in the form of a pharmaceutical composition.

[0211] When used as pharmaceuticals, the compounds disclosed herein (e.g., compounds of Formula I or subformulas thereof, or pharmaceutically acceptable salts or solvates thereof), including pharmaceutically acceptable salts or solvates thereof, can be administered in the form of pharmaceutical compositions. These compositions can be prepared by methods well known in the pharmaceutical arts 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 (to mucous membranes, including transdermal, epithelial, ocular, and intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, 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, or injection or infusion; or intracranial, e.g., intrathecal or intracerebroventricular, administration. Parenteral administration can be in the form of a single bolus dose, e.g., by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0212] Also provided herein are pharmaceutical compositions comprising, as an active ingredient, a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof), in combination with 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 a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the composition is suitable for topical administration. In preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted with the excipient, or enclosed within a carrier in the form of, for example, a capsule, sachet, paper, or other container. When an excipient acts as a diluent, it can be a solid, semi-solid, or liquid substance that acts as a solvent, carrier, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powder, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), for example, ointments containing up to 10% by weight of 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 tablets or capsules.

[0213] Also provided herein is a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula I or a subformula thereof or a pharmaceutically acceptable salt or solvate thereof) together with a pharmaceutically acceptable excipient. Pharmaceutical compositions comprising a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula I or a subformula thereof or a pharmaceutically acceptable salt or solvate thereof) as an active ingredient can be prepared by intimately admixing a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula I or a subformula thereof or a pharmaceutically acceptable salt or solvate thereof) with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a variety of 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, and a description 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 for formulating pharmaceutical compositions are 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 ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphate, Tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures 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 carboxymethylcellulose, polyacrylic acid, waxes, polyethylene-polyoxypropylene-block polymers and wool fat. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives, can also be used to enhance delivery of the compounds provided herein. Dosage forms or compositions containing 0.005% to 100% of the chemicals provided herein, with the remainder consisting of non-toxic additives, can be prepared. Contemplated compositions contain 0.001% to 100%, in some embodiments, 0.1 to 95%, in other embodiments, 75 to 85%, and in further embodiments, 20 to 80% of the chemicals provided herein. Actual methods for preparing such dosage forms will be known or 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 certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, may 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, intracervical, intraantral, intratracheal, enteral, epidural, interstitial, intraabdominal, intraarterial, intrabronchial, intravesical, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intraspinal, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intrathecal, intrasynovial, intratesticular, intrathecal, intraductal, intratumor, intrauterine, intravascular, intravenous, intranasal (e.g., intranasal), nasogastric, oral, parenteral, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal. In certain embodiments, the preferred route of administration is parenteral (eg, intratumoral).

[0218] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or its subformulas, or pharmaceutically acceptable salts or solvates thereof) or pharmaceutical compositions thereof may be formulated for parenteral administration, for example, for injection via intraarterial, intrasternal, intracranial, intravenous, intramuscular, subcutaneous, or intraperitoneal routes. For example, such compositions may be prepared for injection as a liquid solution or suspension; solid forms suitable for use in preparing a solution or suspension by adding a liquid prior to injection may also be prepared; and formulations may also be emulsified. The preparation of such formulations is known to those skilled in the art in light of the present disclosure. In some embodiments, a device is used for parenteral administration. For example, such devices may include needle injectors, microneedle injectors, needleless injectors, and infusion techniques.

[0219] In some embodiments, the pharmaceutical forms suitable for injection include sterile aqueous solution or dispersion; formulations containing sesame oil, peanut oil or aqueous propylene glycol; and sterile powder for the immediate preparation of sterile injectable solution or dispersion.In some embodiments, the form must be sterile and must be fluid enough to be easily injected.In some embodiments, the form must be stable under the conditions of manufacture and storage, and must be protected from the contaminating action of microorganisms such as bacteria and fungi.

[0220] In some embodiments, the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In some embodiments, proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. In some embodiments, the prevention of microbial action can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In some embodiments, isotonic agents, for example, sugars or sodium chloride, are included. In some embodiments, prolonged absorption of injectable compositions can be brought about by using agents that delay absorption in the composition, for example, aluminum monostearate and gelatin.

[0221] In some embodiments, sterile injectable solutions are prepared by incorporating the required amount of a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) into an appropriate solvent, along with various other ingredients as listed above, as needed, followed by filtration sterilization. In some embodiments, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing the basic dispersion medium and the required other ingredients listed above. In some embodiments, sterile powders are prepared for use as sterile injectable solutions. In some embodiments, the preparation method is vacuum drying and freeze-drying technology, which produces a powder containing the active ingredient and any additional desired ingredients from a previously sterilized-filtered solution.

[0222] In some embodiments, pharmaceutically acceptable additives useful in rectal compositions as gels, creams, enemas, or rectal suppositories include cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, almond oil, sorbitol, sodium benzoate, anoxide. The inactive ingredients may include, but are not limited to, one or more of SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-hydroxybenzoate, sodium propyl p-hydroxybenzoate, diethylamine, carbomer, carbopol, methyl hydroxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, disodium 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 subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax, which is solid at ambient temperature but liquid at body temperature and thus melts in the rectum to release the active compound. In some embodiments, a composition for rectal administration is in the form of an enema.

[0224] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition thereof provided herein is formulated for local delivery to the digestive or GI tract via oral administration (e.g., a solid or liquid dosage form).

[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 subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) is administered in a dosage form containing one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) hydroxybenzoates, such as hydroxybenzoates, ... The composition may be mixed with humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) humectants such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, 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, these dosage forms may also contain buffering agents.In some embodiments, similar types of solid compositions may also be used as fillers for soft and hard-filled gelatin capsules, using additives such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0226] In some embodiments, the pharmaceutical composition is in the form of a unit dosage form such as a pill or tablet. Thus, the composition may contain a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) together with a diluent such as lactose, sucrose, or dicalcium phosphate; a lubricant such as magnesium stearate; and a binder such as starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, or a cellulose derivative. In some embodiments, other solid dosage forms, such as powders, quince, solutions, or suspensions (e.g., in propylene carbonate, vegetable oils, PEG, poloxamer 124, or triglycerides) are encapsulated in capsules (gelatin or cellulose-based capsules). In some embodiments, unit dosage forms in which one or more compounds provided herein and a pharmaceutical composition or additional active agent are physically separated are also contemplated; for example, capsules (or tablets within capsules) containing granules of each drug; bilayer tablets; bicompartment gelcaps, etc. In some embodiments, enteric-coated or delayed-release oral dosage forms are also contemplated.

[0227] In certain embodiments, other physiologically acceptable compounds may include wetting agents, emulsifying agents, dispersing agents, or preservatives, which are particularly useful for preventing the growth or action of microorganisms. For example, various preservatives are well known and include, for example, phenol and ascorbic acid.

[0228] In some embodiments, the additives are sterile and generally free from undesirable substances. For example, these compositions can be sterilized using conventional, well-known sterilization techniques. In some embodiments, sterility is not required for additives in various oral dosage forms, such as tablets and capsules. For example, the United States Pharmacopeia / National Formulary (USP / NF) standard may be sufficient.

[0229] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or subformulas thereof, or pharmaceutically acceptable salts or solvates thereof) or pharmaceutical compositions thereof provided herein are formulated for ocular administration. In some embodiments, the ophthalmic compositions may include, but are not limited to, one or more of the following: viscogens (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymers), 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 certain embodiments, the compounds disclosed herein (e.g., compounds of Formula I or subformulas thereof, or pharmaceutically acceptable salts or solvates thereof) or pharmaceutical compositions thereof provided herein are formulated for topical administration to the skin or mucosa (e.g., dermal or transdermal). In certain embodiments, topical compositions can include ointments and creams. In certain embodiments, ointments are semi-solid formulations typically based on petrolatum or other petroleum derivatives. In certain embodiments, creams containing the selected active agent are typically viscous liquids or semi-solid emulsions, often either oil-in-water or water-in-oil. For example, cream bases are typically water-washable and contain an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase, sometimes referred to as the "internal" phase, generally contains petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase is usually, but not necessarily, larger in volume than the oil phase and generally contains a humectant. In certain embodiments, the emulsifier in a cream formulation is typically a nonionic, anionic, cationic, or amphoteric surfactant. In certain embodiments, the ointment base, as well as other carriers or vehicles, must be inert, stable, non-irritating, and non-sensitizing.

[0231] In any of the above embodiments, the pharmaceutical compositions provided herein can include one or more of lipids, interbilayer cross-linked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

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

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

[0234] In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) provided herein is administered at a dose of about 0.0002 mg / Kg to about 100 mg / Kg (e.g., about 0.0002 mg / Kg to about 50 mg / Kg; about 0.0002 mg / Kg to about 25 mg / Kg; about 0.0002 mg / Kg to about 10 mg / Kg; Approx. 0.0002mg / Kg~Approx. 5mg / Kg;Approx. 0.0002mg / Kg~Approx. 1mg / Kg;Approx. 0.0002mg / Kg~Approx. 0.5mg / Kg;Approx. 0.0002mg / Kg~Approx. 0.1m g / Kg; approx. 0.001 mg / Kg ~ approx. 50 mg / Kg; approx. 0.001 mg / Kg ~ approx. 25 mg / Kg; approx. 0.001 mg / Kg ~ approx. 10 mg / Kg; approx. 0.001 mg / Kg ~ approx. 5 m g / Kg; approx. 0.001 mg / Kg ~ approx. 1 mg / Kg; approx. 0.001 mg / Kg ~ approx. 0.5 mg / Kg; approx. 0.001 mg / Kg ~ approx. 0.1 mg / Kg; approx. 0.01 mg / Kg ~ approx. 50 mg / Kg; about 0.01 mg / Kg to about 25 mg / Kg; about 0.01 mg / Kg to about 10 mg / Kg; about 0.01 mg / Kg to about 5 mg / Kg; about 0.01 mg / Kg to about 1 mg / Kg In some embodiments, the compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) is administered at a dose of about 100 mg / kg.

[0235] In certain embodiments, the dosage of a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) can be administered daily (e.g., in a single dose or two or more divided doses) or non-daily (e.g., every other day, every two days, every three days, weekly, twice weekly, biweekly, monthly).

[0236] In some embodiments, the administration period of a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) 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 more. In some embodiments, the period during which administration is suspended 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 more. In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) is administered to a subject for a period of time, followed by another period during which administration of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) is suspended. In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) is administered for a first period of time, followed by a second period in which administration is stopped after the first period, followed by a third period in which administration of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) is initiated, and after the third period of time, administration is stopped for a fourth period of time. For example, the period in which a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) is administered, followed by a period in which administration is stopped, is repeated for a determined or undetermined period of time.In some embodiments, the administration period 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 more. In some embodiments, the period during which administration is suspended 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 more.

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

[0238] In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) is parenterally administered to a subject one or more times daily (e.g., 1 to 4 times, once daily, twice daily, three times daily, four times daily, or once daily dose).

[0239] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) is parenterally administered to a subject weekly.

[0240] Compound synthesis The compounds of the present invention can be prepared, for example, from readily available starting materials using the following general methods and procedures. Where certain process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it is recognized that other process conditions can also be used unless otherwise specified. Optimum reaction conditions will vary with the reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0241] Furthermore, as will be recognized by those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting certain functional groups are well known in the art. For example, numerous protecting groups are described in TW Greene and GM Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references therein.

[0242] Additionally, compounds of the present invention may contain one or more chiral centers. Thus, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., individual enantiomers or diastereomers, or stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present invention, unless otherwise specified. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be resolved, for example, using chiral column chromatography, chiral resolving agents, etc.

[0243] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, CA, USA), EMKA-Chemie GmbH & Co. KG (Eching, Germany), or Millipore Sigma (Burlington, MA, USA). Others are described in 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 Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 5 th These compounds can be prepared by procedures described in standard reference texts such as "Organic Transformations" (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0244] Scheme I shows the 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 2are each independently as defined herein, LG and LG′ are suitable leaving groups such as halo (e.g., Cl, Br, or I), where LG and LG′ are not the same, PG is a suitable carboxyl protecting group such as alkyl or benzyl, and each R 50 are independently alkyl or substituted alkyl, or two R 50 are taken together to form a cyclic boronic ester, which may be optionally substituted (e.g., pinacol boronic ester), and a general method is described that can be used to synthesize the compounds described herein. [ka]

[0245] Compounds of Formula I are prepared by first coupling compound I-1, followed by deprotection to give the free acid of Formula I, where B is a suitable functional group, such as, but not limited to, a boronic acid or a derivative thereof, such as a boronic acid ester (cyclic or acyclic), a zinc or magnesium halide, an organotin compound, such as tributylstannane or trimethylstannane, a fluorosulfonyl ester, tin, sodium, hydrogen, etc. Such reactions are commonly used for aromatic functionalization and are typically carried out in the presence of a suitable catalyst, such as, but not limited to, a palladium catalyst, including, for example, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, Pd(OAc)2, Pd(PPh3)4, PdCl2(PPh3)2, or tris(dibenzylideneacetone)dipalladium(0), or a copper catalyst, such as CuCl or CuI, and, if necessary, a suitable mediator, co-catalyst, and / or base, known to those skilled in the art, using a suitable solvent / solvent mixture. Upon completion of the reaction, the compound of Formula I can be recovered by conventional techniques, such as neutralization, extraction, precipitation, chromatography, filtration, and the like. In certain embodiments, when control of stereochemistry is desired, appropriate control of the reaction conditions and selection of substituents on the reagents can at least partially define or prevent the formation of various stereoisomers. Compounds I-1 and I-2 can be obtained commercially or synthesized de novo. For example, as depicted 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 will be appreciated that the various substituents on 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 enriched before or after the steps described above in Scheme I. The Ring A moiety can be converted to X under substitution reaction conditions. 4 It may be combined with a precursor.

[0247] It should be understood that for any compound depicted in Scheme I, various derivatives can be provided by functional group interconversion at any step. In certain embodiments, various substituents (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, derivatization of compounds I, I-1, I-2, I-3, or I-4 prior to reaction at any step and / or further derivatization of the resulting reaction product will provide various 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 completion of each reaction, each intermediate or final compound can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, and the like, and purified if desired. Other modifications to arrive at the compounds of the present invention are within the skill of those skilled in the art.

[0248] general synthesis Compounds of exemplary embodiments described herein can be synthesized using the following general reaction scheme. In light of the description herein, it is clear that the general scheme can be modified to replace starting materials with other materials of similar structure to yield correspondingly different products. The synthetic description below provides numerous examples of how starting materials can be transformed to yield the corresponding products. Given a desired product with defined substituents, the required starting materials can generally be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. For the synthesis of compounds that are embodiments described herein, each substituent is identified by inspection of the structure of the compound to be synthesized. In light of the examples described herein, the properties of the final product will generally reveal the required starting materials by a simple process of inspection. In general, the compounds described herein are typically stable and can be isolated at room temperature and pressure.

[0249] In certain embodiments, there is provided a method for preparing a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, comprising: [ka] and a compound of formula I-2: [ka] Compounds of [In the above compounds, 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 are independently alkyl or substituted alkyl, or two R50 together form an optionally substituted cyclic boronic acid ester. under conditions sufficient to provide a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0250] In some embodiments, the method further comprises a deprotection step after the contacting step. In some embodiments, the conditions comprise a base. In some embodiments, the conditions comprise an acid. In some embodiments, the conditions comprise a temperature of about 50°C to about 120°C. In some embodiments, the method for preparing compound I-1, or a pharmaceutically acceptable salt or solvate thereof, comprises reacting a compound of formula I-3: [ka] with a compound of formula I-4: [ka] Compounds of [In the above compounds, 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 each independently as defined herein, LG and LG' are suitable leaving groups, where LG and LG' are not the same, and PG is a suitable carboxyl protecting group. under conditions sufficient to provide a compound of formula I-3, or a pharmaceutically acceptable salt or solvate thereof. [Example]

[0251] The following examples are included to demonstrate specific embodiments of the invention. It should be recognized by those of skill in the art that the techniques disclosed in the examples which follow represent techniques which work well in the practice of the invention and, therefore, are considered to constitute specific modes for its practice. However, those of skill in the art will, in light of the present disclosure, recognize that many changes can be made in the specific embodiments which are disclosed and still obtain like or similar results without departing from the spirit and scope of the invention.

[0252] Abbreviations (used here): [Table 11]

[0253] General information: Total evaporation or concentration was performed on a rotary evaporator under reduced pressure. Analytical samples were dried under reduced pressure (1-5 mmHg) at rt. Thin-layer chromatography (TLC) was performed on silica gel plates, and spots were visualized with UV light (214 nm and 254 nm). Purification by column and flash chromatography was performed using silica gel (100-200 mesh). Solvent systems are reported as mixtures by volume. NMR spectra were recorded on a Bruker 400 or Varian (400 MHz) spectrometer. 1 H chemical shifts are reported in δ values ​​(ppm) relative to the deuterated solvent. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant (Hz), integration. LCMS spectra were obtained on a SHIMADZU LC20-MS2020 or Agilent 1260 Series 6125B mass spectrometer or Agilent 1200 Series, 6110, or 6120 mass spectrometer with electrospray ionization unless otherwise indicated.

[0254] Example A1 4-({4-[(cyclopentyloxy)methyl]-5-(3,5-dimethoxy-4-methylphenyl)-6-methylpyridin-2-yl}amino)oxane-4-carboxylic acid (Compound 101) [ka] [ka]

[0255] Step A (2-chloro-6-methylpyridin-4-yl)methanol [ka] To a solution of methyl 2-chloro-6-methylisonicotinate (10.0 g, 53.9 mmol) in THF (100 mL) was slowly added DIBALH (71.8 mL, 107.7 mmol, 1.5 M solution in toluene) at −78°C. The mixture was stirred at 25°C for 16 h under a N atmosphere. The reaction mixture was quenched with HO (4 mL) and 4 N aqueous NaOH (4 mL) at −78°C, diluted with HO (4 mL), and extracted with DCM (20 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash column, eluent: 0–50% EtOAc / PE gradient at 100 mL / min) to give methyl 2-chloro-6-methylisonicotinate (7.0 g, 82% yield). 1 H 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 [ka]

[0257] To a solution of (2-chloro-6-methylpyridin-4-yl)methanol (7.0 g, 44.4 mmol) in DCM (100 mL) was added PBr (12.02 g, 44.42 mmol) dropwise. The mixture was stirred at 25 °C under a N atmosphere for 2 h. The reaction mixture was basified with saturated aqueous NaHCO to pH = 8. The organic layer was separated, and the aqueous layer was extracted with DCM (50 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash column, eluent: 0–20% EtOAc / PE gradient at 100 mL / min) to give 4-(bromomethyl)-2-chloro-6-methylpyridine (9.0 g, 92% yield). 1 H NMR (400 MHz, CDCl3) δ 7.10 (s, 1H), 7.05 (s, 1H), 4.23 (s, 2H), 2.42 (s, 3H).

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

[0259] To a solution of 4-(bromomethyl)-2-chloro-6-methylpyridine (4.0 g, 18.1 mmol) and cyclopentanol (1.88 g, 218 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 × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (10 g SepaFlash® Silica Flash column, eluent: 0–9% EtOAc / PE gradient at 50 mL / min) to give 2-chloro-4-((cyclopentyloxy)methyl)-6-methylpyridine (440 mg, 11% yield). 1H 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 [ka]

[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) was 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 × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (10 g SepaFlash® Silica Flash column, eluent: 0-50% EtOAc / PE gradient at 50 mL / min) to give N-(4-((cyclopentyloxy)methyl)-6-methylpyridin-2-yl)-1,1-diphenylmethanimine (500 mg, 69% yield). LC-MS: m / z 371.0 (M+H) + .

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

[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 with saturated aqueous NaHCO to pH = 8 and extracted with EtOAc (50 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (10 g SepaFlash® Silica Flash column, eluent: 0-50% EtOAc / PE gradient at 50 mL / min) to give 4-((cyclopentyloxy)methyl)-6-methylpyridin-2-amine (250 mg, 90% yield). 1 H 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 [ka]

[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 × 2). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (10 g SepaFlash® Silica Flash column, eluent: 0-40% EtOAc / PE gradient at 50 mL / min) to give 5-bromo-4-(cyclopentoxymethyl)-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 [ka]

[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 HO (0.1 mL) was added XPhos Pd G (29.7 mg, 35.1 μmol) and CsCO (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 × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (10 g SepaFlash® Silica Flash column, eluent: 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, 88% yield). 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) [ka]

[0269] 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) was added NaOH (37.0 mg, 926 μmol), dihydro-2H-pyran-4(3H)-one (61.8 mg, 617 μmol), and subsequently CHCl (111 mg, 926 μmol) at 0° C. The mixture was stirred at 25° C. for 16 hours. 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 × 2). The combined organic layer was dried over anhydrous NaSO, 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 over 7 min) to give 4-((4-((cyclopentyloxy)methyl)-5-(3,5-dimethoxy-4-methylphenyl)-6-methylpyridin-2-yl)amino) tetrahydro-2H-pyran-4-carboxylic acid (5 mg, 3.3% yield). 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).

[0270] Example A2 4-({4-[(cyclopentyloxy)methyl]-5-(3,5-dimethoxy-4-methylphenyl)pyridin-2-yl}amino)oxane-4-carboxylic acid (Compound 102) [ka] [ka]

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

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

[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 HO (50 mL) and extracted with DCM (50 mL × 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (10 g SepaFlash® Silica Flash column, eluent: 0-10% EtOAc / PE gradient at 40 mL / min) to give 5-bromo-2-chloro-4-((cyclopentyloxy)methyl)pyridine (360 mg, 35% yield). LC-MS: m / z 292.0 (M+H) + .

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

[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 HO (3 mL) was added Pd(dppf)Cl (50.4 mg, 68.8 μmol) and NaCO (146 mg, 1.38 mmol). The mixture was stirred at 70 °C for 16 h. The mixture was poured into HO (30 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash column, eluent: 0-5% EtOAc / PE gradient at 100 mL / min) to give 2-chloro-4-(cyclopentoxymethyl)-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) [ka]

[0277] To a solution of 2-chloro-4-(cyclopentoxymethyl)-5-(3,5-dimethoxy-4-methyl-phenyl)pyridine (90 mg, 249 μmol) and methyl 4-aminotetrahydropyran-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. for 2 hours in a Biotage microwave. 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×3). The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash column, eluent: 0–8% MeOH / DCM gradient at 80 mL / min), then further purified by preparative HPLC (column: Phenomenex C18 80 × 40 mm × 3 μm; 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 over 7 min) to give 4-((4-((cyclopentyloxy)methyl)-5-(3,5-dimethoxy-4-methylphenyl)pyridin-2-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (2.36 mg, 2.0% yield).

[0278] LC-MS: m / z 471.2 (M+H) + . 1 H 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).

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

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

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

[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 hours. The mixture was acidified to pH = 7 with 1N HCl and extracted with EtOAc (30 mL × 3). The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified on a 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 [ka]

[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) was added 1.0 M diethylzinc solution in hexanes (22.30 mL, 22.3 mmol) at 0 °C. The mixture was stirred at 0 °C for 3 h. The mixture was quenched with aqueous NH4Cl (30 mL) and extracted with DCM (30 mL × 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 SepaFlash® Silica Flash column, eluent: 0–2% EtOAc / PE gradient at 50 mL / min) to give 2-cyclopropoxy-1-fluoro-4-methoxybenzene (1.28 g, 79% yield). 1 H 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 [ka]

[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] (47 mg, 0.70 mmol) and 4,4'-di-tert-butyl-2,2'-dipyridyl (dtbpy) (38 mg, 0.14 mmol). The mixture was stirred at 80 °C under N for 12 h. The reaction mixture was concentrated. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash column, eluent: 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, 31% yield). 1 H 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] [ka] 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 described in 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 H 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).

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

[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 the addition of HO (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash column, eluent: 0–6% EtOAc / PE gradient at 80 mL / min) to give 1-fluoro-4-methoxy-2-(methoxymethoxy)benzene (5.0 g, 98% yield). LC-MS: m / z 187.1 (M+ H) + .

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

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

[0292] Step C 6-fluoro-3-methoxy-2-methylphenol [ka]

[0293] To a solution of 1-fluoro-4-methoxy-2-(methoxymethoxy)-3-methyl-benzene (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 hours. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over Na SO , filtered, and concentrated to give 6-fluoro-3-methoxy-2-methyl-phenol (5.0 g, 64% yield). 1 H 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 [ka]

[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 × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash column, eluent: 0-8% EtOAc / PE gradient at 40 mL / min) to give 2-ethoxy-1-fluoro-4-methoxy-3-methylbenzene (0.35 g, 59% yield). 1 H 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 [ka]

[0297] To a solution of 2-ethoxy-1-fluoro-4-methoxy-3-methyl-benzene (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] (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 hours. The reaction mixture was concentrated. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash column, eluent: 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, 46% yield). LC-MS: m / z 311.2 (M+ H). + .

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

[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 hours. 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 × 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give a residue. The residue was purified by flash silica gel chromatography (80 g SepaFlash® Silica Flash column, eluent: 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 [ka]

[0301] To a solution of 5-chloro-4-(2-cyclopropylethynyl)pyridin-2-amine (2.5 g, 13.0 mmol) in THF (50 mL) was added NaOH (2.60 g, 64.9 mmol) and tetrahydropyran-4-one (2.60 g, 26.0 mmol, 2.38 mL) at 0 °C. After stirring for 10 min, CHCl (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. The mixture was then diluted with water (150 mL), acidified to pH = 5 with 1 N aqueous HCl, and extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and evaporated to give a residue. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash column, eluent: 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 [ka]

[0303] To a mixture of 4-[[5-chloro-4-(2-cyclopropylethynyl)-2-pyridyl]amino]tetrahydropyran-4-carboxylic acid (800 mg, 2.49 mmol) in toluene (30 mL) was added PtO (170 mg, 748 μmol). After degassing and purging with H three times, the resulting mixture was stirred at 25 °C under a 15 psi H 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 SepaFlash® Silica Flash column, eluent: 0-50% EtOAc / PE gradient at 100 mL / min) to give 4-[[5-chloro-4-(2-cyclopropylethyl)-2-pyridyl]amino]tetrahydropyran-4-carboxylic acid (510 mg, 63% yield). 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 [ka]

[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 HO (1.5 mL) was added XPhos Pd G (52.1 mg, 61.6 μmol) and CsCO (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 1 N aqueous HCl, and extracted with ethyl acetate (50 mL × 3). The combined organic layers were evaporated to give a residue. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash column, eluting with a 0-4% MeOH / DCM gradient at 100 mL / min) and further purified by preparative HPLC (column: Phenomenex C18 80 × 40 mm × 3 μm; 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 over 7 min) to give 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, 28.5% yield). LC-MS: m / z 473.3 (M+ H). + . 1H 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 procedures similar to those described in the above examples, using the appropriate starting materials. [Table 12]

[0307] Biological assays In Vitro LPA1 Calcium Flux Antagonist Assay - Bioduro Protocol CHO-K1 cells overexpressing human LPA1 and G15a were seeded in a total volume of 20 μL (15,000 cells / well) into Matrigel Precode 384-well plates (corning -3764) and incubated at 37°C. After overnight incubation, cells were serum-starved for 4 hours. Assays were 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 for 30 minutes at 37°C. Five μL of 5x compounds titrated in dye-loading buffer was then added to the cells, incubated for 30 minutes, and then challenged with LPA at EC80. Calcium mobilization was measured on a FLIPR Tetra (MDS). For LPA EC determination, starved cells were incubated with 20 μL of dye-loading buffer for 1 h, and then 5 μL of 5× LPA titrated in dye-loading buffer was added to the cells. Calcium signal induction by LPA was measured using a FLIPR.

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

[0309] Table B1 shows the biological activity of compounds in the in vitro LPA1 calcium flux antagonist assay - Bioduro protocol. The activity of the test compounds is shown in Table B1 below. [Table 13]

Claims

1. Formula I: 【Chemistry 1】 [During the ceremony, A is C １－６ Alkyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl; １－６ Alkyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally independently has 1 to 5 Z １ is substituted with; 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; １ C １－３ Alkylene, C ２－３ Alkenylene, C ２－３ Alkynylene or C １－３ The heteroalkylene optionally independently represents C １－９ substituted with 1 to 5 substituents independently selected from 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; ２ C １－３ Alkylene, C ２－３ Alkenylene, C ２－３ Alkynylene or C １－３ The heteroalkylene optionally independently represents C １－９ substituted with 1 to 5 substituents independently selected from alkyl, halo, hydroxy, and cyano; X １ is N or CR ３ and X ２ is N or CR ５ and X ３ is N or CR ７ and X ６ is N or CR ６ and X ４ is O or CHR １１ and A is C. １－６ If it is alkyl, X ４ is O; Y ２ , Y ３ and Y ６ One of them is N, and the other is Y ２ , Y ３ and Y ６ The rest are each independently CR １３ and 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 heterocyclyl; where R １ and R ２ Each C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ The cycloalkyl or heterocyclyl optionally independently has 1 to 5 Z １ is substituted with; or R １ and R ２ are combined with the atoms to which they are bonded to form C ３－１０ forms a cycloalkyl or heterocyclyl; where R ３ C ３－１０ The cycloalkyl or heterocyclyl optionally has 1 to 5 Z １ is substituted with; R ３ is hydrogen, halo, cyano, nitro, -OH, -SH, -NH ２ , —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 heterocyclyl; 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- to 5-membered heterocyclyl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R ４ is halo, 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 heterocyclyl; ４ C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ The cycloalkyl or 3- to 5-membered heterocyclyl optionally independently includes halo, hydroxy, C １－５ substituted with 1 to 5 substituents independently selected from alkoxy and cyano; or R ３ and R ４ together with the atom to which they are attached form a cycloalkyl, aryl, heterocyclyl, or heteroaryl; wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with 1 to 5 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 heterocyclyl, or 5-membered heteroaryl; where R ５ C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ The cycloalkyl, 3- to 5-membered heterocyclyl, or 5-membered heteroaryl optionally independently has 1 to 5 Z １ is substituted with; 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 heterocyclyl; ６ C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R ７ is hydrogen, halo, cyano, nitro, -OH, -SH, -NH ２ , —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 heterocyclyl; ７ -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- to 5-membered heterocyclyl is optionally substituted with 1 to 5 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, heterocyclyl, or heteroaryl; wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R ８ is hydrogen, C １－９ alkyl, halo, hydroxy, or cyano; Each R ９ are 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 heterocyclyl; １０ C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R １１ is hydrogen, C １－９ alkyl, oxo, halo, hydroxy, or cyano; Each R １３ are independently hydrogen, halo, cyano, nitro, —OH, —SH, —NH ２ , —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 heterocyclyl; １３ Each of -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 the cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted with 1 to 5 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 3- to 5-membered heterocyclyl; １４ C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 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 heterocyclyl; １５ C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 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 3- to 5-membered heterocyclyl; １６ C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ the cycloalkyl or 3- to 5-membered heterocyclyl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; Each Z １ are independently halo, cyano, nitro, oxo, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ Cycloalkyl, heterocyclyl, 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-heterocyclyl, -L-aryl or -L-heteroaryl; １ Each C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally independently has 1 to 5 Z １ａ is substituted with; Each L is independently —O—, —S—, or —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) ２ NR ２０ -, -NR ２０ S(O)-, -NR ２０ S(O) ２ -, -NR ２０ S(O)NR ２１ -or-NR ２０ S(O) ２ NR ２１ - and; Each R ２０ and R ２１ are independently hydrogen, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R ２０ Each C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl or heteroaryl and R ２１ optionally independently represent 1 to 5 Z １ａ or R ２０ and R ２１ together with the atoms to which they are attached, independently optionally represent 1 to 5 Z １ａ forming a heterocyclyl substituted with Each Z １ａ are independently halo, hydroxy, cyano, nitro, oxo, —SH, —NH ２ , —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, heterocyclyl, aryl, or heteroaryl; １ａ Each of -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 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may optionally independently be C １－９ and substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy, and cyano. or a pharmaceutically acceptable salt or solvate thereof.

2. Formula IA: 【Chemistry 2】 2. The compound of claim 1, represented by:

3. Formula IB: 【Transformation 3】 2. The compound of claim 1, represented by:

4. Formula IC: 【Chemistry 4】 2. The compound of claim 1, represented by:

5. X ４ is O; and A is C １－６ Alkyl, a compound of any one of claims 1 to 4.

6. A is C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl; and each C of ring A ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally substituted with 1 to 5 Z １ 6. The compound of any one of claims 1 to 5, substituted with

7. A optionally represents 1 to 5 Z １ C substituted with ３－１０ The compound of any one of claims 1 to 6, which is cycloalkyl.

8. L １ is a bond, —O—, —NR １０ -, C １－３ Alkylene or C １－３ The compound of any one of claims 1 to 7, which is heteroalkylene.

9. L １ The compound of any one of claims 1 to 8, wherein is -O- or -NH-.

10. L ２ The compound of any one of claims 1 to 9, wherein is a bond.

11. R １ and R ２ optionally 1 to 5 Z together with the atoms to which they are attached １ C substituted with ３－１０ The compound of any one of claims 1 to 10, which forms a cycloalkyl.

12. R １ and R ２ together with the atoms to which they are attached, optionally 1 to 5 Z １ 11. The compound of any one of claims 1 to 10, wherein the compound forms a heterocyclyl substituted with

13. Each R １３ are independently hydrogen or C １－９ The compound of any one of claims 1 to 12, wherein the compound is alkyl.

14. Formula ID: 【Transformation 5】 [During the ceremony, p is 0, 1 or 2; q is 0, 1 or 2; X ５ Absent, O, NR １７ or C(R １８ ) ２ and R １７ 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) ２ R ２０ , -S(O)NR ２０ R ２１ or -S(O) ２ NR 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 optionally independently represent 1 to 5 Z １ａ is substituted with; and Each R １８ are independently hydrogen or Z １ It is.

2. The compound of claim 1, represented by:

15. X ４ The compound of any one of claims 1 to 14, wherein is O.

16. R ８ The compound of any one of claims 1 to 15, wherein is hydrogen.

17. 17. The compound of any one of claims 1 to 16, wherein n is 0.

18. Formula IE: 【Transformation 6】 15. The compound of claim 14, represented by:

19. X １ is CR ３ The compound of any one of claims 1 to 18,

20. X ２ is CR ５ 20. The compound of any one of claims 1 to 19,

21. X ３ is CR ７ The compound of any one of claims 1 to 20,

22. X ６ is CR ６ 22. The compound of any one of claims 1 to 21,

23. portion 【Transformation 7】 but: 【Transformation 8】 The compound of any one of claims 1 to 22,

24. portion 【Chemistry 9】 but: 【Chemistry 10】 The compound of any one of claims 1 to 23,

25. R ３ is hydrogen, halo or C １－５ alkyl, where C １－５ 25. The compound of any of claims 1-24, wherein the alkyl is optionally substituted with 1 to 5 halo.

26. R ５ is hydrogen, -C(O)-C １－５ Alkyl or C １－５ 26. The compound of any one of claims 1 to 25, wherein the compound is alkyl.

27. R ６ is hydrogen or C １－５ 27. The compound of any one of claims 1 to 26, which is alkoxy.

28. R ７ is hydrogen, halo or C １－５ alkyl, where C １－５ 28. The compound of any of claims 1-27, wherein the alkyl is optionally substituted with 1 to 5 halo.

29. R ４ is C １－５ Alkoxy or —O—C ３－１０ 29. The compound of any one of claims 1 to 28, which is cycloalkyl.

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

31. A pharmaceutical composition comprising a compound of any one of claims 1 to 30 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, comprising administering to a patient in need thereof an effective amount of a compound of any of claims 1 to 30, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of claim 31.

33. LPA-related disease, disorder or condition is LPA １ 33. The method of claim 32, wherein the disease is a related disease.

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

35. 35. The method of claim 34, wherein the fibrosis is pulmonary fibrosis, liver fibrosis, kidney fibrosis, cardiac fibrosis, skin fibrosis, eye fibrosis or pancreatic fibrosis.

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

37. 34. The method of claim 32 or 33, wherein the LPA-associated 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 a compound of formula I of claim 1 or a pharmaceutically acceptable salt or solvate thereof, comprising reacting a compound of formula I-1: 【Chemistry 11】 and a compound of formula I-2: 【Chemistry 12】 Compounds of [In the above compounds, PG is a suitable carboxyl protecting group, LG is a suitable leaving group, and each R ５０ are independently alkyl or substituted alkyl, or two R ５０ together form an optionally substituted cyclic boronic ester. under conditions sufficient to provide a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof.

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

40. 39. A method for preparing a compound of formula I-1 of claim 38, or a pharmaceutically acceptable salt or solvate thereof, comprising reacting a compound of formula I-3: 【Chemistry 13】 with a compound of formula I-4: 【Chemistry 14】 Compounds of [In the above compound, LG and LG' are suitable leaving groups, where LG and LG' are not the same, and PG is a suitable carboxyl protecting group.] under conditions sufficient to provide a compound of formula I-3, or a pharmaceutically acceptable salt or solvate thereof.

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