Compounds and compositions for treating conditions associated with LPA receptor activity

Abstract

The present disclosure provides LPA antagonists and pharmaceutical compositions comprising the compounds disclosed herein. Methods for treating LPA-related diseases, disorders, and conditions are also provided. # imgabs0 #

Description

Cross-references to related applications

[0001] This application claims the benefits of International Patent Application No. PCT / CN2022 / 077844, filed on February 25, 2022; International Patent Application No. PCT / CN2022 / 094839, filed on May 25, 2022; and International Patent Application No. PCT / CN2022 / 117690, filed on September 8, 2022, each of which is incorporated herein by reference in its entirety. Technical Field

[0002] This disclosure provides 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] Various lipid mediators, including eicosanoic acid-like compounds and platelet-activating factor (PAF), are produced by the activity of phospholipases derived from the cell membrane. Lysophospholipids are a class of membrane-derived bioactive lipid mediators and include lysophosphatidic acid (LPA). LPA is not a monomolecular entity but rather a collection of endogenous structural variants of fatty acids with varying lengths and saturations. LPA influences cellular functions including cell proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. These functions affect many biological processes, including neurogenesis, angiogenesis, wound healing, immunity, and tumorigenesis. LPA has roles as a biological effector molecule and exhibits a wide range of physiological effects (such as, but not limited to, effects on blood pressure, platelet activation, and smooth muscle contraction), as well as various cellular effects, including cell growth, cell rounding, neurite synaptic retraction, and 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) with LPA mediates a series of downstream signaling cascades. Summary of the Invention

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

[0005] In one embodiment, this disclosure provides compounds of formula I: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein: A is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C of A 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1 replace; L 1 It is a key, -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -、C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne or C 1-3 Heteroalkylene; wherein L 1 The C mentioned 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne or C 1-3 The heteroalkylene groups are independently and optionally selected from one to five independently selected from C. 1-9 Substitution of alkyl, halogroup, hydroxyl and cyano groups; L 2 It is key, C 1-3 Alkylene, C 2-3 imidene group, C 2-3 alkyne or C 1-3 Heteroalkylene; wherein L 2 The C mentioned 1-3 Alkylene, C 2-3 imidene group, C 2-3 alkyne or C 1-3 The heteroalkylene groups are independently and optionally selected from one to five independently selected from C. 1-9 Substitution of alkyl, halogroup, hydroxyl and cyano groups; X 1 Is it N or CR? 3 ; X 2 Is it N or CR? 5 ; X 3 Is it N or CR? 7 ; X 4 Is it O or CHR? 11 The condition is that A is C. 1-6 When alkyl, then X4 It is O; X 6 Is it N or CR? 6 ; n is 0, 1, or 2; m is 0, 1, 2, or 3; R 1 and R 2 Each is independently hydrogen, C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 cycloalkyl or heterocyclic groups; wherein R 1 and R 2 Each C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 The cycloalkyl or heterocyclic group is independently and optionally surrounded by one to five Z. 1 replace; Or R 1 and R 2 Together with the atoms to which they are attached, they form C 3-10 cycloalkyl or heterocyclic groups; wherein the C 3-10 cycloalkyl or heterocyclic groups are optionally surrounded by one to five Z groups. 1 replace; R 3 It includes hydrogen, halogroup, cyano, nitro, -OH, -SH, -NH2, and -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 group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 3 The -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 group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R 4 It is a halogenated group, cyano group, nitro group, -OR group 14 -N(R) 14 )2、-SR 14C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 4 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally surrounded by one to five independently selected groups, hydroxyl, C. 1-5 Substitution of alkoxy and cyano groups; Or R 3 and R 4 Together with the atoms to which they are attached, they form cycloalkyl, aryl, heterocyclic, or heteroaryl groups; wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl groups are optionally substituted by one to five independent substituents selected from halogen, hydroxyl, and cyano groups; R 5 It is hydrogen, halogroup, 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 group, C 3-5 Cycloalkyl, 3-5 membered heterocyclic or 5 membered heteroaryl; wherein R 5 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 Cycloalkyl, 3-5 membered heterocyclic or 5-membered heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1 replace; R 6 It is hydrogen, halogroup, cyano, nitro, -OR 16 -N(R) 16 )2、-SR 16 C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 6 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R7 It includes hydrogen, halogroup, cyano, nitro, -OH, -SH, -NH2, and -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 group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 7 The -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 group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; Or R 6 and R 7 Together with the atoms to which they are attached, they form cycloalkyl, aryl, heterocyclic, or heteroaryl groups; wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl groups are optionally substituted by one to five independent substituents selected from halogen, hydroxyl, and cyano groups; R 8 It is hydrogen, C 1-9 Alkyl, oxo, halogen, hydroxyl, or cyano groups; R 9 It is hydrogen, C 1-9 Alkyl, oxo, halogen, hydroxyl, or cyano groups; R 10 It is hydrogen, C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 10 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R 11 It is hydrogen, C 1-9 Alkyl, oxo, halogen, hydroxyl, or cyano groups; Each R 13Independently, it can be hydrogen, halogenated, cyano, nitro, -OH, -SH, -NH2, or -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 group, C 3-6 cycloalkyl or 3 to 6-membered heterocyclic groups; wherein R 13 Each -NH-C 1-9 Alkyl, -N(C) 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-6 The cycloalkyl or 3 to 6-membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R 14 It is hydrogen, C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 14 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R 15 It is hydrogen, C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 15 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R 16 It is hydrogen, C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 16 The C mentioned 1-5Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; Each Z 1 Independently, it is a halogenated group, a cyano group, a nitro group, an oxo group, or a C group. 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LH, -LC 1-9 Alkyl, -LC 2-9 alkenyl, -LC 2-9 alkynyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; wherein Z 1 Each C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1a replace; Each L is independently -O-, -S-, -NR 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -、-NR 20 C(O)-、-OC(O)NR 20 -、-NR 20 C(O)O-、-NR 20 C(O)NR 21 -, -S(O)-, -S(O)2-, -S(O)NR 20 -、-S(O)2NR 20 -、-NR 20 S(O)-、-NR 20 S(O)2-、-NR 20 S(O)NR 21 -or-NR 20 S(O)2NR 21 -; Each R 20 and R 21 Independently, it is hydrogen and C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 20 and R 21Each C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1a Replace; or R 20 and R 21 Together with the atoms to which they are attached, they form independently, optionally, one to five Z. 1a Substituted heterocyclic groups; and Each Z 1a Independently, it can be a halogenated group, hydroxyl group, cyano group, nitro group, oxo group, -SH, -NH2, or -NH-C group. 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 group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein Z 1a Each -NH-C 1-9 Alkyl, -N(C) 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally selected from one to five C14 groups. 1-9 Substitution of alkyl, oxo, halogen, hydroxyl and cyano groups.

[0006] This document also provides pharmaceutical compositions comprising a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, and a pharmaceutically acceptable excipient.

[0007] This document also provides methods for treating or preventing LPA-related diseases in subjects of need, the methods comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof) or a pharmaceutical composition thereof. In some embodiments, the LPA-related disease is an LPA1-related disease, such as, but not limited to, fibrosis, transplant rejection, cancer, osteoporosis, or an inflammatory disorder.

[0008] In some embodiments, the LPA-related disease is fibrosis, transplant rejection, cancer, osteoporosis, or an inflammatory disorder. In some of these embodiments, the fibrosis is fibrosis of the lungs, liver, kidneys, heart, skin, eyes, or pancreas. In some embodiments, the cancer is cancer of the bladder, blood, bones, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gallbladder, reproductive organs, genitourinary tract, head, kidneys, larynx, liver, lungs, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testis, or thyroid gland.

[0009] In some implementations, the LPA-related diseases are idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, systemic sclerosis, COVID-19, chronic obstructive pulmonary disease (COPD), neuroinflammation, or multiple sclerosis.

[0010] This document also provides methods for treating or preventing fibrosis in a subject in need, the methods comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, or a pharmaceutical composition thereof.

[0011] In some implementations, the fibrosis is idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), chronic kidney disease, diabetic nephropathy, and systemic sclerosis. For example, the fibrosis may be IPF. Detailed Implementation definition

[0012] The following description illustrates exemplary embodiments of the present invention. However, it should be understood that such description is not intended to be a limitation on the scope of this disclosure, but is provided as a description of exemplary embodiments.

[0013] As used in this specification, the following words, phrases and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0014] A dash ("-") not located between two letters or symbols is used to indicate the attachment point of a substituent. For example, -C(O)NH2 is attached via a carbon atom. Dashes at the beginning or end of chemical groups are for convenience; chemical groups may or may not be depicted with one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in the structure indicates the attachment point of a group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality.

[0015] prefix "C" u-v "Indicates that the following groups have u to v carbon atoms. For example, "C 1-6 "alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0016] This document uses the term "about" to refer to a value or parameter, which includes (and describes) embodiments relating to that value or parameter itself. In some embodiments, the term "about" includes the indicated amount ±10%. In other embodiments, the term "about" includes the indicated amount ±5%. In some still embodiments, the term "about" includes the indicated amount ±1%. Furthermore, the term "about X" includes a description of "X". Additionally, unless the context clearly specifies otherwise, the singular forms "an" and "the" include plural indicators. Thus, for example, reference to "the compound" includes multiple such compounds, and reference to "the assay" includes reference to one or more assays known to those skilled in the art and their equivalents.

[0017] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl groups have 1 to 20 carbon atoms (i.e., C64-C ... 1-20 Alkyl groups, 1 to 12 carbon atoms (i.e., C464) 1-12 Alkyl groups, 1 to 8 carbon atoms (i.e., C464) 1-8 Alkyl groups, 1 to 6 carbon atoms (i.e., C646) 1-6 Alkyl groups or 1 to 4 carbon atoms (i.e., C46) 1-4 Alkyl groups. Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue with a specific number of carbons is named by its chemical name or identified by its molecular formula, all positional isomers having that number of carbons 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).

[0018] "Alkenyl" refers to a group containing at least one (e.g., 1-3 or 1) carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C20, C30, C40, C50, C6 ... 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 Alkyl groups (alkenyl). Examples of alkenyl groups include, for example, vinyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0019] "Alkynyl" refers to an alkyl group that contains at least one (e.g., 1-3 or 1) carbon-carbon triple bond and has 2 to 20 carbon atoms (i.e., C360, C46, ​​C56, C6 ... 2-20 alkynyl group), 2 to 12 carbon atoms (i.e., C12-C12). 2-12 acetylsyl), 2 to 8 carbon atoms (i.e., C10, C20, C30, 2-8 acetylsyl), 2 to 6 carbon atoms (i.e., C10, C20, C30, 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C46) 2-4 (Alkyne group). The term "alkynyl group" also includes those groups that have one triple bond and one double bond.

[0020] Some commonly used alternative chemical names can be used. For example, divalent groups such as divalent "alkyl" groups and divalent "aryl" groups can also be called "alkylene" groups (or "alkylenyl" groups) and "arylene" groups (or "arylenyl" groups), respectively.

[0021] "Alkoxy" refers to the "alkyl-O-" group. Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0022] "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen. For example, in the case where a residue is substituted by more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted by two ("di") or three ("tri") halogen groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl groups include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0023] "Haloalkoxy" refers to an alkoxy group as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by halogens.

[0024] "Hydroxyalkyl" refers to an alkyl group as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by hydroxyl groups.

[0025] "Alkylthio" refers to the "alkyl-S-" group.

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

[0027] "Amide group" refers to the "C-amide group" (which refers to the group -C(O)NR). y R z ) and "N-amide" group (which refers to the -NR group) y C(O)R z ), where R y and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted, or R y and R z Together they form cycloalkyl or heterocyclic groups; each of which may optionally be substituted, as defined herein.

[0028] "Amino" refers to the -NR group. y R z , where R y and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0029] "Amino group" refers to -C(NR) y (NR) z 2), where R y and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0030] "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 groups have 6 to 20 ring carbon atoms (i.e., C64 carbon atoms).6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 Aryl groups. Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthracene. However, aryl groups do not in any way encompass or overlap with heteroaryl groups as defined below. If one or more aryl groups are fused with a heteroaryl group, the resulting ring system is a heteroaryl, regardless of the attachment point. If one or more aryl groups are fused with a heterocyclic group, the resulting ring system is a heterocyclic, regardless of the attachment point. If one or more aryl groups are fused with a cycloalkyl group, the resulting ring system is a cycloalkyl, regardless of the attachment point.

[0031] "Carbamoyl" refers to the "O-carbamoyl" group, which is -OC(O)NR y R z Group; and "N-carbamoyl" group, which refers to -NR y C(O)OR z Group, wherein R y and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0032] "Carboxylic ester" or "ester" refers to -OC(O)R x and -C(O)OR x Of the two, R x It is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0033] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single or multiple rings, including fused, bridged, and spirocyclic systems. The term "cycloalkyl" includes cycloalkenyl (i.e., a cyclic group having at least one double bond) and cycloalkenyl (a cyclic group having at least one sp). 3 Carbon-cyclic fused-ring systems (i.e., at least one non-aromatic ring). As used herein, cycloalkyl groups have 3 to 20 ring carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 3-20 cycloalkyl groups), 3 to 14 cyclic carbon atoms (i.e., C1456 ... 3-12 cycloalkyl groups), 3 to 12 cyclic carbon atoms (i.e., C12+ ... 3-12 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C14 and C24). 3-10 cycloalkyl groups), 3 to 8 cyclic carbon atoms (i.e., C1646-C ... 3-8 cycloalkyl groups), 3 to 6 cyclic carbon atoms (i.e., C164-C ... 3-6Cycloalkyl. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Furthermore, the term cycloalkyl is intended to cover any non-aromatic ring that can fused with an aryl ring, regardless of its attachment to the rest of the molecule. In addition, when having two substitution positions on the same carbon atom, cycloalkyl also includes "spirocycloalkyl", such as spiro[2.5]octyl, spiro[4.5]decyl, or spiro[5.5]undecyl.

[0034] "Imine" refers to the group -C(NR) y )R z , where R y and R z Each is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0035] "Halogen" or "halogenated group" refers to an atom that occupies Group VIIA of the periodic table, such as fluorine, chlorine, bromine, or iodine.

[0036] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatom groups. The term "heteroalkyl" includes unbranched saturated chains or branched saturated chains having carbon atoms and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, etc., where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclic, each of which may optionally be substituted. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may optionally be substituted. As used herein, heteroalkyl groups include 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.

[0037] "Hybrid alkylene" refers to a divalent heteroalkyl group. A "heteroalkylene" group must have at least one carbon atom and at least one heteroatom group within the chain. The term "heteroalkylene" includes unbranched saturated chains or branched saturated chains having carbon atoms and heteroatoms. For example, one, two, or three carbon atoms can be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR. y-, -O-, -S-, -S(O)-, -S(O)2-, etc., among which R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be 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)2CH2-, -CH2CH2S(O)2CH2CH2OCH2-, -CH2NR y CH2-、-CH(CH3)NR y CH2-、-CH2CH2NR y CH2-、-CH2CH2NR y CH2CH2NR y CH2- etc., where R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein. As used herein, a heteroalkylene comprises 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. As used herein, the term "heteroalkylene" does not include groups such as amides or other functional groups having an oxo group on one or more carbon atoms.

[0038] "Heteroaryl" refers to an aromatic group having a monocyclic or multiple fused rings, wherein one or more cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl groups comprise 1 to 20 cyclic carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 1-20 (heteroaryl), 3 to 12 cyclic carbon atoms (i.e., C 3-12 (heteroaryl) or 3 to 8 carbon ring atoms (i.e., C 3-8The heteroaryl group comprises 1 to 5 cyclic heteroatoms, 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomum, wherein the cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. In some cases, the heteroaryl group comprises a 5-10 membered ring system, a 5-7 membered ring system, or a 5-6 membered ring system, each independently having 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomum, wherein the cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinel, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzooxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenolinyl, dibenzofuranyl, and dibenzothienyl / dibenzothiophenyl. Furanyl, isothiazolyl, imidazolyl, indazole, indolyl, indazole, isoindolyl, isoquinolinyl, isoxazolyl, naphridinyl, oxadiazolyl, oxazolyl, 1-oxopyridinyl, 1-oxopyrimidinyl, 1-oxopyrazinyl, 1-oxopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxolinyl, quinolinyl, quininecycloyl, isoquinolinyl, thiophenyl / thienyl, thiazolyl, thiazolyl, triazolyl, tetrazolyl, and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thienyl / benzo[b]thiophenyl, indazole, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridyl, and imidazo[1,5-a]pyridyl, wherein the heteroaryl group can be bonded via either ring of the fused system. Any aromatic ring having a single or multiple fused rings containing at least one heteroatom is considered a heteroaryl, regardless of its attachment to the rest of the molecule (i.e., via any one of the fused rings). Heteroaryl does not encompass aryl groups as defined above or overlaps with aryl groups as defined above.

[0039] "Heterocyclic group" refers to a saturated or partially unsaturated cyclic alkyl group, wherein one or more cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclic group" includes heterocyclic alkenyl groups (i.e., heterocyclic groups having at least one double bond), bridged heterocyclic groups, fused heterocyclic groups, and spirocyclic groups. Heterocyclic groups can be monocyclic or polycyclic, wherein polycyclic groups can be fused, bridged, or spirocyclic, and can include one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O) groups. -The term "heterocyclic group" refers to any non-aromatic ring containing at least one heteroatom, regardless of its attachment (i.e., whether it can be bonded by carbon atoms or heteroatoms). Furthermore, the term "heterocyclic group" is intended to cover any non-aromatic ring containing at least one heteroatom, which may be fused with a cycloalkyl, aryl, or heteroaryl ring, regardless of its attachment to the rest of the molecule. As used herein, a heterocyclic group has 2 to 20 ring carbon atoms (i.e., C64 ... 2-20 Heterocyclic group), 2 to 12 ring carbon atoms (i.e., C 2-12 Heterocyclic group), 2 to 10 ring carbon atoms (i.e., C 2-10 Heterocyclic group), 2 to 8 ring carbon atoms (i.e., C 2-8 Heterocyclic group), 3 to 12 ring carbon atoms (i.e., C 3-12 Heterocyclic group), 3 to 8 ring carbon atoms (i.e., C 3-8 Heterocyclic group), or 3 to 6 ring carbon atoms (i.e., C 3-6 Heterocyclic groups; having 1 to 5 cyclic heteroatoms, 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomium, wherein the cyclic heteroatoms are independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclic groups include, for example, azirrocyclobutyl, azirrocycloheptatrienyl, benzodioxane-pentenyl, benzo[b][1,4]dioxane-heptatrienyl, 1,4-benzodioxyl, benzopyranyl, benzodioxinyl, benzopyranoneyl, benzofuranoneyl, dioxopentyl, dihydropyranyl, hydropyranyl, thiophene[1,3]dithiaalkyl, decahydroisoquinolinyl, furanoneyl, imidazolinyl, imidazoalkyl, indololinyl, indolazinyl, isoindololinyl, isothiazolyl, isoxazolyl, morpholinyl. Octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidyl, 2-oxopiperylalkyl, oxazolylalkyl, ethylene oxide, oxacyclobutyl, phenothiazinyl, phenothiazinyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolylalkyl, pyrazolylalkyl, quininecycloyl, thiazolyl, tetrahydrofuranyl, tetrahydropyranyl, trithiaalkyl, tetrahydroquinolinyl, tetrahydrothiopheneyl (benzo[b]thiopheneyl), thiomorpholinyl, thiozamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term "heterocyclic group" also includes "spiroheterocyclic group" when there are two substitution positions on the same carbon atom. Examples of spiroheterocyclic rings include, for example, bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, and 6-oxa-1-azaspiro[3.3]heptyl. Examples of fused heterocyclic rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridyl, indololinyl, and isoindololinyl, wherein the heterocyclic group can be linked via any ring of the fused system.

[0040] "Sulfonyl" refers to the group -S(O)2R y , where R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein. Examples of sulfonyl groups are methanesulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0041] "alkylsulfonyl" refers to the group -S(O)2R, where R is an alkyl group.

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

[0043] The terms “optional” or “optionally” mean that the event or condition described below may or may not occur, and the description includes both scenarios in which the event or condition occurs and scenarios in which the event or condition does not occur. Furthermore, the term “optionally substituted” means that any one or more hydrogen atoms on a specified atom or group may or may not be substituted with anything other than hydrogen.

[0044] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the described structure. Unless otherwise stated, compounds identified herein as a particular tautomer form by name or structure are intended to include other tautomer forms.

[0045] Some compounds exist as tautomers. These tautomers are in equilibrium with each other. For example, compounds containing amides can exist in equilibrium with imine tautomers. Regardless of which tautomer is exhibited, and regardless of the equilibrium nature between the tautomers, those skilled in the art will understand that a compound includes both amide and imine tautomers. Therefore, compounds containing amides should be understood to include their imine tautomers. Similarly, compounds containing imines should be understood to include their amide tautomers.

[0046] Any compound or structure described herein is intended to represent both the unlabeled and isotopically labeled forms of the compound. These forms may also be referred to as “isotopically enriched analogs.” Isotopically labeled compounds have the structures described herein, except that one or more atoms are replaced by atoms having selected atomic masses or mass numbers. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as… 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. Various isotopically labeled compounds, such as those doped with radioactive isotopes (e.g., ... 3 H and 14 Compounds of type C). These isotope-labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or basal tissue distribution assays), or in the treatment of patients with radiotherapy.

[0047] The term “isotope-enriched analogues” includes “deuterated analogues” of the compounds described herein, wherein one or more hydrogen atoms are replaced by deuterium (as in the case of hydrogen atoms on carbon atoms). These compounds exhibit increased metabolic resistance and are therefore useful for increasing the half-life of any compound when administered to mammals (particularly humans). See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0048] The deuterium-labeled or substituted therapeutic compounds disclosed herein may have improved DMPK (drug metabolism and pharmacokinetics) properties, involving distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope such as deuterium may provide certain therapeutic advantages due to its higher metabolic stability, such as prolonged in vivo half-life, reduced dose requirement, and / or improved therapeutic index. 18 F, 3 H, 11 C-labeled compounds can be used in PET or SPECT or other imaging studies. The isotopically labeled compounds and their prodrugs of this disclosure can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents, by performing the procedures disclosed in the scheme or in the examples and preparations described below. It should be understood that, in this context, deuterium is considered a substituent in the compounds described herein.

[0049] The concentration of such heavier isotopes (particularly deuterium) can be defined by an isotope enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of said atom. Unless otherwise stated, when a position is specifically designated as “H” or “hydrogen,” said position should be understood as hydrogen having its naturally occurring isotopic composition. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0050] In many cases, the compounds of this disclosure are capable of forming acidic and / or basic salts due to the presence of amino and / or carboxyl groups or similar groups.

[0051] Pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human use.

[0052] The term "pharmaceutically acceptable salt" for a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts formed with inorganic acids and salts formed with organic acids. Furthermore, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt (particularly pharmaceutically acceptable addition salts) can be produced by dissolving the free base in a suitable organic solvent and treating said solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize the 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, etc. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. For example, salts derived from inorganic bases include sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of NH3 or primary, secondary, and tertiary amines, such as those derived from N-containing heterocycles, N-containing heteroaryl groups, or those derived from the formula N(R) N )3 amine salts (e.g., HN) + (R N )3 or (alkyl)N + (RN )3), where each R N Independently, it is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, each of which is optionally substituted, such as by one or more (e.g., 1-5 or 1-3) substituents (e.g., haloyl, cyano, hydroxyl, amino, alkyl, alkenyl, alkynyl, alkoxy, or haloalkoxy). Specific examples of suitable amines, by way of example only, include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, etc.

[0053] The term "substitution" means that any one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents that are not hydrogen, provided that the substitution does not exceed the normal valence of the specified atom. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidyl, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidinyl, haloyl, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclic, hydroxyl, hydrazyl, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof.

[0054] Polymers or similar indeterminate structures obtained by defining substituents with an unlimited number of additional substituents (e.g., substituted aryl groups with substituted alkyl groups, said substituted alkyl groups being themselves substituted by substituted aryl groups, said substituted aryl groups being further substituted by substituted heteroalkyl groups, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of successive substitutions in the compounds described herein is three. For example, the successive substitution of an aryl group substituted by two other substituted aryl groups is limited to an aryl group substituted by ((substituted aryl) substituted aryl) substituted. Similarly, the above definitions are not intended to include permissible substitution patterns (e.g., methyl groups substituted by five fluorine atoms or heteroaryl groups having two adjacent oxygen ring atoms). Such permissible substitution patterns are well known to those skilled in the art. When used to modify chemical groups, the term "substituted" may describe other chemical groups as defined herein. Unless otherwise stated, when a group is described as optionally substituted, any substituted element of said group is itself unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, haloyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with a haloyl, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with a haloyl, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, each of which is unsubstituted.

[0055] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutical acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in a therapeutic composition should be considered. Complementary active ingredients may also be incorporated into the composition.

[0056] "Solvates" are formed through the interaction between a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0057] As used herein, the term "LPA-related disease" refers to, but is not limited to, diseases, disorders, or conditions in which activation of at least one LPA receptor via LPA contributes to the symptom or progression of the disease, disorder, or condition. These diseases, disorders, or conditions can be caused by one or more of the following etiologies: genetic, iatrogenic, immune, infectious, metabolic, neoplastic, toxic, surgical, and / or traumatic. Therefore, inhibition of one or more lysophosphatidylcholine (LPA) receptor signaling (e.g., LPA1, LPA2, LPA3, LPA4, LPA5, or LPA6 receptors) can alter the pathology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, LPA-related disease is an LPA1-related disease, wherein modulation of LPA1 receptor signaling can alter the pathology and / or symptoms and / or progression of the disease, disorder, or condition.

[0058] 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, kidneys, liver, joints, lungs, pleural tissue, peritoneum, skin, cornea, retina, musculoskeletal system, and digestive tract.

[0059] As used herein, the term “pharmaceutically acceptable” indicates that a compound or its salt or composition is chemically and / or toxicologically compatible with other components constituting the formulation and / or with the subject being treated therein.

[0060] The term "administration" or "administering" refers to the method of administering a given dose of a compound or pharmaceutical composition to a vertebrate or invertebrate (including mammals, birds, fish, or amphibians). The method of administration can vary depending on various factors, such as the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

[0061] As used herein, the terms “effective amount” or “effective dose” or “pharmaceutically effective amount” or “therapeutic effective amount” mean an adequate amount of a chemical entity (e.g., a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof) applied that will alleviate one or more symptoms of the disease or condition being treated to a certain extent, and may include curing the disease. “Cure” means the elimination of symptoms of an active disease. Results include a reduction and / or mitigation of signs, symptoms, or causes of the disease or any other desired alteration of the biological system. For example, an “effective amount” for therapeutic use is the amount of a composition comprising a compound as disclosed herein required to provide a clinically significant reduction in disease symptoms. The appropriate “effective” amount in any single case is determined using any suitable technique, such as dose escalation studies. In some embodiments, a “therapeutic effective amount” of a compound as provided herein refers to the amount of a compound that is effective as a monotherapy or combination therapy.

[0062] The term "excipient" or "pharmaceuticalally acceptable excipient" means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulation material. In some embodiments, a component is "pharmaceutically acceptable" in the sense that it is compatible with other components of the pharmaceutical formulation and suitable for contact with human or animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, in proportion to a reasonable benefit / risk ratio. See, for example, Remington: The Science and Practice of Pharmacy, 21st edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th edition; edited by Rowe et al.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd edition; edited by Ash and Ash; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd edition; edited by Gibson; CRC Press LLC: Boca Raton, FL, 2009.

[0063] The term "pharmaceutical composition" refers to a compound of Formula I as provided herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, or a mixture thereof with other chemical components (collectively referred to herein as "excipients") (such as carriers, stabilizers, diluents, dispersants, suspending agents and / or thickeners). Pharmaceutical compositions facilitate the administration of compounds to a living organism. Various techniques for administering compounds exist in the art, including but not limited to rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary and topical administration.

[0064] In the context of treating a disease, disorder, or condition, the term “treat, treating, and treatment” is intended to include relieving or eradicating a disorder, disease, or condition or one or more symptoms associated with said disorder, disease, or condition; or slowing the progression, spread, or worsening of a disease, disorder, or condition or one or more symptoms thereof.

[0065] As used herein, the term “prevention” means the complete or partial prevention of the onset, recurrence, or spread of a disease or condition or its symptoms as described herein.

[0066] 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, cattle, sheep, horses, primates, and humans. In some embodiments, the term refers to a subject who desires or requires a diagnosis, prognosis, or therapy, particularly a mammalian subject. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibits at least one symptom of a disease, disorder, or condition to be treated and / or prevented.

[0067] The terms “treatment regimen” and “dosing regimen” are used interchangeably to refer to the dosage and timing of administration of each therapeutic agent in a combination.

[0068] As used herein, the term "drug combination" refers to a pharmaceutical treatment resulting from a mixture or combination of more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients.

[0069] As used herein, the term “combination therapy” refers to a dosing regimen of two different therapeutic agents (i.e., combined components or combination couples) wherein the therapeutic agents are administered together or separately in a manner prescribed by a healthcare professional or in accordance with a regulatory body as defined herein.

[0070] As used herein, the term “modulate, modulating, or modulation” means regulation or adjustment (e.g., increasing or decreasing) and may include, for example, agonistic, partial agonistic, or antagonistic effects. compound

[0071] On one hand, this article provides a compound of formula I: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein: A is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C of A 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1 replace; L 1 It is a key, -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -、C 1-3 Alkylene, C 2-3 imidene group, C 2-3 alkyne or C 1-3 Heteroalkylene; wherein L 1 The C mentioned 1-3 Alkylene, C 2-3 imidene group, C 2-3 alkyne or C 1-3 The heteroalkylene groups are independently and optionally selected from one to five independently selected from C. 1-9 Substitution of alkyl, halogroup, hydroxyl and cyano groups; L 2 It is key, C 1-3 Alkylene, C 2-3 imidene group, C 2-3 alkyne or C 1-3 Heteroalkylene; wherein L 2 The C mentioned 1-3 Alkylene, C 2-3 imidene group, C 2-3 alkyne or C 1-3 The heteroalkylene groups are independently and optionally selected from one to five independently selected from C. 1-9 Substitution of alkyl, halogroup, hydroxyl and cyano groups; X 1 Is it N or CR? 3 ; X 2 Is it N or CR? 5 ; X 3 Is it N or CR? 7 ; X 4 Is it O or CHR? 11The condition is that A is C. 1-6 When alkyl, then X 4 It is O; X 6 Is it N or CR? 6 ; n is 0, 1, or 2; m is 0, 1, 2, or 3; R 1 and R 2 Each is independently hydrogen, C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 cycloalkyl or heterocyclic groups; wherein R 1 and R 2 Each C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 The cycloalkyl or heterocyclic group is independently and optionally surrounded by one to five Z. 1 replace; Or R 1 and R 2 Together with the atoms to which they are attached, they form C 3-10 cycloalkyl or heterocyclic groups; wherein the C 3-10 cycloalkyl or heterocyclic groups are optionally surrounded by one to five Z groups. 1 replace; R 3 It includes hydrogen, halogroup, cyano, nitro, -OH, -SH, -NH2, and -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 group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 3 The -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 group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R 4 It is a halogenated group, cyano group, nitro group, -OR group 14 -N(R)14 )2、-SR 14 C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 4 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally surrounded by one to five independently selected groups, hydroxyl, C. 1-5 Substitution of alkoxy and cyano groups; Or R 3 and R 4 Together with the atoms to which they are attached, they form cycloalkyl, aryl, heterocyclic, or heteroaryl groups; wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl groups are optionally substituted by one to five independent substituents selected from halogen, hydroxyl, and cyano groups; R 5 It is hydrogen, halogroup, 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 group, C 3-5 Cycloalkyl, 3-5 membered heterocyclic or 5 membered heteroaryl; wherein R 5 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 Cycloalkyl, 3-5 membered heterocyclic or 5-membered heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1 replace; R 6 It is hydrogen, halogroup, cyano, nitro, -OR 16 -N(R) 16 )2、-SR 16 C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 6 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R 7 It includes hydrogen, halogroup, cyano, nitro, -OH, -SH, -NH2, and -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 group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 7 The -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 group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; Or R 6 and R 7 Together with the atoms to which they are attached, they form cycloalkyl, aryl, heterocyclic, or heteroaryl groups; wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl groups are optionally substituted by one to five independent substituents selected from halogen, hydroxyl, and cyano groups; R 8 It is hydrogen, C 1-9 Alkyl, oxo, halogen, hydroxyl, or cyano groups; R 9 It is hydrogen, C 1-9 Alkyl, oxo, halogen, hydroxyl, or cyano groups; R 10 It is hydrogen, C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 10 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R 11 It is hydrogen, C 1-9 Alkyl, oxo, halogen, hydroxyl, or cyano groups; Each R 13 Independently, it can be hydrogen, halogenated, cyano, nitro, -OH, -SH, -NH2, or -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 group, C 3-6 cycloalkyl or 3 to 6-membered heterocyclic groups; wherein R 13 Each -NH-C 1-9 Alkyl, -N(C) 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-6 The cycloalkyl or 3 to 6-membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R 14 It is hydrogen, C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 14 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R 15 It is hydrogen, C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 15 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R 16 It is hydrogen, C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R16 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; Each Z 1 Independently, it is a halogenated group, a cyano group, a nitro group, an oxo group, or a C group. 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LH, -LC 1-9 Alkyl, -LC 2-9 alkenyl, -LC 2-9 alkynyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; wherein Z 1 Each C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1a replace; Each L is independently -O-, -S-, -NR 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -、-NR 20 C(O)-、-OC(O)NR 20 -、-NR 20 C(O)O-、-NR 20 C(O)NR 21 -, -S(O)-, -S(O)2-, -S(O)NR 20 -、-S(O)2NR 20 -、-NR 20 S(O)-、-NR 20 S(O)2-、-NR 20 S(O)NR 21 -or-NR 20 S(O)2NR 21 -; Each R 20 and R 21 Independently, it is hydrogen and C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R20 and R 21 Each C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1a Replace; or R 20 and R 21 Together with the atoms to which they are attached, they form independently, optionally, one to five Z. 1a Substituted heterocyclic groups; and Each Z 1a Independently, it can be a halogenated group, hydroxyl group, cyano group, nitro group, oxo group, -SH, -NH2, or -NH-C group. 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 group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein Z 1a Each -NH-C 1-9 Alkyl, -N(C) 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally selected from one to five C14 groups. 1-9 Substitution of alkyl, oxo, halogen, hydroxyl and cyano groups.

[0072] In some embodiments, this document provides a compound of formula II: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein A, R 1 R 2 R 4 R 6 R 8 R 9 R 13 X 1 X 2 X 3 X 4 n, m, L 1 and L2 Each of them is independently as defined in this article.

[0073] In some embodiments, this document provides a compound of formula II: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein: A is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C of A 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1 replace; L 1 It is a key, -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -、C 1-3 Alkylene, C 2-3 imidene group, C 2-3 alkyne or C 1-3 Heteroalkylene; wherein L 1 The C mentioned 1-3 Alkylene, C 2-3 imidene group, C 2-3 alkyne or C 1-3 The heteroalkylene groups are independently and optionally selected from one to five independently selected from C. 1-9 Substitution of alkyl, halogroup, hydroxyl and cyano groups; L 2 It is key, C 1-3 Alkylene, C 2-3 imidene group, C 2-3 alkyne or C 1-3 Heteroalkylene; wherein L 2 The C mentioned 1-3 Alkylene, C 2-3 imidene group, C 2-3 alkyne or C 1-3 The heteroalkylene groups are independently and optionally selected from one to five independently selected from C. 1-9 Substitution of alkyl, halogroup, hydroxyl and cyano groups; X 1 Is it N or CR? 3 ; X 2 Is it N or CR? 5 ; X 3 Is it N or CR? 7 ; X 4Is it O or CHR? 11 The condition is that A is C. 1-6 When alkyl, then X 4 It is O; n is 0, 1, or 2; m is 0, 1, 2, or 3; R 1 and R 2 Each is independently hydrogen, C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 cycloalkyl or heterocyclic groups; wherein R 1 and R 2 Each C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 The cycloalkyl or heterocyclic group is independently and optionally surrounded by one to five Z. 1 replace; Or R 1 and R 2 Together with the atoms to which they are attached, they form C 3-10 cycloalkyl or heterocyclic groups; wherein the C 3-10 cycloalkyl or heterocyclic groups are optionally surrounded by one to five Z groups. 1 replace; R 3 It includes hydrogen, halogroup, cyano, nitro, -OH, -SH, -NH2, and -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 group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 3 The -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 group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R 4 It is a halogenated group, cyano group, nitro group, -OR group 14 -N(R) 14 )2、-SR 14C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 4 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally surrounded by one to five independently selected groups, hydroxyl, C. 1-5 Substitution of alkoxy and cyano groups; Or R 3 and R 4 Together with the atoms to which they are attached, they form cycloalkyl, aryl, heterocyclic, or heteroaryl groups; wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl groups are optionally substituted by one to five independent substituents selected from halogen, hydroxyl, and cyano groups; R 5 It is hydrogen, halogroup, 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 group, C 3-5 Cycloalkyl, 3-5 membered heterocyclic or 5 membered heteroaryl; wherein R 5 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 Cycloalkyl, 3-5 membered heterocyclic or 5-membered heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1 replace; R 6 It is hydrogen, halogroup, cyano, nitro, -OR 16 -N(R) 16 )2、-SR 16 C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 6 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R7 It includes hydrogen, halogroup, cyano, nitro, -OH, -SH, -NH2, and -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 group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 7 The -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 group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; Or R 6 and R 7 Together with the atoms to which they are attached, they form cycloalkyl, aryl, heterocyclic, or heteroaryl groups; wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl groups are optionally substituted by one to five independent substituents selected from halogen, hydroxyl, and cyano groups; R 8 It is hydrogen, C 1-9 Alkyl, oxo, halogen, hydroxyl, or cyano groups; R 9 It is hydrogen, C 1-9 Alkyl, oxo, halogen, hydroxyl, or cyano groups; R 10 It is hydrogen, C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 10 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R 11 It is hydrogen, C 1-9 Alkyl, oxo, halogen, hydroxyl, or cyano groups; Each R 13Independently, it can be hydrogen, halogenated, cyano, nitro, -OH, -SH, -NH2, or -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 group, C 3-6 cycloalkyl or 3 to 6-membered heterocyclic groups; wherein R 13 Each -NH-C 1-9 Alkyl, -N(C) 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-6 The cycloalkyl or 3 to 6-membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R 14 It is hydrogen, C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 14 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R 15 It is hydrogen, C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 15 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R 16 It is hydrogen, C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 16 The C mentioned 1-5Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; Each Z 1 Independently, it is a halogenated group, a cyano group, a nitro group, an oxo group, or a C group. 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LH, -LC 1-9 Alkyl, -LC 2-9 alkenyl, -LC 2-9 alkynyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; wherein Z 1 Each C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1a replace; Each L is independently -O-, -S-, -NR 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -、-NR 20 C(O)-、-OC(O)NR 20 -、-NR 20 C(O)O-、-NR 20 C(O)NR 21 -, -S(O)-, -S(O)2-, -S(O)NR 20 -、-S(O)2NR 20 -、-NR 20 S(O)-、-NR 20 S(O)2-、-NR 20 S(O)NR 21 -or-NR 20 S(O)2NR 21 -; Each R 20 and R 21 Independently, it is hydrogen and C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 20 and R 21Each C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1a Replace; or R 20 and R 21 Together with the atoms to which they are attached, they form independently, optionally, one to five Z. 1a Substituted heterocyclic groups; and Each Z 1a Independently, it can be a halogenated group, hydroxyl group, cyano group, nitro group, oxo group, -SH, -NH2, or -NH-C group. 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 group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein Z 1a Each -NH-C 1-9 Alkyl, -N(C) 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally selected from one to five C14 groups. 1-9 Substitution of alkyl, oxo, halogen, hydroxyl and cyano groups.

[0074] In some embodiments, this document provides a compound of formula IXA: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein A, R 1 R 2 R 4 R 6 R 8 R 9 R 13 X 1 X 2 X 3 X 4 , n, L 1 and L 2 Each of them is independently as defined in this article.

[0075] In some embodiments, this document provides a compound of formula IXB: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein A, R 1 R 2 R 4 R 8 R 9 R 13 X 1 X 2 X 3 X 4 , n, L 1 and L 2 Each of them is independently as defined in this article.

[0076] In some implementations, A is C 1-6 Alkyl group. In some embodiments, A is C. 3-4 Alkyl group. In some embodiments, A is n-propyl, n-butyl, isopropyl, or isobutyl.

[0077] On one hand, this article provides a compound of formula IIA: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein R 1 R 2 R 4 R 6 R 8 R 9 R 13 X 1 X 2 X 3 X 4 n, m, L 1 and L 2 Each of them is independently as defined in this paper, and ring A is C. 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C of ring A 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1 replace.

[0078] On one hand, this article provides a compound of formula IIA: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein: Ring A is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C of ring A 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1 replace; L 1 It is a key, -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -、C 1-3 Alkylene, C 2-3 imidene group, C 2-3 alkyne or C 1-3 Heteroalkylene; wherein L 1 The C mentioned 1-3 Alkylene, C 2-3 imidene group, C 2-3 alkyne or C 1-3 The heteroalkylene groups are independently and optionally selected from one to five independently selected from C. 1-9 Substitution of alkyl, halogroup, hydroxyl and cyano groups; L 2 It is key, C 1-3 Alkylene, C 2-3 imidene group, C 2-3 alkyne or C 1-3 Heteroalkylene; wherein L 2 The C mentioned 1-3 Alkylene, C 2-3 imidene group, C 2-3 alkyne or C 1-3 The heteroalkylene groups are independently and optionally selected from one to five independently selected from C. 1-9 Substitution of alkyl, halogroup, hydroxyl and cyano groups; X 1 Is it N or CR? 3 ; X 2 Is it N or CR? 5 ; X 3 Is it N or CR? 7 ; X 4 Is it O or CHR? 11 ; n is 0, 1, or 2; m is 0, 1, 2, or 3; R 1 and R 2 Each is independently hydrogen, C 1-9 Alkyl, C 2-9 alkenyl, C2-9 alkynyl group, C 3-10 cycloalkyl or heterocyclic groups; wherein R 1 and R 2 Each C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 The cycloalkyl or heterocyclic group is independently and optionally surrounded by one to five Z. 1 replace; Or R 1 and R 2 Together with the atoms to which they are attached, they form C 3-10 cycloalkyl or heterocyclic groups; wherein the C 3-10 cycloalkyl or heterocyclic groups are optionally surrounded by one to five Z groups. 1 replace; R 3 It includes hydrogen, halogroup, cyano, nitro, -OH, -SH, -NH2, and -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 group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 3 The -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 group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R 4 It is a halogenated group, cyano group, nitro group, -OR group 14 -N(R) 14 )2、-SR 14 C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 4 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; Or R 3 and R 4 Together with the atoms to which they are attached, they form cycloalkyl, aryl, heterocyclic, or heteroaryl groups; wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl groups are optionally substituted by one to five independent substituents selected from halogen, hydroxyl, and cyano groups; R 5 It is hydrogen, halogroup, 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 group, C 3-5 Cycloalkyl, 3-5 membered heterocyclic or 5 membered heteroaryl; wherein R 5 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 Cycloalkyl, 3-5 membered heterocyclic or 5-membered heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1 replace; R 6 It is hydrogen, halogroup, cyano, nitro, -OR 16 -N(R) 16 )2、-SR 16 C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 6 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R 7 It includes hydrogen, halogroup, cyano, nitro, -OH, -SH, -NH2, and -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 group, C3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 7 The -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 group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; Or R 6 and R 7 Together with the atoms to which they are attached, they form cycloalkyl, aryl, heterocyclic, or heteroaryl groups; wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl groups are optionally substituted by one to five independent substituents selected from halogen, hydroxyl, and cyano groups; R 8 It is hydrogen, C 1-9 Alkyl, oxo, halogen, hydroxyl, or cyano groups; R 9 It is hydrogen, C 1-9 Alkyl, oxo, halogen, hydroxyl, or cyano groups; R 10 It is hydrogen, C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 10 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R 11 It is hydrogen, C 1-9 Alkyl, oxo, halogen, hydroxyl, or cyano groups; Each R 13 Independently, it can be hydrogen, halogenated, cyano, nitro, -OH, -SH, -NH2, or -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 group, C 3-6 cycloalkyl or 3 to 6-membered heterocyclic groups; wherein R 13Each -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 group, C 3-6 The cycloalkyl or 3 to 6-membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R 14 It is hydrogen, C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 14 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R 15 It is hydrogen, C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 15 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; R 16 It is hydrogen, C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 16 The C mentioned 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups; Each Z 1 Independently, it is a halogenated group, a cyano group, a nitro group, an oxo group, or a C group. 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LH, -LC 1-9 Alkyl, -LC 2-9 alkenyl, -LC 2-9 alkynyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; wherein Z 1 Each C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1a replace; Each L is independently -O-, -S-, -NR 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -、-NR 20 C(O)-、-OC(O)NR 20 -、-NR 20 C(O)O-、-NR 20 C(O)NR 21 -, -S(O)-, -S(O)2-, -S(O)NR 20 -、-S(O)2NR 20 -、-NR 20 S(O)-、-NR 20 S(O)2-、-NR 20 S(O)NR 21 -or-NR 20 S(O)2NR 21 -; Each R 20 and R 21 Independently, it is hydrogen and C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 20 and R 21 Each C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1a Replace; or R 20 and R 21 Together with the atoms to which they are attached, they form independently, optionally, one to five Z. 1a Substituted heterocyclic groups; and Each Z 1a Independently, it can be a halogenated group, hydroxyl group, cyano group, nitro group, oxo group, -SH, -NH2, or -NH-C group. 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 group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein Z 1a Each -NH-C 1-9 Alkyl, -N(C) 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally selected from one to five C14 groups. 1-9 Substitution of alkyl, oxo, halogen, hydroxyl and cyano groups.

[0079] On one hand, this article provides a compound of formula IIB: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein R 1 R 2 R 4 R 6 R 8 R 9 R 13 X 1 X 2 X 3 X 4 n, m, L 1 and L 2 Each of them is independently as defined in this paper, and ring A is C. 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C of ring A 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1 replace.

[0080] On one hand, this article provides a compound of formula IIC: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein R 1 R 2 R 4 R 8 R 9 R 10 R 13 X 1 X 2 X 3 X 4 X 6 A, n, m and L 2 Each of them is independently as defined in this article.

[0081] On one hand, this paper provides a compound of formula IID: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein R 1 R 2 R 4 R 6 R 8 R 9 R 10 R 13 X 1 X 2 X 3 X 4 A, n and L 2 Each of them is independently as defined in this article.

[0082] On one hand, this article provides a compound of formula IIE: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein R 1 R 2 R 4 R 8 R 9 R 10 R 13 X 1 X 2 X 3 X 4 A, n, m and L 2 Each of them is independently as defined in this article.

[0083] On one hand, this paper provides a compound of formula IIF: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein R 1 R 2 R 4 R 6 R 8 R 9 R 10 R 13 X 1 X 2 X 3 X 4 Rings A, n, and L 2 Each of them is independently as defined in this article.

[0084] In some embodiments, compounds of formula I or II are represented by formula IA: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein R 1 R 2 R 4 R 6 R 8 R 9 R 13 X 1 X 2 X 3 X 4 Ring A, n, L 1 and L 2 Each of them is independently as defined in this article.

[0085] In some implementation schemes, X 1 It is N. In some implementations, X 1 It is CR 3 .

[0086] In some implementation schemes, X 2 It is N. In some implementations, X 2 It is CR 5 .

[0087] In some implementation schemes, X 3 It is N. In some implementations, X 3 It is CR 7 .

[0088] In some implementation schemes, X 1 It is N, X 2It is N, and X 3 It is N. In some implementations, X 1 It is N, X 2 It is N, and X 3 It is CR 7 In some implementations, X 1 It is N, X 2 It is CR 5 And X 3 It is N. In some implementations, X 1 It is CR 3 X 2 It is N, and X 3 It is N. In some implementations, X 1 It is CR 3 X 2 It is N, and X 3 It is CR 7 In some implementations, X 1 It is CR 3 X 2 It is CR 5 And X 3 It is N. In some implementations, X 1 It is CR 3 X 2 It is CR 5 And X 3 It is CR 7 In some implementations, X 1 It is N, X 2 It is CR 5 And X 3 It is CR 7 .

[0089] In some implementation schemes, R 3 It includes hydrogen, halogroup, cyano, nitro, -OH, -SH, -NH2, and -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 group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 3 The -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, C2-5 alkynyl group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups.

[0090] In some implementation schemes, R 3 It is hydrogen, halogroup or C 1-5 Alkyl, wherein C 1-5 The alkyl group is optionally substituted with one to five halogroups. In some embodiments, R 3 It is hydrogen, halogenated group, C 1-5 Alkyl or C 1-5 Halogenated alkyl groups. In some embodiments, R 3 It is hydrogen, fluorine, chlorine, methyl, ethyl, or difluoromethyl. In some embodiments, R 3 It is hydrogen. In some implementations, R 3 It is a halogenated group. In some implementations, R 3 It is C 1-5 Alkyl group. In some embodiments, R 3 It is C 1-5 Halogenated alkyl groups.

[0091] In some implementation schemes, R 4 Yes - OR 14 -N(R) 14 )2 or C 1-5 Alkyl, wherein C 1-5 Alkyl groups are optionally replaced by hydroxyl groups or C. 1-5 Alkyl substitution. In some embodiments, R 4 Yes - OR 14 Or C 1-5 Alkyl, wherein C 1-5 Alkyl groups are optionally replaced by hydroxyl groups or C. 1-5 Alkyl-substituted.

[0092] In some implementation schemes, R 4 Yes - OR 14 or -N(R) 14 )2. In some implementation schemes, R 4 Yes - OC 1-5 Alkyl, -OC 3-5 cycloalkyl or -NH-C 1-5 Alkyl group. In some embodiments, R 4 It is methoxy, ethoxy, isobutoxy, cyclopropoxy, or ethylamino.

[0093] In some implementation schemes, R 4 Yes - OR 14 In some implementations, R 4 Yes - OC 1-5Alkyl group. In some embodiments, R 4 It is hydroxyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, methyl, ethyl, n-propyl, isopropyl, 2-hydroxyethyl, or methoxymethyl. In some embodiments, R 4 Yes - OR 14 And R 14 It is C 1-5 Alkyl or C 3-5 Cycloalkyl. In some embodiments, R 4 It is hydroxyl, methoxy, ethoxy, n-propoxy, cyclopropoxy, cyclobutoxy, methyl, ethyl, n-propyl, 2-hydroxyethyl, or methoxymethyl. In some embodiments, R 4 It is hydroxyl, methoxy, ethoxy, or cyclopropyloxy. In some embodiments, R 4 It is hydroxyl, methoxy, or ethoxy. In some embodiments, R 4 It is methoxy or ethoxy. In some embodiments, R 4 It is a methoxyl group. In some embodiments, R 4 It is ethoxylated. In some embodiments, R 4 It is cyclopropyloxy group.

[0094] In some implementation schemes, R 3 and R 4 Together with the atoms to which they are attached, they form cycloalkyl, aryl, heterocyclic, or heteroaryl groups; wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl groups are optionally substituted by one to five substituents independently selected from halogen, hydroxyl, and cyano groups.

[0095] In some implementation schemes, R 3 and R 4 Together with the atoms to which they are attached, they form cycloalkyl groups, which are optionally substituted by one to five independent substituents selected from halogen, hydroxyl, and cyano groups. In some embodiments, R 3 and R 4 Together with the atoms to which they are attached, they form a C6 cycloalkyl group, which is optionally substituted by one to five independent substituents selected from halogen, hydroxyl, and cyano groups. In some embodiments, R 3 and R 4 Together with the atoms to which they are attached, they form a C5 cycloalkyl group, which is optionally substituted by one to five independent substituents selected from halogen, hydroxyl, and cyano groups. In some embodiments, the cycloalkyl group is unsubstituted.

[0096] In some implementation schemes, R 3 and R 4Together with the atoms to which they are attached, they form an aryl group, which is optionally substituted by one to five independent substituents selected from halogenated, hydroxyl, and cyano groups. In some embodiments, R 3 and R 4 Together with the atoms to which they are attached, they form a C6 aryl group, which is optionally substituted by one to five independent substituents selected from halogens, hydroxyl groups, and cyano groups. In some embodiments, the aryl group is unsubstituted.

[0097] In some implementation schemes, R 3 and R 4 Together with the atoms to which they are attached, they form heterocyclic groups, which are optionally substituted by one to five independent substituents selected from halogen groups, hydroxyl groups, and cyano groups. In some embodiments, R 3 and R 4 Together with the atoms to which they are attached, they form 5- or 6-membered heterocyclic groups, which are optionally substituted by one to five independent substituents selected from halogenated, hydroxyl, and cyano groups. In some embodiments, R 3 and R 4 Together with the atoms to which they are attached, they form a 5-membered heterocyclic group, which is optionally substituted by one to five independent substituents selected from halogenated, hydroxyl, and cyano groups. In some embodiments, R 3 and R 4 Together with the atoms to which they are attached, they form a 5-membered oxygen-containing heterocyclic group, which is optionally substituted by one to five independent substituents selected from halogen groups, hydroxyl groups, and cyano groups. In some embodiments, the heterocyclic group is unsubstituted.

[0098] In some implementation schemes, R 3 and R 4 Together with the atoms to which they are attached, they form heteroaryl groups, which are optionally substituted by one to five independent substituents selected from halogenated, hydroxyl, and cyano groups. In some embodiments, R 3 and R 4 Together with the atoms to which they are attached, they form 5- or 6-membered heteroaryl groups, which are optionally substituted by one to five independent substituents selected from halogens, hydroxyl groups, and cyano groups. In some embodiments, R 3 and R 4 Together with the atoms to which they are attached, they form a 6-membered heteroaryl group, which is optionally substituted by one to five independent substituents selected from halogens, hydroxyl groups, and cyano groups. In some embodiments, the heteroaryl group is unsubstituted.

[0099] In some implementation schemes, R 6 It is hydrogen, cyano, -OR 16 Or C 1-5 Alkyl group. In some embodiments, R 6It is hydrogen, cyano, -OC 1-5 Alkyl or C 1-5 Alkyl group. In some embodiments, R 6 Yes - OR 16 In some implementations, R 6 Yes - OC 1-5 Alkyl group. In some embodiments, R 6 It is hydroxyl, cyano, methoxy, or ethoxy. In some embodiments, R 6 It is a methoxy group.

[0100] In some implementation schemes, R 4 Yes - OR 14 or -N(R) 14 )2, and R 6 It is hydrogen, cyano, -OR 16 Or C 1-5 Alkyl group. In some embodiments, R 4 Yes - OC 1-5 Alkyl, -OC 3-5 cycloalkyl or -NH-C 1-5 Alkyl, and R 6 It is hydrogen, cyano, -OC 1-5 Alkyl or C 1-5 Alkyl group. In some embodiments, R 4 It is methoxy, ethoxy, isobutoxy, cyclopropoxy, or ethylamino, and R 6 It is hydroxyl, cyano, methoxy, or ethoxy.

[0101] In some implementation schemes, R 4 Yes - OC 1-5 Alkyl, and R 6 It is hydrogen, cyano, -OR 16 Or C 1-5 Alkyl group. In some embodiments, R 4 Yes - OC 1-5 Alkyl, and R 6 It is hydrogen, cyano, -OC 1-5 Alkyl or C 1-5 Alkyl group. In some embodiments, R 4 Yes - OC 1-5 Alkyl, and R 6 Yes - OR 16 In some implementations, R 4 Yes - OC 1-5 Alkyl, and R 6 Yes - OC 1-5 Alkyl group. In some embodiments, R 4 Yes - OC 1-5 Alkyl, and R6 It is hydroxyl, cyano, methoxy, or ethoxy. In some embodiments, R 4 Yes - OC 1-5 Alkyl, and R 6 It is a methoxyl group. In some embodiments, R 4 It is a methoxy group, and R 6 It is hydrogen. In some implementations, R 4 It is a methoxy group, and R 6 It is a methoxy group.

[0102] In some implementation schemes, R 5 It is hydrogen, halogroup, cyano, -C(O)-C 1-5 Alkyl or C 1-5 Alkyl, the C 1-5 The alkyl group is optionally surrounded by one to three independently selected from a halogen group, a hydroxyl group, and a C-group. 1-5 Alkyl group substitution. In some embodiments, R 5 It is hydrogen, cyano, -C(O)-C 1-5 Alkyl or C 1-5 Alkyl, the C 1-5 The alkyl group is optionally substituted with one to three substituents independently selected from halogenated and hydroxyl groups. In some embodiments, R 5 It is hydrogen. In some implementations, R 5 It is cyano. In some implementations, R 5 It is a halogenated group. In some implementations, R 5 It is fluorine. In some implementations, R 5 It is -C(O)-C 1-5 Alkyl group. In some embodiments, R 5 It is C 1-5 The alkyl group is optionally substituted with one to three substituents independently selected from halogenated and hydroxyl groups. In some embodiments, R 5 It is C 1-5 Halogenated alkyl groups.

[0103] In some implementation schemes, R 4 Yes - OC 1-5 Alkyl, R 5 It is hydrogen, cyano, -C(O)-C 1-5 Alkyl or C 1-5 Alkyl, the C 1-5 The alkyl group is optionally substituted with one to three independent substituents selected from halogenated and hydroxyl groups, and R 6 It is hydrogen, cyano, -OR 16 Or C 1-5 alkyl.

[0104] In some implementation schemes, R7 It includes hydrogen, halogroup, cyano, nitro, -OH, -SH, -NH2, and -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 group, C 3-5 cycloalkyl or 3-5 membered heterocyclic groups; wherein R 7 The -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 group, C 3-5 The cycloalkyl or 3-5 membered heterocyclic group is independently and optionally substituted by one to five substituents independently selected from halogen, hydroxyl and cyano groups.

[0105] In some implementation schemes, R 7 Is it hydrogen, halogroup, or C? 1-5 Alkyl or C 1-5 Halogenated alkyl groups. In some embodiments, R 7 It is hydrogen, fluorine, chlorine, methyl, ethyl, or difluoromethyl. In some embodiments, R 7 Is it hydrogen or C? 1-5 Alkyl group. In some embodiments, R 7 It is hydrogen, methyl, or ethyl. In some embodiments, R 7 It is hydrogen. In some implementations, R 7 It is a halogenated group. In some implementations, R 7 It is C 1-5 Alkyl group. In some embodiments, R 7 It is C 1-5 Halogenated alkyl groups.

[0106] In some implementation schemes, R 3 It is hydrogen, and R 7 Is it hydrogen, halogroup, or C? 1-5 Alkyl or C 1-5 Halogenated alkyl groups. In some embodiments, R 3 It is a halogenated group, and R 7 Is it hydrogen, halogroup, or C? 1-5 Alkyl or C 1-5 Halogenated alkyl groups. In some embodiments, R 3 It is C 1-5 Alkyl, and R7 Is it hydrogen, halogroup, or C? 1-5 Alkyl or C 1-5 Halogenated alkyl groups. In some embodiments, R 3 It is C 1-5 Halogenated alkyl groups, and R 7 Is it hydrogen, halogroup, or C? 1-5 Alkyl or C 1-5 Halogenated alkyl groups.

[0107] In some implementation schemes, R 3 It is hydrogen, and R 7 It is hydrogen.

[0108] In some implementation schemes, R 7 It is hydrogen, and R 3 Is it hydrogen, halogroup, or C? 1-5 Alkyl or C 1-5 Halogenated alkyl groups. In some embodiments, R 7 It is a halogenated group, and R 3 Is it hydrogen, halogroup, or C? 1-5 Alkyl or C 1-5 Halogenated alkyl groups. In some embodiments, R 7 It is C 1-5 Alkyl, and R 3 Is it hydrogen, halogroup, or C? 1-5 Alkyl or C 1-5 Halogenated alkyl groups. In some embodiments, R 7 It is C 1-5 Halogenated alkyl groups, and R 3 Is it hydrogen, halogroup, or C? 1-5 Alkyl or C 1-5 Halogenated alkyl groups.

[0109] In some implementations, A or ring A is C 3-10 Cycloalkyl or heterocyclic groups, wherein each is independently and optionally surrounded by one to five Z groups. 1 Replacement. In some implementations, A or ring A is C. 3-10 Cycloalkyl or heterocyclic groups.

[0110] In some implementations, A or ring A is optionally divided by one to five Z. 1 Replacement C 3-10 Cycloalkyl. In some embodiments, A or cycloA is C. 3-10 Cycloalkyl group, optionally substituted by one to five independent substituents selected from the following: halogroup, hydroxyl group, cyano group, nitro group, oxogroup, -SH group, -NH2 group, -NH-C group. 1-9 Alkyl group, -NHC(O)-C 1-9 Alkyl, -N(C) 1-9 Alkyl)2, -SC1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each -NH-C 1-9 Alkyl, -N(C) 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally selected from one to five C14 groups. 1-9 Substitution with alkyl, oxo, halogen, hydroxyl, and cyano groups. In some embodiments, A or ring A is C. 3-10 Cycloalkyl groups, optionally substituted by one to five independent substituents selected from the following: C 1-9 Alkyl, oxo, halogen, hydroxyl, and cyano groups.

[0111] In some embodiments, A or ring A is a heterocyclic group, which is optionally surrounded by one to five Z groups. 1 Substitution. In some embodiments, A or ring A is a heterocyclic group, which is optionally substituted by one to five substituents independently selected from the following: halogroup, hydroxyl group, cyano group, nitro group, oxogroup, -SH group, -NH2 group, -NH-C group. 1-9 Alkyl group, -NHC(O)-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 group, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each -NH-C 1-9 Alkyl, -N(C) 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally selected from one to five C14 groups. 1-9 Alkyl, oxo, halo, hydroxy, and cyano substituents are used. In some embodiments, A or ring A is a heterocyclic group, optionally substituted by one to five independent substituents selected from: C1-9 Alkyl, oxo, halogen, hydroxyl, and cyano groups.

[0112] In some embodiments, A or cyclic A is an aryl group, which is optionally surrounded by one to five Z groups. 1 Substitution. In some embodiments, A or ring A is an aryl group, which is optionally substituted by one to five substituents independently selected from the following: halogroup, hydroxyl group, cyano group, nitro group, oxogroup, -SH group, -NH2 group, -NH-C group. 1-9 Alkyl group, -NHC(O)-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 group, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each -NH-C 1-9 Alkyl, -N(C) 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally selected from one to five C14 groups. 1-9 Substituents of alkyl, oxo, halo, hydroxy, and cyano groups. In some embodiments, A or ring A is an aryl group, optionally substituted by one to five substituents independently selected from the following: C 1-9 Alkyl, oxo, halogen, hydroxyl, and cyano groups.

[0113] In some embodiments, A or cyclic A is a heteroaryl group, which is optionally surrounded by one to five Z groups. 1 Substitution. In some embodiments, A or ring A is a heteroaryl group, which is optionally substituted by one to five substituents independently selected from the following: halogroup, hydroxyl group, cyano group, nitro group, oxogroup, -SH group, -NH2 group, -NH-C group. 1-9 Alkyl group, -NHC(O)-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 group, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each -NH-C 1-9 Alkyl, -N(C) 1-9Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally selected from one to five C14 groups. 1-9 Substituents of alkyl, oxo, halo, hydroxy, and cyano groups. In some embodiments, A or ring A is a heteroaryl group, optionally substituted by one to five independent substituents selected from: C 1-9 Alkyl, oxo, halogen, hydroxyl, and cyano groups.

[0114] In any of the embodiments described herein, for groups having two or more substituents, these substituents may be the same or different. For example, in -N(C 1-5 alkyl)2 or -N(C 1-9 In alkyl)2, the alkyl groups can be the same or different, and in the case of further substitution, these substituents can also be the same or different (e.g., -N(CH3)2, -N(CH3)CH2CH3, -N(CH3)CH2CF3, -N(CHF2)CH2CH2CN, etc.).

[0115] In some implementation schemes, X 4 It is O. In some implementations, X 4 It is CHR 11 In some implementations, X 4 It is CH2.

[0116] In some implementation schemes, R 8 It is hydrogen.

[0117] In some implementation schemes, R 9 It is hydrogen.

[0118] In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is either 0 or 1. In some implementations, n is either 1 or 2.

[0119] In some implementation schemes, R 13 It is hydrogen, halogen, hydroxyl, C 1-9 Alkyl, C 1-9 Halogenated alkyl or C 1-9 Alkyl-CN.

[0120] In some implementation schemes, R 13 It is hydrogen, halogroup or C 1-9 Alkyl group. In some embodiments, R 13 It is hydrogen.

[0121] In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 1, and R 13 It is hydrogen, halogroup or C 1-9 alkyl.

[0122] In some implementations, L 1 It is a key, -O-, -NR 10 -、C 1-3 Alkylene or C 1-3 Heteroalkylene compounds. In some embodiments, L 1 It is -O-, -NR 10 -or C 1-3 Alkylene, and R 10 Is it hydrogen or C? 1-9 Alkyl group. In some embodiments, L 1 It is a bond, -O-, -NH-, -NCH3-, C 1-3 Alkylene or C 1-3 Heteroalkylene compounds. In some embodiments, L 1 It is a key. In some implementations, L 1 Yes -O-. In some implementations, L 1 Yes -NR 10 - In some implementations, L 1 Is it -O- or -NR? 10 - In some implementations, L 1 It is -NH- or -NCH3-. In some implementations, L 1 It is -NH-. In some implementations, L 1 It is -O- or -NH-. In some implementations, L 1 It is C 1-3 Alkylene. In some embodiments, L 1 It is C 1-3 Heteroalkylene compounds. In some embodiments, L 1 It is -O-CH2-.

[0123] In some implementations, L 2 It is a key.

[0124] In some implementations, L 1 It is a key, -O-, -NR 10 -、C 1-3 Alkylene or C 1-3 Heteroalkylene, and L 2 It is a key. In some implementations, L 1 Is a key, -O-, or -NR 10 - and L 2It is a key. In some implementations, L 1 Is it -O- or -NR? 10 - and L 2 It is a key.

[0125] In some implementations, a compound of formula IB is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein m, R 1 R 2 R 4 R 13 X 1 X 2 X 3 X 4 X 6 Ring A and L 1 Each of them is independently as defined in this article.

[0126] In some implementations, a compound of formula IC is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein R 1 R 2 R 4 R 13 X 1 X 2 X 3 X 4 X 6 Ring A and L 1 Each of them is independently as defined in this article.

[0127] In some implementations, a compound of formula ID is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein m, R 1 R 2 R 6 R 13 R 14 X 1 X 2 X 3 X 4 Ring A and L 1 Each of them is independently as defined in this article.

[0128] In some implementations, a compound of formula IE is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein R 1 R 2 R 6 R 13 R 14 X 1 X 2 X 3 X 4 Ring A and L 1 Each of them is independently as defined in this article.

[0129] In some implementations, a compound of formula IF is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein m, R 1 R 2 R 4 R 6 R 13 X 1 X 2 X 3 X 4 Ring A and L 1 Each of them is independently as defined in this article.

[0130] In some embodiments, a compound of formula IG is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein m, R 1 R 2 R 4 R 6 R 13 X 1 X 2 X 3 X 4 Ring A and L 1 Each of them is independently as defined in this article.

[0131] In some embodiments, a compound of formula IH is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein R 1 R 2 R 4 R 6 R 13 X 1 X 2 X 3 X 4 Ring A and L 1 Each of them is independently as defined in this article.

[0132] In some embodiments, a compound of formula IJ is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein R 1 R 2 R 4 R 6 R 13 X 1 X 2 X 3 X 4 Ring A and L 1 Each of them is independently as defined in this article.

[0133] In some embodiments, a compound of formula IK is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein m, R 1 R 2 R 6 R 13 R 14 X 1 X 2 X 3 X 4 Ring A and L 1 Each of them is independently as defined in this article.

[0134] In some implementations, a compound of the formula IL is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein m, R 1 R 2 R6 R 13 R 14 X 1 X 2 X 3 X 4 Ring A and L 1 Each of them is independently as defined in this article.

[0135] In some implementations, a compound of formula IM is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein R 1 R 2 R 6 R 13 R 14 X 1 X 2 X 3 X 4 Ring A and L 1 Each of them is independently as defined in this article.

[0136] In some implementations, a compound of formula IN is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein R 1 R 2 R 6 R 13 R 14 X 1 X 2 X 3 X 4 Ring A and L 1 Each of them is independently as defined in this article.

[0137] In some implementation schemes, R 14 It is C 1-5 Alkyl or C 3-5 Cycloalkyl. In some embodiments, R 14 It is methyl, ethyl, or cyclopropyl.

[0138] In some implementation schemes, R 14 It is C 3-5 Cycloalkyl. In some embodiments, R 14 It is cyclopropyl. In some implementations, R 14 It is cyclobutyl.

[0139] In some implementation schemes, R 14 It is C 1-5 Alkyl group. In some embodiments, R 14 It is methyl or ethyl. In some embodiments, R 14 It is methyl. In some embodiments, R 14 It is an ethyl group.

[0140] In some implementation schemes, R 1 and R 2 Each is C independently 1-9 Alkyl group. In some embodiments, R 1 and R 2 Each is a methyl group. In some embodiments, R 1 and R 2 Each is hydrogen.

[0141] In some implementation schemes, R 1 and R 2 Together with the atoms to which they are attached, they form C 3-10 cycloalkyl, the C 3-10 The cycloalkyl group is optionally surrounded by one to five Z. 1 Replacement. In some implementations, R 1 and R 2 Together with the atoms to which they are attached, they form C 3-6 cycloalkyl, the C 3-6 The cycloalkyl group is optionally surrounded by one to five Z. 1 Replacement. In some implementations, R 1 and R 2 Together with the atoms to which they are attached, they form C 3-4 cycloalkyl, the C 3-4 The cycloalkyl group is optionally surrounded by one to five Z. 1 Substitution. In some embodiments, the cycloalkyl group is unsubstituted. In some embodiments, the cycloalkyl group is replaced by one to five halogroups, hydroxyl groups, C... 1-9 Alkyl, C 1-9 Alkyl group, -CH2-OC 1-9 Alkyl or -NHC(O)OC 1-9 Alkyl substitution.

[0142] In some implementation schemes, R 1 and R 2 Together with the atoms to which they are attached, they form heterocyclic groups, which are optionally surrounded by one to five Zn groups. 1 Replacement. In some implementations, R 1 and R 2 Together with the atoms to which they are attached, they form 4- to 6-membered heterocyclic groups, which are optionally surrounded by one to five Zn groups. 1Substitution. In some embodiments, the heterocyclic group is unsubstituted. In some embodiments, the heterocyclic group is replaced by one to five C atoms. 1-9 Alkyl, -C(O)-C 1-9 Alkyl, -C(O)OC 1-9 Alkyl or -C(O)-CH2-OC 1-9 Alkyl substitution.

[0143] In some implementation schemes, R 1 and R 2 Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 4- to 6-membered heterocyclic groups, wherein each is optionally substituted with one to five halogen groups, hydroxyl groups, C-terminal groups, or other substituted groups. 1-9 Alkyl, C 1-9 Alkyl group, -CH2-OC 1-9 Alkyl, -NHC(O)OC 1-9 Alkyl, -C(O)-C 1-9 Alkyl, -C(O)OC 1-9 Alkyl or -C(O)-CH2-OC 1-9 alkyl.

[0144] In some implementation schemes, R 13 It is hydrogen, halogroup or C 1-9 alkyl.

[0145] In some implementations, m is 0. In some implementations, m is 1.

[0146] In some embodiments, a compound of formula III is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein m, R 4 X 6 R 13 X 1 X 2 X 3 X 4 Each of the elements in ring A is independently as defined herein.

[0147] In some embodiments, a compound of formula III is provided, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein m, R 4 X 6 R 13 X 1 X 2 X 3X 4 And each of the rings in A is independently defined as in this paper. p is 0, 1, or 2; q is 0, 1, or 2; s is 0, 1, 2, or 3; X 5 It does not exist, or it is O or NR. 17 or C(R) 18 )2; R 17 It is hydrogen, C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R 20 -C(O)OR 20 -C(O)NR 20 -S(O)R 20 -S(O)2R 20 -S(O)NR 20 R 21 or -S(O)2NR 20 R 21 ;where R 17 Each C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1a Replace; and Each R 18 Independently hydrogen or Z 1 .

[0148] In some implementations, m is 1, X 4 It is -O-, and R 4 Yes - OR 14 In some implementations, m is 0, X 4 It is -O-, and R 4 Yes - OR 14 In some implementations, p is 1, q is 1, m is 0 or 1, and X is 1. 4 It is -O-, and R 4 Yes - OR 14 .

[0149] In some embodiments, a compound of formula IIIA is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein m, R 4 R 6 R 13 R 17 R 18 X 1 X 2 X 3 X 4 X 5 Each of p, q, s and ring A is independently as defined herein.

[0150] In some embodiments, a compound of formula IIIA is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein m, R 4 R 6 R 13 X 1 X 2 X 3 X 4 And each of the elements in ring A independently as defined in this paper: p is 0, 1, or 2; q is 0, 1, or 2; s is 0, 1, 2, or 3; X 5 It does not exist, or it is O or NR. 17 or C(R) 18 )2; R 17 It is hydrogen, C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R 20 -C(O)OR 20 -C(O)NR 20 -S(O)R 20 -S(O)2R 20 -S(O)NR 20 R 21 or -S(O)2NR 20 R 21 ;where R 17 Each C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1a Replace; and Each R 18 Independently hydrogen or Z 1 .

[0151] In some embodiments, a compound of formula IIIB is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein m, R 4 R 13 R 17 R 18 X 1 X 2 X 3 X 4 X 5 Each of p, q, s and ring A is independently as defined herein.

[0152] In some embodiments, a compound of formula IIIC is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein R 4 R 6 R 13 X 1 X 2 X 3 X 4 And each of the elements in ring A independently as defined in this paper: p is 0, 1, or 2; q is 0, 1, or 2; s is 0, 1, 2, or 3; X 5 It does not exist, or it is O or NR. 17 or C(R) 18 )2; R 17 It is hydrogen, C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R 20 -C(O)OR 20 -C(O)NR 20 -S(O)R 20 -S(O)2R 20-S(O)NR 20 R 21 or -S(O)2NR 20 R 21 ;where R 17 Each C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1a Replace; and Each R 18 Independently hydrogen or Z 1 .

[0153] In some embodiments, a compound of formula IIID is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein m, R 6 R 13 R 14 X 1 X 2 X 3 And each of the elements in ring A independently as defined in this paper: p is 0, 1, or 2; q is 0, 1, or 2; s is 0, 1, 2, or 3; X 5 It does not exist, or it is O or NR. 17 or C(R) 18 )2; R 17 It is hydrogen, C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R 20 -C(O)OR 20 -C(O)NR 20 -S(O)R 20 -S(O)2R 20 -S(O)NR 20 R 21 or -S(O)2NR 20 R 21 ;where R 17 Each C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1a Replace; and Each R 18 Independently hydrogen or Z 1 .

[0154] In some embodiments, a compound of formula IIIE is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein R 6 R 13 R 14 X 1 X 2 X 3 And each of A independently as defined in this paper: p is 0, 1, or 2; q is 0, 1, or 2; s is 0, 1, 2, or 3; X 5 It does not exist, or it is O or NR. 17 or C(R) 18 )2; R 17 It is hydrogen, C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R 20 -C(O)OR 20 -C(O)NR 20 -S(O)R 20 -S(O)2R 20 -S(O)NR 20 R 21 or -S(O)2NR 20 R 21 ;where R 17 Each C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1a Replace; and Each R 18 Independently hydrogen or Z 1 .

[0155] In some embodiments, a compound of formula IIIF is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein R 6 R 13 R 14 X 1 X 2 X 3 And each of the elements in ring A independently as defined in this paper: p is 0, 1, or 2; q is 0, 1, or 2; s is 0, 1, 2, or 3; X 5 It does not exist, or it is O or NR. 17 or C(R) 18 )2; R 17 It is hydrogen, C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R 20 -C(O)OR 20 -C(O)NR 20 -S(O)R 20 -S(O)2R 20 -S(O)NR 20 R 21 or -S(O)2NR 20 R 21 ;where R 17 Each C 1-9 Alkyl, C 2-9 alkenyl, C 2-9 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1a Replace; and Each R 18 Independently hydrogen or Z 1 .

[0156] In some implementation schemes, R 14 It is C 1-5 Alkyl group. In some embodiments, R 14 It is methyl or ethyl. In some embodiments, R 14 It is methyl. In some embodiments, R 14 It is an ethyl group.

[0157] In some implementation schemes, X 5 It does not exist. In some implementations, X5 It is O. In some implementations, X 5 It is NR 17 In some implementations, X 5 It is C(R) 18 )2.

[0158] In some implementations, each R 18 Independently hydrogen or Z 1 In some implementations, each R 18 It is hydrogen. In some implementations, X 5 It is CH2. In some implementations, each R 18 Z is independent 1 In some implementations, each R 18 Independently, it is a halogenated group. In some implementations, each R... 18 It's fluorine.

[0159] In some implementation schemes, R 17 It is hydrogen, C 1-9 Alkyl, -C(O)R 20 or -C(O)OR 20 .

[0160] In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2.

[0161] In some implementations, q is 0. In some implementations, q is 1. In some implementations, q is 2.

[0162] In some implementations, s is 0. In some implementations, s is 1. In some implementations, s is 2. In some implementations, s is 3.

[0163] In some embodiments, a compound of formula IIIG is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein R 4 R 13 X 1 X 2 X 3 X 5 X 6 Each of A is independently as defined in this paper.

[0164] In some implementation schemes, X 6 It is CR 6 In some implementation schemes, X 6It is N, and in some implementations, X 5 It is O. In some implementations, A is ring A.

[0165] In some embodiments, a compound of formula IIIH is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein R 4 R 6 R 13 X 1 X 2 X 3 Each of A is independently as defined in this paper.

[0166] In some implementation schemes, R 13 It is hydrogen. In some implementations, A is C. 1-6 Alkyl group. In some embodiments, A is C. 3-4 Alkyl group. In some embodiments, A is C. 3-10 Cycloalkyl or heterocyclic groups. In some embodiments, R 4 Yes - OR 14 .

[0167] In some embodiments, a compound of formula IIIJ is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein R 4 R 13 X 1 X 2 X 3 Each of A is independently as defined in this paper.

[0168] In some implementation schemes, R 13 It is hydrogen. In some implementations, A is C. 1-6 Alkyl group. In some embodiments, A is C. 3-4 Alkyl group. In some embodiments, A is C. 3-10 Cycloalkyl or heterocyclic groups. In some embodiments, R 4 Yes - OR 14 .

[0169] In some embodiments, a compound of formula IIIK is provided: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein R 4 R 6 R 13 X 1 X 2 X 3 Each of the elements in ring A is independently as defined herein.

[0170] In some implementation schemes, R 13 It is hydrogen. In some implementations, ring A is C. 3-10 Cycloalkyl or heterocyclic groups. In some embodiments, R 4 Yes - OR 14 .

[0171] In some embodiments, a compound selected from Table 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof is provided: Table 1

[0172] The compounds of Formula I provided herein cover stereochemical forms of the compounds, such as optical isomers (e.g., enantiomers, diastereomers, and mixtures thereof, e.g., mixtures of enantiomers and / or diastereomers, including racemic mixtures, and homogeneous or heterogeneous mixtures of individual enantiomers and / or diastereomers). All stereochemical forms are considered in this disclosure. Unless otherwise indicated, when a disclosed compound is named or described structurally without specifying a stereochemistry and has one or more chiral centers, it should be understood to represent all possible stereoisomers of the compound. Representative stereochemical forms are provided throughout the specification, including but not limited to those described in Table 2. In some embodiments, a compound selected from Table 2 is provided, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof: Table 2

[0173] Compounds of Formula I include their pharmaceutically acceptable salts. Additionally, compounds of Formula I include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts and can be used as intermediates for the preparation and / or purification of compounds of Formula I and / or the isolation of enantiomers of compounds of Formula I. Non-limiting examples of pharmaceutically acceptable salts of compounds of Formula I include trifluoroacetate salts.

[0174] It should be further understood that compounds of Formula I or their salts can be isolated as solvates, and accordingly, any such solvates are included within the scope of this disclosure. For example, compounds of Formula I and their salts can exist in non-solventized forms as well as in solvated forms formed with pharmaceutically acceptable solvents such as water, ethanol, etc. Treatment methods and uses

[0175] The methods described herein can be applied to cell populations either in vivo or in vitro. "In vivo" means within a living individual, such as an animal or human. In this context, the methods described herein can be used therapeutically in an individual. "In vitro" means outside a living individual. Examples of in vitro cell populations include in vitro cell cultures and biological samples (including fluid or tissue samples obtained from an individual). Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used in vitro to determine the optimal timing and / or dosage of the compounds of this disclosure for a given indication, cell type, individual, and other parameters. Information gathered from such uses can be used for experimental purposes or in clinical settings to establish in vivo treatment regimens. Other in vitro uses of the compounds and compositions described herein are described below or will become apparent to those skilled in the art. Selected compounds can be further characterized to examine safety or tolerable doses in human or non-human subjects. Such properties can be examined using methods well known to those skilled in the art.

[0176] The compounds described herein, or their pharmaceutically acceptable salts or solvates, or pharmaceutical compositions thereof, may be used as inhibitors of one or more LPA receptors. As further described herein, compounds that antagonize LPA receptors may be used to prevent and / or treat diseases such as those including various classes of diseases such as fibrosis (e.g., renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis, systemic sclerosis), urinary system diseases, cancer-related diseases, proliferative diseases, inflammatory / immune system diseases, diseases caused by secretory dysfunction, brain-related diseases, and chronic diseases.

[0177] In some embodiments, this disclosure provides methods for treating a subject (e.g., a person) suffering from a disease, disorder, or condition in which inhibition of one or more LPA receptors (i.e., LPA-related diseases) is beneficial for treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, the methods provided herein may include or further include treating one or more conditions, comorbidities, or sequelae associated with any of the conditions provided herein.

[0178] This document provides a method for treating LPA-related diseases, the method comprising administering to a subject in need an effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof) or a pharmaceutical composition as disclosed herein.

[0179] In some implementations, LPA-related diseases include, but are not limited to, fibrosis of the treatment organ (e.g., liver, kidney, lung, heart, and skin), liver diseases (acute hepatitis, chronic hepatitis, liver fibrosis, cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), impaired liver function, hepatic blood flow disorders, etc.), proliferative diseases (e.g., cancers, including solid tumors, metastatic solid tumors, angiofibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia and chronic lymphocytic leukemia (CLL) and invasive metastases of cancer cells), inflammatory diseases (e.g., psoriasis, kidney disease, and pneumonia), gastrointestinal diseases (e.g., irritable bowel syndrome (TBS), inflammatory bowel disease (IBD), and pancreatic secretion disorders), kidney diseases, urinary tract-related diseases (e.g., symptoms associated with benign prostatic hyperplasia or neurogenic bladder), spinal cord tumors, and lumbar disc herniation. Disorders, spinal stenosis, symptoms originating from diabetes, lower urinary tract diseases (e.g., lower urinary tract obstruction), inflammatory diseases of the lower urinary tract, dysuna and urinary frequency), pancreatic diseases, diseases related to abnormal angiogenesis (e.g., arterial embolism), scleroderma, brain-related diseases (e.g., cerebral infarction and cerebral hemorrhage), neuropathic pain, peripheral neuropathy, and eye diseases (e.g., age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, and glaucoma filtration surgery scarring).

[0180] In some embodiments, this document provides methods for treating or preventing fibrosis, the methods comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or a pharmaceutical composition as disclosed herein. For example, the methods may include treating renal fibrosis, pulmonary fibrosis, liver fibrosis, arterial fibrosis, or systemic sclerosis. In some embodiments, this document provides methods for treating pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis (IPF)), the methods comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or a pharmaceutical composition as provided herein.

[0181] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions as provided herein are used to treat or prevent fibrosis in a subject. For example, the compositions disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions as provided herein may be used to treat fibrosis of organs or tissues in a subject. In some embodiments, a method for preventing fibrotic conditions in a subject is provided herein, the method comprising administering a therapeutically effective amount of the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions as 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 fibrosis of organs or tissues. 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 susceptibility to developing organ or tissue fibrosis. In some embodiments, the subject is administered a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof) or a pharmaceutical composition as provided herein to prevent or minimize scarring following injury. For example, the injury may include surgery.

[0182] Examples of diseases, disorders, or conditions involving fibrosis include, but are not limited to: fibrosis-associated lung diseases (e.g., idiopathic pulmonary fibrosis); iatrogenic drug-induced or occupational / environment-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 accumulation disorders). Pulmonary fibrosis secondary to systemic inflammatory diseases (such as rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrotic alveolitis, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, bleomycin-induced pulmonary fibrosis, chronic asthma, silicosis, asbestos-induced pulmonary or pleural fibrosis, acute lung injury, acute respiratory distress syndrome (ARDS), and acute respiratory distress (including bacterial pneumonia-induced, trauma-induced, viral pneumonia-induced, ventilator-induced, non-pulmonary sepsis-induced, and aspiration-induced)).Chronic kidney disease associated with injury / fibrosis, renal fibrosis (kidney fibrosis, renal fibrosis), secondary to systemic inflammatory diseases (such as lupus and scleroderma), tubulointerstitial fibrosis, glomerulonephritis, glomerulosclerosis, focal segmental glomerulosclerosis, diabetes mellitus, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allogeneic transplantation, and Allport syndrome. Glomerulonephritis (a type of glomerulonephritis); dermatological disorders, intestinal fibrosis (e.g., scleroderma and radiation-induced intestinal fibrosis); liver fibrosis, such as cirrhosis, alcohol-induced liver fibrosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), toxic / drug-induced liver fibrosis (e.g., hemochromatosis), bile duct injury, primary biliary cirrhosis, infection or virus-induced fibrosis (e.g., chronic HCV infection), inflammatory / immune disorders and autoimmune hepatitis; head and neck fibrosis, such as corneal scarring (e.g., LASIK, laser-assisted in situ keratomileusis), corneal transplantation and trabeculectomy); proliferative scarring, Duputren's disease, cutaneous fibrosis, cutaneous scleroderma. Sceroderma, keloids (e.g., burn-induced or postoperative); and other fibrotic diseases such as sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, restenosis, atherosclerosis, arteriosclerosis, Wechsler granulomatosis, chronic lymphocytic leukemia, tumor metastasis, organ transplant rejection (e.g., bronchiolitis obliterans), endometriosis, neonatal respiratory distress syndrome, and neuropathic pain, fibromyalgia, mixed connective tissue disease, and Peyronie's disease.

[0183] This document provides a method for improving lung function in a subject, the method comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or a pharmaceutical composition as 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 pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or a pharmaceutical composition as provided herein is used to treat a subject with idiopathic pulmonary fibrosis. In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or a pharmaceutical composition as provided herein is used to treat a subject with interstitial pneumonia vulgaris.

[0184] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates thereof) or pharmaceutical compositions as provided herein are used to treat a subject with diffuse interstitial lung disease, such as iatrogenic drug-induced, occupational / environment-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., H.P. syndrome, tuberous sclerosis, neurofibromatosis, metabolic accumulation disorders, and familial interstitial lung disease).

[0185] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates thereof) or pharmaceutical compositions as provided herein may be used to treat post-transplant fibrosis associated with chronic rejection in a subject, such as bronchiolitis obliterans after lung transplantation.

[0186] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates thereof) or pharmaceutical compositions as provided herein may be used to treat skin fibrosis in subjects, such as scleroderma, palmofascitis contracture, and keloids.

[0187] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions as provided herein may be used to treat a subject with or without liver fibrosis. Examples include 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.

[0188] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates thereof) or pharmaceutical compositions as provided herein may be used to treat a subject with renal fibrosis (e.g., tubulointerstitial fibrosis and glomerular sclerosis).

[0189] Further examples of diseases, disorders, or conditions provided in this article include atherosclerosis, thrombosis, heart disease, vasculitis, scar tissue formation, restenosis, phlebitis, COPD (chronic obstructive pulmonary disease), pulmonary hypertension, pulmonary fibrosis, lung inflammation, intestinal adhesions, bladder fibrosis and cystitis, nasal fibrosis, sinusitis, neutrophil-mediated inflammation, and fibroblast-mediated fibrosis.

[0190] In some embodiments, a compound disclosed herein (e.g., a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or a pharmaceutical composition as provided herein, combined with one or more other agents for treating fibrosis, is administered to a subject who has organ or tissue fibrosis or is prone to developing organ or tissue fibrosis. In some embodiments, said one or more agents include corticosteroids, immunosuppressants, B-cell antagonists, and uterine globin.

[0191] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions as provided herein are used to treat a subject with a dermatological disorder. Such dermatological disorders include, but are not limited to, proliferative or inflammatory disorders of the skin, such as atopic dermatitis, bullous disorders, collagen lesions, psoriasis, scleroderma, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea, wound healing disorders, scars, hypertrophic scars, keloids, Kawasaki disease, rosacea, Sjogren-Larsso syndrome, or urticaria. In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates thereof) are used to treat systemic sclerosis.

[0192] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) may be used to treat or prevent inflammation in a subject. For example, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) may be used to treat or prevent inflammatory or immune disorders in a subject.

[0193] Examples of inflammatory / immune disorders include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, eczema, allogeneic or xenograft (organ, bone marrow, stem cells, and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory diseases, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjögren's syndrome, thyroiditis (e.g., Hashimoto's thyroiditis and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, and atopic dermatitis.

[0194] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions as provided herein are used to treat pain in a subject. In some embodiments, the pain is acute or chronic. In some embodiments, the pain is neuropathic pain.

[0195] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions as provided herein are used to treat fibromyalgia. Fibromyalgia is believed to originate from the formation of fibrous scar tissue in contractile muscles (voluntary muscles). Fibromyalgia constricts tissue and inhibits blood flow, thereby causing pain.

[0196] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions as provided herein are used to treat cancer. In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions as provided herein are used to treat malignant and benign proliferative diseases. In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates thereof) or pharmaceutical compositions as provided herein are used to prevent or alleviate tumor cell proliferation, cancer invasion and metastasis, pleural mesothelioma (Yamada, Cancer Sci., 2008, 99(8), 1603-1610) or peritoneal mesothelioma, cancer pain, bone metastases (Boucharaba et al., J Clin. Invest., 2004, 114(12), 1714-1725; Boucharaba et al., Proc. Natl. Acad. Sci., 2006, 103(25) 9643-9648). This document provides a method for treating a subject with cancer, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof) or a pharmaceutical composition as provided herein. In some embodiments, the method provided herein further comprises administering a second therapeutic agent, wherein the second therapeutic agent is an anticancer agent.

[0197] As used in this article, the term "cancer" refers to the abnormal growth of cells that tend to proliferate in an uncontrolled manner and, in some cases, metastasize (spread). Types of cancer include, but are not limited to, solid tumors (such as those of the bladder, intestines, brain, breast, endometrium, heart, kidneys, lungs, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (thyroid), prostate, skin (melanoma or basal cell carcinoma)) or hematologic malignancies (such as leukemia) at any stage of disease, with or without metastasis.

[0198] Other non-limiting examples of cancer include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendiceal cancer, astrocytoma, atypical teratoma / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brainstem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumor, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric / stomach cancer, and gastrointestinal carcinoid tumors. Tumors, gastrointestinal stromal tumors (GIST), gastrointestinal stromal cell tumors, germ cell tumors, gliomas, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi's sarcoma, renal cell carcinoma, Langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphoblastic leukemia,Acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medullary epithelioma, melanoma, mesothelioma, mouth cancer, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, ovarian low malignant potential tumor. Tumors, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, moderately differentiated pineal parenchymal tumor, pineal blastoma and supratentorial primitive neuroectodermal tumor, pituitary adenoma, plasma cell tumor / multiple myeloma, pleural pulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing's sarcoma family tumors, sarcoma, Kaposi's sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach / gastric cancer, supratentorial primitive neuroectodermal tumor, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia and nephroblastoma.

[0199] In some embodiments, this document provides a method for treating an allergic disorder in a subject, the method comprising administering a therapeutically effective amount of a compound disclosed herein as provided herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof). In some embodiments, the compounds disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof) may be used to treat a respiratory disease, disorder, or condition in a subject. For example, the compounds disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof) may treat asthma (e.g., chronic asthma) in a subject.

[0200] As used herein, the term "respiratory disease" refers to a disease affecting organs involved in breathing, such as the nose, pharynx, larynx, Eustachian tubes, trachea, bronchi, lungs, related muscles (e.g., diaphragm and intercostal spaces), and nerves. Non-limiting examples of respiratory diseases include asthma, adult-onset respiratory distress syndrome and allergic (exogenous) 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).

[0201] As used herein, the term "asthma" refers to any lung disorder characterized by changes in lung airflow associated with airway narrowing of any cause (intrinsic, extrinsic, or both; allergic or non-allergic). The term asthma may be used with one or more adjectives to indicate the cause.

[0202] This document further provides a method for treating or preventing chronic obstructive pulmonary disease (COPD) in a subject, the method comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof). Examples of COPD include, but are not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or airway inflammation, and cystic fibrosis.

[0203] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) may be used to treat or prevent neurological disorders in a subject. As used herein, the term “neurological disorder” refers to a condition that alters the structure or function of the brain, spinal cord, or peripheral nervous system, including but not limited to Alzheimer’s disease, cerebral edema, cerebral ischemia, stroke, multiple sclerosis, neuropathy, Parkinson’s disease, conditions found after blunt trauma or surgical injury (including postoperative cognitive impairment and spinal cord or brainstem injury); and neurological disorders (such as degenerative disc disease and sciatica).

[0204] In some implementations, this document provides a method for treating or preventing CNS disorders in a subject. Non-limiting examples of CNS disorders include multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, postoperative cognitive impairment, migraine, peripheral neuropathy / neuralgia, spinal cord injury, cerebral edema, and head injury.

[0205] This article also provides methods for treating or preventing cardiovascular disease in subjects. As used herein, “cardiovascular disease” means a disease affecting the heart or blood vessels or both, including but not limited to: arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina pectoris; cardiac rhythm disturbance; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis; stroke; peripheral obstructive arterial disease of limbs, organs or tissues; ischemia-reperfusion injury to the brain, heart or other organs or tissues; endotoxic shock, surgical shock or traumatic shock; hypertension, valvular heart disease, heart failure, blood pressure abnormalities; shock; vasoconstriction (including vasoconstriction associated with migraine); vascular abnormalities, inflammation, dysfunction limited to a single organ or tissue. For example, this article provides methods for treating or preventing vasoconstriction, atherosclerosis and its sequelae, myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis and stroke, said methods comprising administering a therapeutically effective amount of the compound disclosed herein (e.g., a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof).

[0206] In some embodiments, this document provides a method for mitigating cardiac reperfusion injury following myocardial ischemia and / or endotoxin shock, the method comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof).

[0207] This document further provides methods for reducing vasoconstriction in a subject, the methods comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof). For example, this document provides methods for lowering blood pressure in a subject or preventing an increase in blood pressure in a subject, the methods comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof).

[0208] The ability of a test compound to act as an LGA receptor inhibitor can be demonstrated using assays known in the art. The activity of the compounds and compositions provided herein as LGA receptor inhibitors can be determined in vitro, in vivo, or in cell lines.

[0209] For example, Chinese hamster ovary cells overexpressing human LPA1 can be plated overnight in DMEM / F12 medium in microplates (15,000 cells / well). After overnight culture, the cells are loaded with calcium indicator dye and incubated at 37°C for 30 minutes. The cells are then equilibrated to room temperature for 30 minutes before assay. The test compound dissolved in DMSO is transferred to a porous unbound surface plate and diluted to a final concentration of 0.5% DMSO with assay buffer (e.g., IX HBSS with calcium / magnesium, 20 mM HEPES, and 0.1% fatty acid-free BSA). The diluted compound is added to the cells at a final concentration ranging from 0.08 nM to 5 mM, and then incubated at room temperature for 20 minutes, at which point LPA is added at a final concentration of 10 nM to stimulate the cells. The IC50 of the compound is then measured. 50 The IC value is defined as the concentration of the test compound that inhibits calcium flux induced by LPA alone by 50%. The IC value can be determined by fitting the data to a 4-parameter logistic equation. 50 value.

[0210] In another example, prior to LPA stimulation, CD-1 female mice were orally administered a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof) for 2 hours. The mice were then administered LPA (2 pg / pL) in 0.15 mL of 0.1% BSA / PBS via the tail vein (IV). Mice were euthanized by decapitation exactly 2 minutes after LPA stimulation, and trunk blood was collected. These samples were centrifuged collectively, and individual 75 pL samples were frozen at -20°C until histamine determination. Plasma histamine analysis could be performed using a standard EIA (enzyme immunoassay) method. Plasma samples were thawed and diluted 1:30 in 0.1% BSA in PBS. The EIA protocol for histamine analysis as described above could be used for this assay.

[0211] LPA acts as a biological effector molecule and has a wide range of physiological effects (including effects on blood pressure, platelet activation, and smooth muscle contraction), as well as various cellular effects, including cell growth, cell rounding, neurite fold retraction, actin stress fiber formation, and cell migration. These effects are primarily receptor-mediated.

[0212] LPA activation of LPA receptors (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) mediates a series of downstream signaling cascades. Non-limiting examples include mitogen-activated protein kinase (MAPK) activation, adenylate cyclase (AC) inhibition / activation, phospholipase C (PLC) activation / Ca2+ mobilization, arachidonic acid release, Akt / PKB activation, and activation of small GTPases, Rho, ROCK, Rae, and Ras. Other pathways affected by LPA receptor activation include, for example, cyclic adenosine monophosphate (cAMP), cell cycle 42 / GTP-binding protein (Cdc42), proto-oncogene serine / threonine protein kinase Raf (c-RAF), proto-oncogene tyrosine protein kinase Src (c-src), extracellular signal-regulated kinase (ERK), focal adhesion kinase (FAK), guanine nucleotide exchange factor (GEF), glycogen synthase kinase 3b (GSK3b), c-jun N-terminal kinase (JNK), MEK, myosin light chain II (MLCII), nuclear factor kappa B (NF-kB), N-methyl-D-aspartate (NMDA) receptor activation, phosphatidylinositol 3-kinase (PBK), protein kinase A (PKA), protein kinase C (PKC), and ms-associated C3 botulinum toxin substrate 1 (RAC1). Several LPA receptor subtypes are co-expressed in the cells, tissues, and organs of almost all mammals, indicating that LPA receptors conduct signal transduction in a cooperative manner. LPA1, LPA2, and LPA3 share high amino acid sequence similarity.

[0213] LPA1 (formerly known as VZG-l / EDG-2 / mrecl.3) and three classes of G proteins (G i / o G q and G 12 / 13 ( ) Coupling. By activating these G proteins, LPA induces a series of cellular responses via LPA1, including, for example, cell proliferation, activation of serum response elements (SRE), activation of mitogen-activated protein kinase (MAPK), inhibition of adenylate cyclase (AC), activation of phospholipase C (PLC), and Ca2+. 2+ Mobilization, Akt activation, and Rho activation.

[0214] LPA1 expression was observed in the testes, brain, heart, lungs, small intestine, stomach, spleen, thymus, and skeletal muscle of mice. Similarly, LPA1 was expressed in human tissues such as the brain, heart, lungs, placenta, colon, small intestine, prostate, testes, ovaries, pancreas, spleen, kidneys, skeletal muscle, and thymus.

[0215] LPA2 (EDG-4) also interacts with three classes of G proteins (G... i / o G q and G 12 / 13LPA2 is coupled to mediate LPA-induced cell signaling. Expression of LPA2 has been observed in the testes, kidneys, lungs, thymus, spleen, and stomach of adult mice, as well as in the testes, pancreas, prostate, thymus, spleen, and peripheral blood leukocytes of humans. LPA2 expression is upregulated in various cancer cell lines, and several human LPA2 transcriptomorphs with mutations in the 3'-untranslated region have been observed.

[0216] LPA3 can mediate pleiotropic LPA-induced signal transduction, including PLC activation and Ca2+ activation. 2+ Mobilization, AC inhibition / activation, and MAPK activation. Overexpression of LPA3 in neuroblastoma cells leads to neurite elongation. LPA3 expression has been observed in the testes, kidneys, lungs, small intestine, heart, thymus, and brain of adult mice. In humans, it has been found in the heart, pancreas, prostate, testes, lungs, ovaries, and brain (cortical frontal lobe, hippocampus, and amygdala).

[0217] Compared to LPA1, LPA2, and LPA3, LPA4 (p2y9 / GPR23) has a different sequence and is more similar to the platelet-activating factor (PAF) receptor. LPA4 mediates LPA-induced Ca2+. 2+ It mobilizes and accumulates cAMP, and is functionally coupled with G proteins Gs to activate AC, as well as coupled with other G proteins. The LPA4 gene is expressed in the ovary, pancreas, thymus, kidney, and skeletal muscle.

[0218] LPA5 (GPR92) is a member of the purinocluster of GPCRs and is structurally most closely related to LPA4. LPA5 is expressed in the human heart, placenta, spleen, brain, lungs, and intestines. LPA also shows very high expression in the CD8+ lymphocyte compartments of the gastrointestinal tract.

[0219] LPA6 (p2y5) is a member of the purinocluster of GPCRs and is structurally most closely related to LPA4. LPA6 is an LPA receptor coupled to the Gl2 / 13-Rho signaling pathway and is expressed in the inner root sheath of human hair follicles.

[0220] Any improvements to the above-mentioned reaction criteria are specifically provided by the methods described in this disclosure. Combination therapy

[0221] The compounds described herein, or their pharmaceutically acceptable salts or solvates, or pharmaceutical compositions thereof, may be used as inhibitors of one or more LPA receptors. As further described herein, compounds that antagonize LPA receptors may be used to prevent and / or treat diseases such as those including various classes of diseases such as fibrosis (e.g., renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis, systemic sclerosis), urinary system diseases, cancer-related diseases, proliferative diseases, inflammatory / immune system diseases, diseases caused by secretory dysfunction, brain-related diseases, and chronic diseases.

[0222] In some embodiments, this disclosure provides methods for treating a subject (e.g., a person) suffering from a disease, disorder, or condition in which inhibition of one or more LPA receptors (i.e., LPA-related diseases) is beneficial for treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, the methods provided herein may include or further include treating one or more conditions, comorbidities, or sequelae associated with any of the conditions provided herein.

[0223] This document provides a method for treating LPA-related diseases, the method comprising administering to a subject in need an effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof) or a pharmaceutical composition as disclosed herein.

[0224] In some implementations, LPA-related diseases include, but are not limited to, fibrosis of the treatment organ (e.g., liver, kidney, lung, heart, and skin), liver diseases (acute hepatitis, chronic hepatitis, liver fibrosis, cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), impaired liver function, hepatic blood flow disorders, etc.), proliferative diseases (e.g., cancers, including solid tumors, metastatic solid tumors, angiofibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia and chronic lymphocytic leukemia (CLL) and invasive metastases of cancer cells), inflammatory diseases (e.g., psoriasis, kidney disease, and pneumonia), gastrointestinal diseases (e.g., irritable bowel syndrome (TBS), inflammatory bowel disease (IBD), and pancreatic secretion disorders), kidney diseases, urinary tract-related diseases (e.g., symptoms associated with benign prostatic hyperplasia or neurogenic bladder), spinal cord tumors, and lumbar disc herniation. Disorders, spinal stenosis, symptoms originating from diabetes, lower urinary tract diseases (e.g., lower urinary tract obstruction), inflammatory diseases of the lower urinary tract, dysuna and urinary frequency), pancreatic diseases, diseases related to abnormal angiogenesis (e.g., arterial embolism), scleroderma, brain-related diseases (e.g., cerebral infarction and cerebral hemorrhage), neuropathic pain, peripheral neuropathy, and eye diseases (e.g., age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, and glaucoma filtration surgery scarring).

[0225] In some embodiments, this document provides methods for treating or preventing fibrosis, the methods comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or a pharmaceutical composition as disclosed herein. For example, the methods may include treating renal fibrosis, pulmonary fibrosis, liver fibrosis, arterial fibrosis, or systemic sclerosis. In some embodiments, this document provides methods for treating pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis (IPF)), the methods comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or a pharmaceutical composition as provided herein.

[0226] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions as provided herein are used to treat or prevent fibrosis in a subject. For example, the compositions disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions as provided herein may be used to treat fibrosis of organs or tissues in a subject. In some embodiments, a method for preventing fibrotic conditions in a subject is provided herein, the method comprising administering a therapeutically effective amount of the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions as 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 fibrosis of organs or tissues. 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 susceptibility to developing organ or tissue fibrosis. In some embodiments, the subject is administered a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof) or a pharmaceutical composition as provided herein to prevent or minimize scarring following injury. For example, the injury may include surgery.

[0227] Examples of diseases, disorders, or conditions involving fibrosis include, but are not limited to: fibrosis-associated lung diseases (e.g., idiopathic pulmonary fibrosis); iatrogenic drug-induced or occupational / environment-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 accumulation disorders). Pulmonary fibrosis secondary to systemic inflammatory diseases (such as rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrotic alveolitis, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, bleomycin-induced pulmonary fibrosis, chronic asthma, silicosis, asbestos-induced pulmonary or pleural fibrosis, acute lung injury, acute respiratory distress syndrome (ARDS), and acute respiratory distress (including bacterial pneumonia-induced, trauma-induced, viral pneumonia-induced, ventilator-induced, non-pulmonary sepsis-induced, and aspiration-induced)).Chronic kidney disease associated with injury / fibrosis, renal fibrosis (kidney fibrosis, renal fibrosis), secondary to systemic inflammatory diseases (such as lupus and scleroderma), tubulointerstitial fibrosis, glomerulonephritis, glomerulosclerosis, focal segmental glomerulosclerosis, diabetes mellitus, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allogeneic transplantation, and Allport syndrome. Glomerulonephritis (a type of glomerulonephritis); dermatological disorders, intestinal fibrosis (e.g., scleroderma and radiation-induced intestinal fibrosis); liver fibrosis, such as cirrhosis, alcohol-induced liver fibrosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), toxic / drug-induced liver fibrosis (e.g., hemochromatosis), bile duct injury, primary biliary cirrhosis, infection or virus-induced fibrosis (e.g., chronic HCV infection), inflammatory / immune disorders and autoimmune hepatitis; head and neck fibrosis, such as corneal scarring (e.g., LASIK, laser-assisted in situ keratomileusis), corneal transplantation and trabeculectomy); proliferative scarring, Duputren's disease, cutaneous fibrosis, cutaneous scleroderma. Sceroderma, keloids (e.g., burn-induced or postoperative); and other fibrotic diseases such as sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, restenosis, atherosclerosis, arteriosclerosis, Wechsler granulomatosis, chronic lymphocytic leukemia, tumor metastasis, organ transplant rejection (e.g., bronchiolitis obliterans), endometriosis, neonatal respiratory distress syndrome, and neuropathic pain, fibromyalgia, mixed connective tissue disease, and Peyronie's disease.

[0228] This document provides a method for improving lung function in a subject, the method comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or a pharmaceutical composition as 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 pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or a pharmaceutical composition as provided herein is used to treat a subject with idiopathic pulmonary fibrosis. In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or a pharmaceutical composition as provided herein is used to treat a subject with interstitial pneumonia vulgaris.

[0229] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates thereof) or pharmaceutical compositions as provided herein are used to treat a subject with diffuse interstitial lung disease, such as iatrogenic drug-induced, occupational / environment-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., H.P. syndrome, tuberous sclerosis, neurofibromatosis, metabolic accumulation disorders, and familial interstitial lung disease).

[0230] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates thereof) or pharmaceutical compositions as provided herein may be used to treat post-transplant fibrosis associated with chronic rejection in a subject, such as bronchiolitis obliterans after lung transplantation.

[0231] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates thereof) or pharmaceutical compositions as provided herein may be used to treat skin fibrosis in subjects, such as scleroderma, palmofascitis contracture, and keloids.

[0232] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions as provided herein may be used to treat a subject with or without liver fibrosis. Examples include 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.

[0233] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates thereof) or pharmaceutical compositions as provided herein may be used to treat a subject with renal fibrosis (e.g., tubulointerstitial fibrosis and glomerular sclerosis).

[0234] Further examples of diseases, disorders, or conditions provided in this article include atherosclerosis, thrombosis, heart disease, vasculitis, scar tissue formation, restenosis, phlebitis, COPD (chronic obstructive pulmonary disease), pulmonary hypertension, pulmonary fibrosis, lung inflammation, intestinal adhesions, bladder fibrosis and cystitis, nasal fibrosis, sinusitis, neutrophil-mediated inflammation, and fibroblast-mediated fibrosis.

[0235] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates thereof) or pharmaceutical compositions as provided herein may be used to treat one or more symptoms of COVID-19.

[0236] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates thereof) or pharmaceutical compositions as provided herein may be used to treat chronic obstructive pulmonary disease (COPD).

[0237] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates thereof) or pharmaceutical compositions as provided herein may be used to treat neuroinflammatory diseases.

[0238] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates thereof) or pharmaceutical compositions as provided herein may be used to treat multiple sclerosis.

[0239] In some embodiments, a compound disclosed herein (e.g., a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or a pharmaceutical composition as provided herein, combined with one or more other agents for treating fibrosis, is administered to a subject who has organ or tissue fibrosis or is prone to developing organ or tissue fibrosis. In some embodiments, said one or more agents include corticosteroids, immunosuppressants, B-cell antagonists, and uterine globin.

[0240] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions as provided herein are used to treat a subject with a dermatological disorder. Such dermatological disorders include, but are not limited to, proliferative or inflammatory disorders of the skin, such as atopic dermatitis, bullous disorders, collagen lesions, psoriasis, scleroderma, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea, wound healing disorders, scars, hypertrophic scars, keloids, Kawasaki disease, rosacea, Sjogren-Larsso syndrome, or urticaria. In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates thereof) are used to treat systemic sclerosis.

[0241] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) may be used to treat or prevent inflammation in a subject. For example, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) may be used to treat or prevent inflammatory or immune disorders in a subject.

[0242] Examples of inflammatory / immune disorders include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, eczema, allogeneic or xenograft (organ, bone marrow, stem cells, and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory diseases, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjögren's syndrome, thyroiditis (e.g., Hashimoto's thyroiditis and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, and atopic dermatitis.

[0243] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions as provided herein are used to treat pain in a subject. In some embodiments, the pain is acute or chronic. In some embodiments, the pain is neuropathic pain.

[0244] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions as provided herein are used to treat fibromyalgia. Fibromyalgia is believed to originate from the formation of fibrous scar tissue in contractile muscles (voluntary muscles). Fibromyalgia constricts tissue and inhibits blood flow, thereby causing pain.

[0245] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions as provided herein are used to treat cancer. In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions as provided herein are used to treat malignant and benign proliferative diseases. In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates thereof) or pharmaceutical compositions as provided herein are used to prevent or alleviate tumor cell proliferation, cancer invasion and metastasis, pleural mesothelioma (Yamada, Cancer Sci., 2008, 99(8), 1603-1610) or peritoneal mesothelioma, cancer pain, bone metastases (Boucharaba et al., J Clin. Invest., 2004, 114(12), 1714-1725; Boucharaba et al., Proc. Natl. Acad. Sci., 2006, 103(25) 9643-9648). This document provides a method for treating a subject with cancer, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof) or a pharmaceutical composition as provided herein. In some embodiments, the method provided herein further comprises administering a second therapeutic agent, wherein the second therapeutic agent is an anticancer agent.

[0246] As used in this article, the term "cancer" refers to the abnormal growth of cells that tend to proliferate in an uncontrolled manner and, in some cases, metastasize (spread). Types of cancer include, but are not limited to, solid tumors (such as those of the bladder, intestines, brain, breast, endometrium, heart, kidneys, lungs, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (thyroid), prostate, skin (melanoma or basal cell carcinoma)) or hematologic malignancies (such as leukemia) at any stage of disease, with or without metastasis.

[0247] Other non-limiting examples of cancer include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendiceal cancer, astrocytoma, atypical teratoma / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brainstem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumor, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric / stomach cancer, and gastrointestinal carcinoid tumors. Tumors, gastrointestinal stromal tumors (GIST), gastrointestinal stromal cell tumors, germ cell tumors, gliomas, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi's sarcoma, renal cell carcinoma, Langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphoblastic leukemia,Acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medullary epithelioma, melanoma, mesothelioma, mouth cancer, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, ovarian low malignant potential tumor. Tumors, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, moderately differentiated pineal parenchymal tumor, pineal blastoma and supratentorial primitive neuroectodermal tumor, pituitary adenoma, plasma cell tumor / multiple myeloma, pleural pulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing's sarcoma family tumors, sarcoma, Kaposi's sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach / gastric cancer, supratentorial primitive neuroectodermal tumor, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia and nephroblastoma.

[0248] In some embodiments, this document provides a method for treating an allergic disorder in a subject, the method comprising administering a therapeutically effective amount of a compound disclosed herein as provided herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof). In some embodiments, the compounds disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof) may be used to treat a respiratory disease, disorder, or condition in a subject. For example, the compounds disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof) may treat asthma (e.g., chronic asthma) in a subject.

[0249] As used herein, the term "respiratory disease" refers to a disease affecting organs involved in breathing, such as the nose, pharynx, larynx, Eustachian tubes, trachea, bronchi, lungs, related muscles (e.g., diaphragm and intercostal spaces), and nerves. Non-limiting examples of respiratory diseases include asthma, adult-onset respiratory distress syndrome and allergic (exogenous) 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).

[0250] As used herein, the term "asthma" refers to any lung disorder characterized by changes in lung airflow associated with airway narrowing of any cause (intrinsic, extrinsic, or both; allergic or non-allergic). The term asthma may be used with one or more adjectives to indicate the cause.

[0251] This document further provides a method for treating or preventing chronic obstructive pulmonary disease (COPD) in a subject, the method comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof). Examples of COPD include, but are not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or airway inflammation, and cystic fibrosis.

[0252] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) may be used to treat or prevent neurological disorders in a subject. As used herein, the term “neurological disorder” refers to a condition that alters the structure or function of the brain, spinal cord, or peripheral nervous system, including but not limited to Alzheimer’s disease, cerebral edema, cerebral ischemia, stroke, multiple sclerosis, neuropathy, Parkinson’s disease, conditions found after blunt trauma or surgical injury (including postoperative cognitive impairment and spinal cord or brainstem injury); and neurological disorders (such as degenerative disc disease and sciatica).

[0253] In some implementations, this document provides a method for treating or preventing CNS disorders in a subject. Non-limiting examples of CNS disorders include multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, postoperative cognitive impairment, migraine, peripheral neuropathy / neuralgia, spinal cord injury, cerebral edema, and head injury.

[0254] This article also provides methods for treating or preventing cardiovascular disease in subjects. As used herein, “cardiovascular disease” means a disease affecting the heart or blood vessels or both, including but not limited to: arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina pectoris; cardiac rhythm disturbance; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis; stroke; peripheral obstructive arterial disease of limbs, organs or tissues; ischemia-reperfusion injury to the brain, heart or other organs or tissues; endotoxic shock, surgical shock or traumatic shock; hypertension, valvular heart disease, heart failure, blood pressure abnormalities; shock; vasoconstriction (including vasoconstriction associated with migraine); vascular abnormalities, inflammation, dysfunction limited to a single organ or tissue. For example, this article provides methods for treating or preventing vasoconstriction, atherosclerosis and its sequelae, myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis and stroke, said methods comprising administering a therapeutically effective amount of the compound disclosed herein (e.g., a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof).

[0255] In some embodiments, this document provides a method for mitigating cardiac reperfusion injury following myocardial ischemia and / or endotoxin shock, the method comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof).

[0256] This document further provides methods for reducing vasoconstriction in a subject, the methods comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof). For example, this document provides methods for lowering blood pressure in a subject or preventing an increase in blood pressure in a subject, the methods comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof). Pharmaceutical Compositions and Administration Methods

[0257] The compounds described herein are typically administered in the form of pharmaceutical compositions.

[0258] When used as a medicine, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates thereof) (including pharmaceutically acceptable salts or solvates thereof) may be administered in the form of pharmaceutical compositions. These compositions may be prepared in ways well known in the pharmaceutical field and may be administered via a variety of routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration may be external (including transdermal, epidermal, ocular, and mucous membrane delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or blowing of powders or aerosols, including via nebulizers; intratracheal or intranasal), oral, or parenteral. Oral administration may include formulations intended for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose or, for example, via a continuous infusion pump. Pharmaceutical compositions and formulations for external application can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional drug carriers, aqueous, powder, or oil-based matrices, thickeners, etc., may be necessary or desired.

[0259] This document also provides pharmaceutical compositions comprising, as an active ingredient, a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof (e.g., a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof of a compound disclosed herein or thereof) and one or more pharmaceutically acceptable excipients (carriers). For example, pharmaceutical compositions prepared using a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof of a compound disclosed herein or thereof (e.g., a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof of a compound disclosed herein or thereof). In some embodiments, the composition is suitable for topical application. In manufacturing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted with the excipient, or encapsulated within a carrier, such as a capsule, sachet, paper, or other container. When the excipient is used as a diluent, it can be a solid, semi-solid, or liquid material that acts as a medium, carrier, or carrier of the active ingredient. Therefore, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments (containing, for example, up to 10% by weight of the active compound), soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In some embodiments, the compositions are formulated for oral administration. In some embodiments, the compositions are solid oral formulations. In some embodiments, the compositions are formulated as tablets or capsules.

[0260] This document further provides pharmaceutical compositions comprising a compound disclosed herein or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof (e.g., a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof) and a pharmaceutically acceptable excipient. Pharmaceutical compositions containing a compound disclosed herein or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate) as an active ingredient can be prepared according to conventional pharmaceutical compounding techniques by closely mixing the compound disclosed herein or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate) with a drug carrier. The carrier can take many forms depending on the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition.

[0261] Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0262] Methods for preparing pharmaceutical compositions have been described in numerous publications, such as Pharmaceutical Dosage Forms: Tablets, 2nd 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.

[0263] Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS), such as d-α-tocopherol polyethylene glycol 1000 succinate; surfactants used in pharmaceutical dosage forms, such as Tween, poloxamer, or other similar polymer delivery matrices; serum proteins, such as human serum albumin; buffering substances, such as phosphates, tris, glycine, sorbic acid, potassium sorbate; mixtures of saturated vegetable fatty acid metaglycerides; water, salts, or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; cellulose-based substances; polyethylene glycol; sodium carboxymethyl cellulose; polyacrylates; waxes; polyethylene-polyoxypropylene block copolymers; and lanolin. Cyclodextrins (such as α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin) or chemically modified derivatives such as hydroxyalkylcyclodextrins (including 2- and 3-hydroxypropyl-β-cyclodextrin) or other soluble derivatives can also be used to enhance the delivery of compounds as provided herein. Dosage forms or compositions containing 0.005% to 100% of the chemical entities provided herein, with the remainder consisting of non-toxic excipients, can be prepared. The compositions considered may contain 0.001% to 100%, 0.1% to 95% in one embodiment, 75% to 85% in another embodiment, and 20% to 80% in yet another embodiment of the chemical entities provided herein. Practical methods for preparing such dosage forms are known to or will be apparent to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 22nd edition (Pharmaceutical Press, London, UK. 2012).

[0264] In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates (e.g., compounds of Formula I or their pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates) or pharmaceutical compositions as provided herein may be administered to a subject in need via any recognized route of administration. Acceptable routes of administration include, but are not limited to, buccal, skin, intracervical, intranasal sinus, intratracheal, intraintestinal, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intracystic, intracerebral, intracisary, intracoronary, intradermal, intracatheter, intraduodenal, intradural, intraepithelial, intraepithelial, intraesophageal, intragastric, intragingival, intraileum, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intraspinal, intrasynovial, intratestinal, intrasheath, intraductal, intratumoral, intrauterine, intravascular, intravenous, nasal (e.g., intranasal), nasogastric, oral, parenteral, percutaneous, transdural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, tracheal, ureteral, urethral, ​​and vaginal. In some embodiments, the preferred route of administration is parenteral (e.g., intratumoral).

[0265] In some embodiments, compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions thereof, as provided herein, may be formulated for parenteral administration, for example, for injection via intra-arterial, intrasternal, intracranial, intravenous, intramuscular, subcutaneous, or intraperitoneal routes. Such compositions may be prepared as injectable formulations, as liquid solutions or suspensions; they may also be prepared in solid forms suitable for the addition of liquid prior to injection to prepare solutions or suspensions; and formulations may also be emulsified. The preparation of such formulations will be known to those skilled in the art in light of this disclosure. In some embodiments, parenteral administration is performed using a device. Such devices may include, for example, needle injectors, microneedle injectors, needle-free injectors, and infusion techniques.

[0266] In some embodiments, suitable injectable drug forms include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or propylene glycol; and sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. In some embodiments, the form must be sterile and must be fluid in a manner that facilitates injection. In some embodiments, the form should be stable under manufacturing and storage conditions and must be preserved against contamination by microorganisms such as bacteria and fungi.

[0267] In some embodiments, the carrier may also be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In some embodiments, suitable flowability can be maintained, for example, by using a coating (e.g., lecithin), in the case of a dispersion, by maintaining a desired particle size, and by using a surfactant. In some embodiments, the antimicrobial effect can be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.). In some embodiments, isotonic agents, such as sugars or sodium chloride, are included. In some embodiments, the absorption of the injectable composition can be prolonged by using a delayed-absorption agent (e.g., aluminum monostearate and gelatin) in the composition.

[0268] In some embodiments, the sterile injectable solution is prepared by incorporating the desired amount of the compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) into a suitable solvent having a variety of other components listed above, and then sterilizing by filtration. In some embodiments, the dispersion is prepared by incorporating various sterile active ingredients into a sterile medium containing a base dispersion medium and desired other components from those listed above. In some embodiments, sterile powders are used to prepare the sterile injectable solution. In some embodiments, the preparation method is a vacuum drying and freeze-drying technique, which produces a powder of the active ingredient plus any other desired components from its previously sterile filtered solution.

[0269] In some embodiments, pharmacologically acceptable excipients that may be used in rectal compositions as gels, creams, enemas, or rectal suppositories include, but are not limited to, any one or more of the following: glyceryl cocoa butter, synthetic polymers (such as polyvinylpyrrolidone), PEG (such as PEG ointment), glycerin, glycerin-treated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycol and polyethylene glycol fatty acid esters of various molecular weights, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxidase, etc. SBN, vanilla essential oil, aerosols, parabens in phenoxyethanol, sodium methylparaben, sodium propylparaben, diethylamine, carbomer, carbopol, methylparaben, polyethylene glycol cetearyl ether, cocoylcaprylocaprate, isopropanol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metasulfite, sodium edetate, sodium benzoate, potassium metasulfite, grapefruit seed extract, methanesulfonylmethane (MSM), lactic acid, glycine, vitamins (such as vitamins A and E), and potassium acetate.

[0270] In some embodiments, the suppository can be prepared by mixing a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof) or a pharmaceutical composition as provided herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and thus melts in the rectum and releases the active compound. In some embodiments, the composition for rectal administration is in the form of an enema.

[0271] In some embodiments, compounds disclosed herein as provided (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates thereof) or pharmaceutical compositions thereof are formulated for local delivery to the digestive tract or GI tract via oral administration (e.g., solid or liquid dosage forms).

[0272] In some embodiments, solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates (e.g., compounds of Formula I or their pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates) are mixed with one or more pharmaceutically acceptable excipients such as sodium citrate or dicalcium phosphate and / or the following: a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) Binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) Humectants, such as glycerin; d) Disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) Solution blockers, such as paraffin; f) Absorption enhancers, such as quaternary ammonium compounds; g) Wetting agents, such as cetyl alcohol and glyceryl monostearate; h) Adsorbents, such as kaolin and bentonite; and i) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. For example, in the case of capsules, tablets, and pills, the dosage form may also contain a buffer. In some embodiments, similar type of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or toffee and high molecular weight polyethylene glycol.

[0273] In some embodiments, the pharmaceutical composition will be in the form of a unit dosage form such as pills or tablets, and therefore, in addition to the compounds disclosed herein as provided (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof), the composition also contains diluents such as lactose, sucrose, dicalcium phosphate, etc.; lubricants such as magnesium stearate, etc.; and binders such as starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives, etc. In some embodiments, powders, granules, solutions, or suspensions (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) as another solid dosage form are encapsulated in capsules (gelatin or cellulose matrix capsules). In some embodiments, unit dosage forms in which one or more compounds and pharmaceutical compositions or additional active agents, as provided herein, are physically separated are also considered; for example, capsules (or tablets in capsules) having particles of each drug; two-layer tablets; two-compartment gel caps, etc. In some embodiments, enteric-coated or delayed-release oral dosage forms are also considered.

[0274] In some embodiments, other physiologically acceptable compounds may include wetting agents, emulsifiers, dispersants, or preservatives specifically designed to prevent microbial growth or activity. Various preservatives are well-known and include, for example, phenol and ascorbic acid.

[0275] In some embodiments, the excipients are sterile and generally free of undesirable substances. For example, these compositions can be sterilized using conventional, well-known sterilization techniques. In some embodiments, sterilization is not required for various oral dosage form excipients, such as tablets and capsules. For example, United States Pharmacopeia / National Formulary (USP / NF) standards may be sufficient.

[0276] In some embodiments, compounds disclosed herein as provided (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions thereof are formulated for ocular application. In some embodiments, the ocular composition may include, but is not limited to, one or more of the following: viscogen (e.g., carboxymethyl cellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizer (e.g., pluronic (triblock copolymer), cyclodextrin); preservative (e.g., benzalkonium chloride, EDTA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloride complex; Allergan, Inc.)).

[0277] In some embodiments, compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions thereof are formulated for topical application to the skin or mucous membranes (e.g., transdermal or percutaneous). In some embodiments, the topical composition may include ointments and creams. In some embodiments, ointments are typically semi-solid formulations based on petrolatum or other petroleum derivatives. In some embodiments, creams containing selected active agents are typically viscous liquids or semi-solid emulsions, often oil-in-water or water-in-oil. For example, the cream matrix is ​​typically water-washable and contains an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase, sometimes referred to as the “internal” phase, typically consists of petrolatum and fatty alcohols such as cetyl alcohol or stearyl alcohol; although not essential, the aqueous phase typically exceeds the volume of the oil phase and usually contains a humectant. In some embodiments, the emulsifier in the cream formulation is typically a nonionic, anionic, cationic, or amphoteric surfactant. In some embodiments, like other carriers or media, the ointment base should be inert, stable, non-irritating, and non-sensitizing.

[0278] In any of the foregoing embodiments, the pharmaceutical composition provided herein may comprise one or more of the following: lipids, interlayer cross-linked multilayer vesicles, biodegradable poly(D,L-lactic acid-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0279] In some embodiments, the dosage of the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) is determined based on a variety of factors, including but not limited to the subject's type, age, weight, sex, medical condition; the severity of the subject's medical condition; the route of administration; and the activity of the compound or pharmaceutically acceptable salts or solvates thereof. In some embodiments, the appropriate dosage for a particular situation can be determined by a person skilled in the medical field. In some embodiments, the total daily dose can be divided into multiple doses and administered in multiple doses throughout the day or by means of a continuous delivery method.

[0280] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) are administered in doses of about 0.01 to about 1000 mg. For example, 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.

[0281] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) are applied at a concentration 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...). Approximately 10 mg / kg; approximately 0.0002 mg / kg to approximately 5 mg / kg; approximately 0.0002 mg / kg to approximately 1 mg / kg; approximately 0.0002 mg / kg to approximately 0.5 mg / kg; approximately 0.0002 mg / kg to approximately 0.1 mg / kg; approximately 0.001 mg / kg to approximately 50 mg / kg; approximately 0.001 mg / kg to approximately 25 mg / kg; approximately 0.001 mg / kg to approximately 10 mg / kg; approximately 0.001 mg / kg to about 5mg / kg; about 0.001mg / kg to about 1mg / kg; about 0.001mg / kg to about 0.5mg / kg; about 0.001mg / kg to about 0.1mg / kg; about 0.01mg / kg to about 50mg / kg; about 0.01mg / kg to about 25mg / kg; about 0.01mg / kg to about 10mg / kg; about 0.01mg / kg to about 5mg / kg; about 0.01mg / kg to about The dosage is 1 mg / Kg; about 0.01 mg / Kg to about 0.5 mg / Kg; about 0.01 mg / Kg to about 0.1 mg / Kg; about 0.1 mg / Kg to about 50 mg / Kg; about 0.1 mg / Kg to about 25 mg / Kg; about 0.1 mg / Kg to about 10 mg / Kg; about 0.1 mg / Kg to about 5 mg / Kg; about 0.1 mg / Kg to about 1 mg / Kg; about 0.1 mg / Kg to about 0.5 mg / Kg. In some embodiments, the compound disclosed herein as provided herein (e.g., a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof) is administered at a dosage of about 100 mg / Kg.

[0282] In some embodiments, the aforementioned dose of the compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof) may be administered on a daily basis (e.g., as a single dose or as two or more separate doses) or on a non-daily basis (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month).

[0283] In some embodiments, the administration time for compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, or solvates thereof) is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In some implementation schemes, the period for discontinuing application is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In some embodiments, the compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof) is administered to a subject for a period of time, followed by a separate period of time during which administration of the compound disclosed herein or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof) is discontinued. In some embodiments, the compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof) is administered to a subject for a first time period, followed by a second time period, during which administration is discontinued, and then a third time period in which administration of the compound disclosed herein or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof) is initiated, followed by a fourth time period after the third time period, during which administration is discontinued. For example, the time period during which the compound disclosed herein (e.g., a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof) is administered, followed by the time period during which administration is discontinued, is repeated within a defined or indeterminate time period.In some implementations, the application 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 longer. In some implementations, the discontinuation 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 longer.

[0284] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates thereof) are administered orally to a subject once or more daily (e.g., once daily, twice daily, three times daily, four times daily or a single daily dose).

[0285] In some embodiments, the compounds disclosed herein (compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates thereof) are administered to subjects via parenteral administration once or more daily (e.g., 1 to 4 times, once daily, twice daily, three times daily, four times daily or a single daily dose).

[0286] In some implementations, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs or solvates thereof) are administered to subjects weekly via parenteral administration. Compound Synthesis

[0287] The compounds disclosed herein can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be understood that, unless otherwise stated, other process conditions may also be used where certain process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given. Optimal reaction conditions may vary depending on the reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization procedures.

[0288] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting certain functional groups, are well known in the art. For example, many protecting groups are described in, for example, TW Greene and GMWuts (1999), Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and the references cited therein.

[0289] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Therefore, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as mixtures enriched with stereoisomers, if desired. Unless otherwise indicated, all such stereoisomers (and mixtures enriched with stereoisomers) are included within the scope of this disclosure. Pure stereoisomers (or mixtures enriched with stereoisomers) can be prepared using, for example, photoactive starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0290] The starting materials used in the following reactions are typically known compounds, or can be prepared by known procedures or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), EMKA-Chemie GmbH & Co. KG (Escherich, Germany), or Millipore Sigma (Burlington, Massachusetts, USA) Other starting materials may be prepared by procedures described in standard reference texts, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1–15 (John Wiley, and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1–5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1–40 (John Wiley, and Sons, 1991); March's Advanced Organic Chemistry (John Wiley, and Sons, 5th Edition, 2001); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0291] Scheme I describes a general method that can be used to synthesize the compounds disclosed herein, wherein R 1 R 2 R 4 R 8 R 9 R 13 X 1 X 2 X 3 X 4 X 6 A, m, n, L 1 and L 2 Each of these, independently as defined herein, consists of a suitable leaving group, such as a halogroup (e.g., Cl, Br, or I), wherein LG and LG' are not identical, PG is a suitable carboxyl protecting group, such as an alkyl or benzyl group, and B is a suitable coupling functional group, such as, but not limited to, boric acid or its derivatives, such as borate esters (e.g., -B(R)). 50 )2, where each R 50 Independently alkyl or substituted alkyl, or two R50 Linked to form cyclic borate esters, which may optionally be substituted (e.g., pinacol borate ester)). Option I

[0292] Compounds of Formula I are prepared by first coupling compound I-1, followed by deprotection to obtain the free acid of Formula I, wherein B is a suitable coupling functional group, such as, but not limited to, boric acid or its derivatives (e.g., borate esters (cyclic or acyclic)), zinc or magnesium halides, organotin compounds (e.g., tributyltin or trimethyltin), fluorosulfonyl esters, tin, sodium, etc. Such reactions are typically used for aromatic functionalization, and are usually carried out in the presence of a suitable catalyst, such as, but not limited to, palladium catalysts, including [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride, Pd(OAc)2, Pd(PPh3)4, PdCl2(PPh3)2, or tris(dibenzylacetone)dipalladium(O), etc.; or copper catalysts, such as CuCl or CuI; and, if desired, suitable media, co-catalysts, and / or bases known to those skilled in the art as suitable solvents / solvent mixtures. After the reaction is complete, the compound of formula I can be recovered using conventional techniques (such as neutralization, extraction, precipitation, chromatography, filtration, etc.). In some embodiments, when stereochemistry needs to be controlled, appropriate control of the reaction conditions and the selection of substituents used for the reagents can at least partially determine or maintain the formation of multiple stereoisomers. Compounds I-1 and I-2 can be commercially available or synthesized de novo. For example, as shown in Scheme I above, compound I-1 can be prepared under standard nucleophilic aromatic substitution conditions by coupling compound I-3 with compound I-4.

[0293] Scheme II describes a general method that can be used to synthesize the compounds disclosed herein, wherein R 1 R 2 R 4 R 6 R 8 R 9 R 13 X 1 X 2 X 3 X 4 A, m, n, L 1 and L 2 Each of these, independently as defined herein, consists of a suitable leaving group, such as a halogroup (e.g., Cl, Br, or I), wherein LG and LG' are not identical, PG is a suitable carboxyl protecting group, such as an alkyl or benzyl group, and B is a suitable coupling functional group, such as, but not limited to, boric acid or its derivatives, such as borate esters (e.g., -B(R)). 50)2, where each R 50 Independently alkyl or substituted alkyl, or two R 50 Linked to form cyclic borate esters, which may optionally be substituted (e.g., pinacol borate ester)). Option II

[0294] Compounds of Formula II are prepared by first coupling compound II-1, followed by deprotection to obtain the free acid of Formula II, wherein B is a suitable functional group, such as, but not limited to, boric acid or its derivatives (e.g., borate esters (cyclic or acyclic)), zinc or magnesium halides, organotin compounds (e.g., tributyltin or trimethyltin), fluorosulfonyl esters, tin, sodium, hydrogen, etc. Such reactions are typically used for aromatic functionalization, and are usually carried out in the presence of a suitable catalyst, such as, but not limited to, palladium catalysts, including [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride, Pd(OAc)2, Pd(PPh3)4, PdCl2(PPh3)2, or tris(dibenzylacetone)dipalladium(O), etc.; or copper catalysts, such as CuCl or CuI; and, if desired, suitable media, co-catalysts, and / or bases known to those skilled in the art as suitable solvents / solvent mixtures. After the reaction is complete, the compound of formula II can be recovered using conventional techniques (such as neutralization, extraction, precipitation, chromatography, filtration, etc.). In some embodiments, when stereochemistry needs to be controlled, appropriate control of the reaction conditions and the selection of substituents for the reagents can at least partially determine or maintain the formation of multiple stereoisomers. Compounds I-1 and II-2 can be commercially available or synthesized de novo.

[0295] Scheme III describes a general method that can be used to synthesize the compounds disclosed herein, wherein R 1 R 2 R 4 R 6 R 8 R 9 R 13 X 1 X 2 X 3 X 4 Ring A, m, n, L 1 and L 2 Each of these, independently as defined herein, consists of a suitable leaving group, such as a halogroup (e.g., Cl, Br, or I), wherein LG and LG' are not identical, PG is a suitable carboxyl protecting group, such as an alkyl or benzyl group, and B is a suitable coupling functional group, such as, but not limited to, boric acid or its derivatives, such as borate esters (e.g., -B(R)). 50)2, where each R 50 Independently alkyl or substituted alkyl, or two R 50 Linked to form cyclic borate esters, which may optionally be substituted (e.g., pinacol borate ester)). Option III

[0296] Compounds of formula IIA are prepared by first coupling compound IIA-1, followed by deprotection to obtain the free acid of formula IIA, wherein B is a suitable functional group, such as, but not limited to, boric acid or its derivatives (e.g., borate esters (cyclic or acyclic)), zinc or magnesium halides, organotin compounds (e.g., tributyltin or trimethyltin), fluorosulfonyl esters, 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, palladium catalysts, including [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride, Pd(OAc)2, Pd(PPh3)4, PdCl2(PPh3)2, or tris(dibenzylacetone)dipalladium(O), etc.; or copper catalysts, such as CuCl or CuI; and, if desired, suitable media, co-catalysts, and / or bases known to those skilled in the art as suitable solvents / solvent mixtures. After the reaction is complete, the compound of formula IIA can be recovered using conventional techniques (such as neutralization, extraction, precipitation, chromatography, filtration, etc.). In some embodiments, when stereochemistry needs to be controlled, appropriate control of the reaction conditions and the selection of substituents used in the reagents can at least partially determine or maintain the formation of multiple stereoisomers. Compounds IIA-1 and II-2 can be commercially available or synthesized de novo. For example, as shown in Scheme III above, compound IIA-1 can be prepared under standard nucleophilic aromatic substitution conditions by coupling compound IIA-3 with compound I-4.

[0297] It should be understood that various substituents in each intermediate (e.g., compounds I-1, II-1, I-2, I-3, II-3, and I-4) can be modified or added before or after the addition of the I-2 or II-2 moiety (as shown in Scheme I, Scheme II, or Scheme III). For example, A or cyclic A can be added before or after the steps shown in the above schemes. The A or cyclic A moiety can be coupled to X under substitution reaction conditions. 4 Precursor.

[0298] For any compound shown in Scheme I, Scheme II, or Scheme II, it should be understood that multiple derivatives can be provided by interconversion of functional groups at any step. In some embodiments, multiple substituents of formula I-1, II-1, IIA-1, I-2, II-2, I-3, II-3, IIA-3, or I-4 (e.g., A, ring A, R) 1 R 2 R 4 R 6 R 8 R 9 R 13 X 1 X 2 X 3 X 4 X 6 m, n, L 1 and L 2 As defined herein. However, derivatization of compounds I, II, IIA, I-1, II-1, IIA-1, I-2, II-2, I-3, II-3, IAI-3, or I-4 prior to any step of the reaction and / or further derivatization of the resulting reaction product provides a variety of compounds of formula I, II, or IIA. Suitable starting materials and reagents may be commercially available or prepared by methods known to those skilled in the art. After each reaction is completed, each of the intermediates or final compounds may be recovered and optionally purified by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, etc. Modifications of other compounds used to achieve the purposes of this disclosure are within the scope of the art. General Synthesis

[0299] Typical embodiments of the compounds described herein can be synthesized using the general reaction scheme described below. Given the description herein, it should be apparent that the general scheme can be modified by substituting the starting materials with other materials having similar structures to produce correspondingly different products. The following description of the synthesis provides numerous examples of how the starting materials can be varied to provide the corresponding products. Given the desired product with defined substituents, the necessary starting materials can generally be determined by examination. Starting materials are typically obtained from commercial sources or synthesized using publicly available methods. To synthesize the compounds as embodiments described in this disclosure, examination of the structure of the compound to be synthesized will provide the identity of each substituent. Given the embodiments herein, the identity of the final product will generally make the identity of the necessary starting materials apparent through a simple examination process. Generally, the compounds described herein are typically stable and separable at room temperature and pressure. Example

[0300] The following embodiments are included to illustrate specific implementations of this disclosure. Those skilled in the art will understand that the techniques disclosed in the following embodiments represent techniques that work well in the practice of this disclosure and can therefore be considered as specific patterns constituting its practice. However, based on this disclosure, those skilled in the art will understand that many changes can be made to the disclosed specific embodiments without departing from the spirit and scope of this disclosure and still obtaining the same or similar results.

[0301] Abbreviations (as used in this article):

[0302] General Information: All evaporation or concentration was performed under vacuum using a rotary evaporator. Analytical samples were dried under vacuum (1-5 mmHg) at room temperature. Thin-layer chromatography (TLC) was performed on silica gel plates, with spots visualized using UV light (214 and 254 nm). Purification was performed using silica gel (100-200 mesh) via column chromatography and rapid chromatography. 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 as δ values ​​in ppm, with the deuterated solvent used as an internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad peak, m = multiply), coupling constant (Hz), and integral. Unless otherwise specified, LCMS spectra were obtained on a SHIMADZU LC20-MS2020 or Agilent 1260 series 6125B mass spectrometer or an Agilent 1200 series 6110 or 6120 mass spectrometer with electrospray ionization. Example A1 3-((2-(((2,3-dihydro-1H-inden-2-yl)oxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)oxy)propionic acid (compound 105)

[0303] Step A: Ethyl 3-(4-bromo-3-methylphenoxy)propionate

[0304] DMAP (522 mg, 4.28 mmol) was added to a mixture of 4-bromo-3-methylphenol (3.20 g, 17.10 mmol) and ethyl acrylate (14 mL) at room temperature. The mixture was stirred at 120 °C for 5 h under microwave irradiation. The reaction mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc = 20:1) to give ethyl 3-(4-bromo-3-methylphenoxy)propionate (1.20 g, 24% yield). 1 H NMR(400MHz, CDCl3) δ7.39(d,J=8.8Hz,1H),6.80(d,J=2.8Hz,1H),6.62(dd,J=8.8Hz,3 .2Hz,1H),4.25-4.13(m,4H),2.77(t,J=6.4Hz,2H),2.35(s,3H),1.27(t,J=7.2Hz,3H).

[0305] Step B: Ethyl 3-(4-bromo-3-(bromomethyl)phenoxy)propionate

[0306] NBS (222 mg, 1.25 mmol), AIBN (7 mg, 0.042 mmol), and AcOH (0.15 mL) were added to a mixture of ethyl 3-(4-bromo-3-methylphenoxy)propionate (300 mg, 1.04 mmol) in CCl4 (8 mL). The reaction mixture was heated to 70 °C and stirred for 16 h. The reaction mixture was concentrated. The residue was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (PE / EtOAc = 7 / 1) to give ethyl 3-(4-bromo-3-(bromomethyl)phenoxy)propionate (200 mg, 52% yield). 1 H NMR (400MHz, CDCl3) δ7.44(d,J=8.8Hz,1H),7.01(d,J=3.2Hz,1H),6.74(dd,J=8.8Hz,2 .8Hz,1H),4.54(s,2H),4.28-4.13(m,4H),2.78(t,J=6.4Hz,2H),1.28(t,J=7.2Hz,3H).

[0307] Step C: Ethyl 3-(4-bromo-3-(((2,3-dihydro-1H-inden-2-yl)oxy)methyl)phenoxy)propionate

[0308] At room temperature, 2,6-di-tert-butylpyridine (197 mg, 1.80 mmol) and AgOTf (269 mg, 1.05 mmol) were added to a mixture of ethyl 3-(4-bromo-3-(bromomethyl)phenoxy)propionate (220 mg, 0.60 mmol) and 2,3-dihydro-1H-indene-2-ol (139 mg, 1.05 mmol) in a DCE (8 mL). The mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc = 10:1) to give ethyl 3-(4-bromo-3-(((2,3-dihydro-1H-indene-2-yl)oxy)methyl)phenoxy)propionate (100 mg, 40% yield). 1 H NMR (400MHz, CDCl3) δ7.39(d,J=8.4Hz,1H),7.25-7.20(m,2H),7.19-7.14(m,2H),7.04(d,J=3.2Hz,1H),6.70(dd,J=8.8Hz,2.8Hz,1H),4.59(s,2H) ,4.54-4.47(m,1H),4.28-4.12(m,4H),3.23(dd,J=16.4Hz,6.4Hz,2H),3. 10(dd,J=16.0Hz,4.8Hz,2H), 2.76(t,J=6.4Hz,2H), 1.27(t,J=6.8Hz,3H).

[0309] Step D: Ethyl 3-((2-(((2,3-dihydro-1H-inden-2-yl)oxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)oxy)propionate

[0310] At room temperature, ethyl 3-(4-bromo-3-(((2,3-dihydro-1H-inden-2-yl)oxy)methyl)phenoxy)propionate (20.0 mg, 0.048 mmol) in 1,4-dioxane / H₂O (1 mL / 0.2 mL) was added to a mixture of 2-(3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane (20.0 mg, 0.072 mmol), Na₂CO₃ (15.2 mg, 0.144 mmol), and Pd(dppf)Cl₂.CH₂Cl₂ (2.00 mg, 0.0024 mmol). The reaction mixture was stirred at 90 °C for 1 h under microwave irradiation. After cooling, the reaction mixture was filtered, and the filter cake was washed with EtOAc (10 mL). The filtrate was dried over Na₂SO₄ and concentrated. The residue was purified by preparative TLC (PE / EtOAc = 5 / 1) to give ethyl 3-((2-(((2,3-dihydro-1H-indene-2-yl)oxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-yl)oxy)propionate (13.0 mg, yield 56%). 1 H NMR(400MHz, CDCl3)δ7.21(d,J=8.4Hz,1H),7.17-7.12(m,4H),7.09(d,J=2.4Hz,1H), 6.88(dd,J=8.4Hz,2.4Hz,1H),6.51(s,2H),4.44(s,2H),4.42-4.35(m,1H),4.28(t,J =6.4Hz,2H),4.20(q,J=7.2Hz,2H),3.77(s,6H),3.12(dd,J=16.0Hz,6.4Hz,2H),2.97 (dd, J = 16.0Hz, 4.4Hz, 2H), 2.80 (t, J = 6.4Hz, 2H), 2.14 (s, 3H), 1.29 (d, J = 7.2Hz, 3H).

[0311] Step E: 3-((2-(((2,3-dihydro-1H-inden-2-yl)oxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)oxy)propionic acid (compound 105)

[0312] Ethyl 3-((2-(((2,3-dihydro-1H-indene-2-yl)oxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-yl)oxy)propionate (50.0 mg, 0.102 mmol) was stirred at 60 °C for 4 h in a mixture of AcOH (2 mL) and 5 M HCl aqueous solution (2 mL). The reaction mixture was concentrated. The residue was purified by preparative TLC (PE / EtOAc = 1 / 2) and further purified by preparative HPLC (0.1% formic acid in H2O and MeOH) to give 3-((2-(((2,3-dihydro-1H-indene-2-yl)oxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)oxy)propionate (12.0 mg, 32% yield). LC-MS: m / z 485.3 (M+Na) + . 1 H NMR (400MHz, CDCl3) δ7.21(d,J=8.4Hz,1H),7.19-7.11(m,4H),7.09(d,J=2.4Hz,1H),6.88(dd,J=8.4Hz,2.8Hz,1H),6.50(s,2H),4.45(s,2H),4.41- 4.36(m,1H),4.29(t,J=6.4Hz,2H),3.77(s,6H),3.12(dd,J=16.0Hz,6.4H z, 2H), 2.97 (dd, J = 16.4Hz, 4.4Hz, 2H), 2.87 (t, J = 6.0Hz, 2H), 2.14 (s, 3H). Example A2 3-((2-(((2,3-dihydro-1H-inden-2-yl)oxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)propionic acid (compound 101)

[0313] Step A: (3',5'-Dimethoxy-4'-methyl-4-nitro-[1,1'-biphenyl]-2-yl)methanol

[0314] To a solution of (2-bromo-5-nitro-phenyl)methanol (2 g, 8.62 mmol) and 2-(3,5-dimethoxy-4-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane ... The residue was purified by silica gel column chromatography (PE / EtOAc = 10 / 1) to give (3',5'-dimethoxy-4'-methyl-4-nitro-[1,1'-biphenyl]-2-yl)methanol (2.2 g, 84% yield). 1 H NMR (400MHz, CD3OD) δ8.50(d,J=2.4Hz,1H),8.20(dd,J=8.4Hz,2.4Hz,1H),7.53(d,J=8.4Hz,1H),6.62(s,2H),4.64(s,2H),3.85(s,6H),2.11(s,3H).

[0315] Step B: (3',5'-Dimethoxy-4'-methyl-4-nitro-[1,1'-biphenyl]-2-yl)methylmethanesulfonate

[0316] TEA (1.47 g, 14.51 mmol) and MsCl (1.25 g, 10.88 mmol) were added to a solution of [2-(3,5-dimethoxy-4-methyl-phenyl)-5-nitro-phenyl]methanol (2.2 g, 7.25 mmol) in THF (25 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The mixture was then diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc = 10 / 1) to give (3',5'-dimethoxy-4'-methyl-4-nitro-[1,1'-biphenyl]-2-yl)methylmethanesulfonate (2.50 g, 90% yield). 1H NMR(400MHz,DMSO-d6)δ8.49(d,J=2.4Hz,1H),8.32(dd,J=8.4Hz,2.4Hz,1H),7.70 (d,J=8.4Hz,1H),6.67(s,2H),5.32(s,2H),3.83(s,6H),3.24(s,3H),2.06(s,3H).

[0317] Step C: 2-((3',5'-dimethoxy-4'-methyl-4-nitro-[1,1'-biphenyl]-2-yl)methoxy)-2,3-dihydro-1H-indene

[0318] NaH (424.71 mg, 10.62 mmol, 60% wt in mineral oil) was added to a solution of indan-2-ol (1.42 g, 10.62 mmol) in THF (20 mL) at 0 °C. After stirring for 30 min, (3',5'-dimethoxy-4'-methyl-4-nitro-[1,1'-biphenyl]-2-yl)methylmethanesulfonate (2.7 g, 7.08 mmol) in THF (10 mL) was added to the above solution. The mixture was stirred at 25 °C for 12 h. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc = 10 / 1) to give 2-((3',5'-dimethoxy-4'-methyl-4-nitro-[1,1'-biphenyl]-2-yl)methoxy)-2,3-dihydro-1H-indene (220 mg, 7% yield). LC-MS: m / z 442.1 (M+Na) + .

[0319] Step D: 4-(3,5-Dimethoxy-4-methyl-phenyl)-3-(indan-2-yloxymethyl)aniline

[0320] Under nitrogen atmosphere, 10% Pd / C (100 mg) was added to a solution of 2-((3',5'-dimethoxy-4'-methyl-4-nitro-[1,1'-biphenyl]-2-yl)methoxy)-2,3-dihydro-1H-indene (200 mg, 47.68 μmol) in EtOAc (5 mL). The suspension was degassed under vacuum and purged three times with H2. The mixture was stirred at 25 °C for 1 h under H2 (15 psi). The mixture was filtered and the filtrate was concentrated to give 4-(3,5-dimethoxy-4-methyl-phenyl)-3-(indene-2-yloxymethyl)aniline (170 mg, 91% yield), which was used in the next step unpurified. LC-MS: m / z 390.1 (M+H) + .

[0321] Step E: Methyl 3-((2-(((2,3-dihydro-1H-inden-2-yl)oxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)propionate

[0322] TFA (3.23 g, 28.37 mmol) and Et3SiH (167 mg, 1.44 mmol) were added to a solution of 4-(3,5-dimethoxy-4-methyl-phenyl)-3-(indan-2-yloxymethyl)aniline (170 mg, 436.47 μmol) and methyl 3,3-dimethoxypropionate (64.67 mg, 436.47 μmol) in DCE (5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc = 5 / 1) to give methyl 3-((2-(((2,3-dihydro-1H-inden-2-yl)oxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)propionate (70 mg, 33% yield). LC-MS: m / z 476.2 (M+H) + .

[0323] Step F: 3-((2-(((2,3-dihydro-1H-inden-2-yl)oxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)propionic acid (compound 101)

[0324] LiOH·H2O (22 mg, 525.68 μmol) was added to a solution of methyl 3-[4-(3,5-dimethoxy-4-methyl-phenyl)-3-(indan-2-yloxymethyl)aniline]propionate (50 mg, 105.14 μmol) in MeOH (1 mL), THF (1 mL), and H2O (1 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was acidified to pH 4 with 1 N HCl and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*30mm*3um; mobile phase: [water (10mMNH4HCO3)-CH3CN]; B%: 12%-82%, 9 min) to give 3-((2-(((2,3-dihydro-1H-inden-2-yl)oxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)propionic acid (43 mg, yield 87%). LC-MS: m / z 462.0 (M+H) + . 1 H NMR (400MHz, CD3OD) δ7.18-7.06(m,5H),6.81(d,J=2.4Hz,1H),6.67(dd,J=8.0Hz,2.4Hz,1H),6.54(s,2H),4.43(s,2H),4.41-4.36(m,1H ), 3.73 (s, 6H), 3.43 (t, J = 6.8Hz, 2H), 3.09 (dd, J = 16.0Hz, 8.0Hz, 2H), 2.89 (dd, J = 16.0Hz, 4.0Hz, 2H), 2.59 (t, J = 6.8Hz, 2H), 2.09 (s, 3H). Example A3 4-({2-[(2,3-dihydro-1H-indene-2-yloxy)methyl]-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl}amino)oxane-4-carboxylic acid (compound 111)

[0325] Step A: 1-Bromo-2-(Bromomethyl)-4-iodobenzene

[0326] A mixture of bromo-4-iodo-2-methylbenzene (20.0 g, 67.36 mmol), AIBN (5.53 g, 33.68 mmol), and NBS (11.99 g, 67.36 mmol) in CCl4 (300 mL) was heated to 80 °C and stirred for 16 h. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (100% PE) to give 1-bromo-2-(bromomethyl)-4-iodobenzene (8.0 g, yield 31.6%). Alternatively, 1-bromo-2-(bromomethyl)-4-iodobenzene can be prepared from (2-bromo-5-iodophenyl)methanol at 25 °C using PPh3 and CBr4.

[0327] Step B: 2-[(2-bromo-5-iodophenyl)methoxy]-2,3-dihydro-1H-indene

[0328] NaH (319 mg, 7.98 mmol, 60% wt in mineral oil) was added to a solution of 2,3-dihydro-1H-inden-2-ol (0.86 g, 6.39 mmol) in DMF (40 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 1 h. Then, a solution of 1-bromo-2-(bromomethyl)-4-iodobenzene (2.00 g, 5.32 mmol) in DMF (10 mL) was added to the above solution. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then quenched with a saturated aqueous solution of NH4Cl (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (0%-10% EtOAc in PE) to give 2-[(2-bromo-5-iodophenyl)methoxy]-2,3-dihydro-1H-indene (450 mg, yield 19.7%).

[0329] Step C: 4-({4-bromo-3-[(2,3-dihydro-1H-inden-2-yloxy)methyl]phenyl}amino)oxane-4-carboxylic acid

[0330] CuI (40 mg, 0.21 mmol), 4-aminotetrahydro-1H-indene (304 mg, 2.10 mmol), and DBU (93.13 mg, 0.61 mmol) were added to a solution of 2-[(2-bromo-5-iodophenyl)methoxy]-2,3-dihydro-1H-indene (450 mg, 1.05 mmol) in DMAc (10 mL). The resulting mixture was stirred at 120 °C for 5 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and poured into water (20 mL). The pH was adjusted to 7 with acetic acid. The resulting mixture was extracted with CH2Cl2 (20 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (0%-10% MeOH in CH2Cl2) to give 4-({4-bromo-3-[(2,3-dihydro-1H-inden-2-yloxy)methyl]phenyl}amino)oxane-4-carboxylic acid (35 mg, yield 44.9%). LC-MS: m / z 447.9 (M+H) + .

[0331] Step D: 4-({2-[(2,3-dihydro-1H-inden-2-yloxy)methyl]-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl}amino)oxane-4-carboxylic acid (compound 111)

[0332] A mixture of 4-({4-bromo-3-[(2,3-dihydro-1H-indene-2-yloxy)dihydro]phenyl}amino)oxane-4-carboxylic acid (190 mg, 0.43 mmol), 2-(3,5-dimethoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane (118 mg, 0.43 mmol), Na₂CO₃ (135 mg, 1.28 mmol), and Pd(dppf)Cl₂.CH₂Cl₂ (69.35 mg, 0.09 mmol) in 1,4-dioxane (4 mL) / water (1 mL) was stirred for 3 h at 100 °C under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated. The residue was purified by preparative HPLC (column: Xselect CSH C18OBD column 30*150mm*5μm; mobile phase A: water (0.05% FA), mobile phase B: CH3CN; flow rate: 60 mL / min; gradient: 30% B to 81% B over 10 min) to give 4-({2-[(2,3-dihydro-1H-inden-2-yloxy)methyl]-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl}-amino)oxane-4-carboxylic acid (102.8 mg, yield 45.9%). LC-MS: m / z 518.4 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.20-7.18(m,2H),7.16-7.08(m,2H),7.02(d,J=8.4Hz,1H),6.77(d,J=2.6Hz,1H),6.51(s,2H),6.50-6.37(m,1H)4.36-4 .33(m,3H),3.72(s,6H),3.71-3.59(m,4H),3.10(dd,J=16.4Hz,6.3Hz,2 H), 2.87 (dd, J = 16.4Hz, 3.7Hz, 2H), 2.08-1.97 (m, 2H), 1.91-1.89 (m, 2H). Example A4 1-((2-(((2,3-dihydro-1H-inden-2-yl)oxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)cyclopropane-1-carboxylic acid (compound 109)

[0333] 1-((2-(((2,3-dihydro-1H-inden-2-yl)oxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)cyclopropane-1-carboxylic acid (compound 109) was synthesized in step C using 1-aminocyclopropane-1-carboxylic acid according to the procedure (steps C and D) described for the preparation of Example A3. LC-MS: m / z 496.2 (M+Na) + . 1 HNMR(400MHz, CDCl3)δ12.29(brs,1H),7.21-7.16(m,2H),7.15-7.09(m,2H ),7.04(d,J=8.0Hz,1H),6.74(d,J=2.4Hz,1H),6.58-6.56(m,2H),6.54(s,2 H),4.38-4.30(m,3H),3.73(s,6H),3.08(dd,J=16.4Hz,6.0Hz,2H),2.85(d d, J=16.4Hz, 3.6Hz, 2H), 2.01 (s, 3H), 1.47-1.39 (m, 2H), 1.03-0.96 (m, 2H). Example A5 1-({2-[(2,3-dihydro-1H-indene-2-yloxy)methyl]-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl}oxy)cyclopropane-1-carboxylic acid (compound 117)

[0334] Step A: 2-[(2-bromo-5-methoxyphenyl)methoxy]-2,3-dihydro-1H-indene

[0335] At 0 °C, NaH (1.07 g, 26.79 mmol, 60% wt in mineral oil) was added to a solution of 2,3-dihydro-1H-inden-2-ol (3.59 g, 26.79 mmol) in DMF (50 mL). The reaction mixture was stirred at 0 °C for 0.5 h. Then, 1-bromo-2-(bromomethyl)-4-anisole (5.00 g, 17.86 mmol) was added to the above solution. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (0% to 10% EtOAc in PE) to give 2-[(2-bromo-5-methoxyphenyl)methoxy]-2,3-dihydro-1H-indene (4.10 g, yield 68.9%).

[0336] Step B: 4-Bromo-3-[(2,3-dihydro-1H-inden-2-yloxy)methyl]phenyl

[0337] A mixture of dodecane-1-thiol (5.52 g, 32.41 mmol) and t-BuOK (3.64 g, 32.41 mmol) in NMP (100 mL) was stirred at room temperature for 10 min under a nitrogen atmosphere. Then, 2-[(2-bromo-5-methoxyphenyl)methoxy]-2,3-dihydro-1H-indene (9.00 g, 27.01 mmol) was added to the mixture. The resulting mixture was stirred at 120 °C for 2 h under a nitrogen atmosphere. After cooling, the reaction mixture was diluted with water (200 mL) and neutralized to pH 7 with a saturated aqueous NH4Cl solution. The resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase rapid column chromatography (30%–80% CH3CN in water) to give 4-bromo-3-[(2,3-dihydro-1H-inden-2-yloxy)methyl]phenol (4.0 g, yield 11.6%). LC-MS: m / z 318.9 (MH) - .

[0338] Step C: Methyl 4-bromo-2-{4-bromo-3-[(2,3-dihydro-1H-inden-2-yloxy)methyl]phenoxy}-butyrate

[0339] A mixture of 4-bromo-3-[(2,3-dihydro-1H-indene-2-yloxy)methyl]phenol (500 mg, 1.57 mmol), methyl 2,4-dibromobutyrate (489 mg, 1.88 mmol), and K₂CO₃ (432.98 mg, 3.13 mmol) in DMF (10 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give crude methyl 4-bromo-2-{4-bromo-3-[(2,3-dihydro-1H-indene-2-yloxy)methyl]phenoxy}butyrate (720 mg, 92.3% yield). LC-MS: m / z 520.8 (M+Na) + .

[0340] Step D: Methyl 1-({4-bromo-3-[(2,3-dihydro-1H-inden-2-yloxy)methyl]phenyl}oxy)cyclopropane-1-carboxylate)

[0341] A mixture of methyl 4-bromo-2-{4-bromo-3-[(2,3-dihydro-1H-indene-2-yloxy)methyl]phenoxy}butyrate (710 mg, 1.43 mmol) and potassium tert-butoxy (320 mg, 2.85 mmol) in THF (10 mL) was stirred at room temperature for 2.5 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated to give crude methyl 1-({4-bromo-3-[(2,3-dihydro-1H-indene-2-yloxy)methyl]phenyl}oxy)cyclopropane-1-carboxylate (520 mg, 90.5% yield). LC-MS: m / z 440.9 (M+Na) + .

[0342] Step E: 1-({2-[(2,3-dihydro-1H-inden-2-yloxy)methyl]-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl}oxy)cyclopropane-1-carboxylic acid (compound 117)

[0343] Pd(dppf)Cl2.CH2Cl2 (190 mg, 0.23 mmol) was added to a mixture of 1-{4-bromo-3-[(2,3-dihydro-1H-indene-2-yloxy)methyl]phenoxy}cyclopropane-1-carboxylic acid (470 mg, 1.17 mmol), 2-(3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane (400 mg, 1.44 mmol), and Na2CO3 (370.58 mg, 3.50 mmol) in 1,4-dioxane (8 mL) and water (2 mL). The reaction mixture was heated to 90 °C and stirred at 90 °C for 1 h under nitrogen irradiation with microwave. After cooling, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (column: CHIRAL ART Cellulose-SB, 4.6*100 mm, 3 μm; mobile phase A: Hex (0.1% FA): EtOH = 90:10; flow rate: 1 mL / min; gradient: 0% B to 0% B; injection volume: 5 mL) to give 1-({2-[(2,3-dihydro-1H-inden-2-yloxy)methyl]-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl}oxy)cyclopropane-1-carboxylic acid (8.3 mg, yield 1.5%). LC-MS: m / z 497.2 (M+Na) + . 1 H NMR (400MHz, DMSO-d6) δ7.21-7.07(m,5H),6.97(d,J=2.6Hz,1H),6.86(dd,J=8.4Hz,2.7Hz,1H),6.56(s,2H),4.38(s,2H) ,4.37-4.36(m,1H),3.73(s,6H),3.10-3.00(m,2H),2.90-2.80(m,2H),2.02(s,3H),1.42-1.30(m,2H),1.00-0.90(m,2H). Example A6 1-{2-[(2,3-dihydro-1H-inden-2-yloxy)methyl]-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl}cyclopropane-1-carboxylic acid (compound 118)

[0344] Step A: 1-(4-bromo-3-methylphenyl)cyclopropane-1-carboxynitrile

[0345] Sodium hydride (1.14 g, 28.56 mmol, 60% wt in mineral oil) was added to a solution of 2-(4-bromo-3-methylphenyl)acetonitrile (6.00 g, 28.56 mmol) in THF (120 mL) at 0 °C. After stirring for 15 min, dibromoethane (5.37 g, 28.56 mmol) was added to the above reaction mixture. The resulting reaction mixture was allowed to be warmed to room temperature and stirred for 4 h. The reaction mixture was quenched with ice water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (10% to 20% EtOAc in PE) to give 1-(4-bromo-3-methylphenyl)cyclopropane-1-carboxynitrile (800 mg, 11.9% yield).

[0346] Step B: 1-[4-bromo-3-(bromomethyl)phenyl]cyclopropane-1-carboxynitrile

[0347] AIBN (278 mg, 1.70 mmol) was added to a mixture of 1-(4-bromo-3-methylphenyl)cyclopropane-1-carboxynitrile (800 mg, 3.39 mmol) and NBS (1.21 g, 6.78 mmol) in CCl4 (16 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred under reflux for 16 h. After cooling, the reaction mixture was washed with water (100 mL) and extracted with CH2Cl2 (20 mL x 3). The combined organic layers were washed with water (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (10%–20% EtOAc in PE) to give 1-[4-bromo-3-(bromomethyl)phenyl]cyclopropane-1-carboxynitrile (550 mg, 51.5% yield).

[0348] Step C: 1-{4-bromo-3-[(2,3-dihydro-1H-inden-2-yloxy)methyl]phenyl}cyclopropane-1-carboxynitrile

[0349] Sodium hydride (190 mg, 4.76 mmol, 60% wt in mineral oil) was added to a solution of 1-[4-bromo-3-(bromomethyl)phenyl]cyclopropane-1-carboxynitrile (500 mg, 1.59 mmol) in DMF (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min. 2,3-Dihydro-1H-inden-2-ol (639 mg, 4.76 mmol) was added to the above reaction mixture. The resulting reaction mixture was allowed to be warmed to room temperature and stirred for 16 h. The reaction mixture was quenched with ice water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (10%-20% EtOAc in PE) to give 1-{4-bromo-3-[(2,3-dihydro-1H-indene-2-yloxy)methyl]phenyl}cyclopropane-1-carboxynitrile (370 mg, yield 63.3%).

[0350] Step D: 1-{2-[(2,3-dihydro-1H-inden-2-yloxy)methyl]-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl}cyclopropane-1-carboxynitrile

[0351] Under a nitrogen atmosphere at room temperature, Pd(dppf)Cl2.CH2Cl2 (49 mg, 0.06 mmol) was added to a stirred solution of 1-{4-bromo-3-[(2,3-dihydro-1H-indene-2-yloxy)methyl]phenyl}cyclopropane-1-carboxynitrile (220 mg, 0.60 mmol), 2-(3,5-dimethoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane (199 mg, 0.716 mmol) and Na2CO3 (190 mg, 1.79 mmol) in 1,4-dioxane (4 mL) and water (0.8 mL). The resulting mixture was stirred at 90 °C for 2 h. After cooling, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-30% EtOAc in PE) to give 1-{2-[(2,3-dihydro-1H-inden-2-yloxy)methyl]-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl}cyclopropane-1-carboxynitrile (220 mg, yield 83.8%). LC-MS: m / z 440.0 (M+H) + .

[0352] Step E: 1-{2-[(2,3-dihydro-1H-inden-2-yloxy)methyl]-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl}cyclopropane-1-carboxylic acid (compound 118)

[0353] A solution of NaOH (500 mg, 12.5 mmol) in water (1 mL) was added to a stirred solution of 1-{2-[(2,3-dihydro-1H-indene-2-yloxy)methyl]-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl}cyclopropane-1-carboxynitrile (100 mg, 0.29 mmol) in EtOH (5 mL). The reaction mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. After cooling, the reaction mixture was acidified to pH 5 with 2 M HCl. The resulting mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by preparative HPLC (column: Xselect CSH C18 OBD column 30*150mm 5μm; mobile phase A: water (0.05% HCl), mobile phase B: CH3CN; flow rate: 60 mL / min; gradient: 50% B to 90% B over 10 min) to give 1-{2-[(2,3-dihydro-1H-inden-2-yloxy)methyl]-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl}-cyclopropane-1-carboxylic acid (40.6 mg, yield 38.9%). LC-MS: m / z 457.0 (MH) - . 1 HNMR(400MHz,DMSO-d6)δ12.33(s,1H),7.41(d,J=1.9Hz,1H),7.30(dd,J=7.8H z,1.9Hz,1H),7.23(d,J=7.9Hz,1H),7.20-7.16(m,2H),7.14-7.09(m,2H),6.6 1(s,2H),4.43-4.31(m,3H),3.73(s,6H),3.08(dd,J=16.4Hz,6.3Hz,2H),2.86 (dd,J=16.4Hz,3.7Hz,2H),2.03(s,3H),1.46-1.44(m,2H),1.14-1.12(m,2H). Example A7 (2S)-1-((2-(((2,3-dihydro-1H-indene-2-yl)oxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)-2-methylcyclopropane-1-carboxylic acid (compound 119)

[0354] Step A: (2S)-1-((diphenylmethylene)amino)-2-methylcyclopropane-1-carboxylic acid ethyl ester

[0355] NaH (1.35 g, 56.11 mmol, in mineral oil 60% wt) was added to a solution of ethyl 2-[(diphenylmethylene)amino]acetate (5 g, 18.70 mmol) in THF (50 mL) at 0 °C. After stirring for 15 min, (R)-(-)-4-methyl-2,2-dioxo-1,3,2-dioxathiopentane (2.28 g, 14.30 mmol) was added to the above solution. The resulting mixture was heated to 50 °C and stirred for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with hexane (50 mL), filtered, and the filter cake was washed with hexane (10 mL x 3). The combined filtrates were concentrated under reduced pressure to give ethyl (2S)-1-[(diphenylmethylene)amino]-2-methylcyclopropane-1-carboxylate (3.4 g, crude product). LC-MS: m / z 308.0 (M+H) + .

[0356] Step B: (2S)-1-amino-2-methylcyclopropane-1-carboxylic acid ethyl ester hydrochloride

[0357] A 6M HCl aqueous solution (3.87 mL, 13.27 mmol) was added to a stirred solution of (2S)-1-[(diphenylmethylene)amino]-2-methylcyclopropane-1-carboxylate (3.4 g, 11.06 mmol) in ether (35 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was extracted with EtOAc (20 mL x 2). The combined aqueous layers were concentrated under reduced pressure to give (2S)-1-amino-2-methylcyclopropane-1-carboxylate hydrochloride (1.2 g, 60.4% yield).

[0358] (2S)-1-((2-(((2,3-dihydro-1H-indene-2-yl)oxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)-2-methylcyclopropane-1-carboxylic acid (compound 119) was synthesized in step C using ethyl (2S)-1-amino-2-methylcyclopropane-1-carboxylic acid hydrochloride, according to the procedure (steps C and D) described for the preparation of Example A3. LC-MS: m / z 488.2 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ7.22-7.15(m,2H),7.16-7.09(m,2H),7.05-7.00(m,1H),6.76(s,1H),6.62-6.51(m,3H),6.3 9(s,1H),4.36-4.35(m,3H),3.73(s,6H),3.12-3.04(m,2H),2.89-2.82(m,2H),2.01(s,3H),1.94-1.45(m,2H),1.15 -1.10(m,3H),0.62-0.60(m,1H). Example A8 1-({4'-acetyl-2-[(2,3-dihydro-1H-indene-2-yloxy)methyl]-3',5'-dimethoxy-[1,1'-biphenyl]-4-yl}amino)cyclopropane-1-carboxylic acid (compound 121)

[0359] Step A: 1-[2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]acetone

[0360] [Ir(COD)(OMe)]₂ (0.18 g, 0.28 mmol) was added to a stirred mixture of 2',6'-dimethoxyacetylbenzene (1.00 g, 5.55 mmol), bis(pinacol)diboron (1.69 g, 6.66 mmol), and 4,4'-di-tert-butyl-2,2'-bipyridine (dtbpy) (0.30 g, 1.11 mmol) in THF (10 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 16 h under a nitrogen atmosphere. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (3% to 7% MeOH in CH2Cl2) to give 1-[2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]acetone (600 mg, 35.3%). LC-MS: m / z 306.9 (M+H) + .

[0361] 1-({4'-acetyl-2-[(2,3-dihydro-1H-indene-2-yloxy)methyl]-3',5'-dimethoxy-[1,1'-biphenyl]-4-yl}amino)cyclopropane-1-carboxylic acid (compound 121) was synthesized according to the procedure (steps C and D) described for the preparation of Example A3 by using 1-aminocyclopropane-1-carboxylic acid in step C and 1-[2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]acetone in step D. LC-MS: m / z 502.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.20-7.18(m,2H),7.13-7.10(m,2H),7.06(d,J=8.3Hz,1H),6.74(d,J=2.0Hz,1H),6.63-6.61(m,3H),6.54(s,1H),4.3 6-4.35(m,3H),3.71(s,6H),3.09(dd,J=16.4Hz,6.3Hz,2H),2.85(dd,J=16.3Hz,3.7Hz,2H),2.38(s,3H),1.39-1.37(m,2H),0.94-0.90(m,2H). Example A9 4-({3',5'-dimethoxy-4'-methyl-2-[2-(2-methyl-1,3-benzodioxacyclopenten-2-yl)ethyl]-[1,1'-biphenyl]-4-yl}amino)oxane-4-carboxylic acid (compound 132)

[0362] Step A: Methyl 2-[(2-bromo-5-iodophenyl)methyl]-3-oxobutyrate

[0363] NaOMe (540 mg, 9.99 mmol) was added to a solution of methyl 3-oxobutyrate (927 mg, 7.99 mmol) in MeOH (20 mL). After stirring for 10 min, 1-bromo-2-(bromomethyl)-4-iodobenzene (2.5 g, 6.66 mmol) was added to the mixture. The resulting mixture was stirred at 65 °C for 6 h. After cooling, the mixture was poured into water (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc = 10 / 1) to give methyl 2-(2-bromo-5-iodophenyl)-3-oxobutyrate (1.7 g, yield 52.3%, purity 80%).

[0364] Step B: 4-(2-bromo-5-iodophenyl)but-2-one

[0365] Lithium chloride (361 mg, 8.52 mmol) was added to a solution of methyl 2-[(2-bromo-5-iodophenyl)methyl]-3-oxobutyrate (700 mg, 1.70 mmol) in DMF (10 mL) under nitrogen atmosphere. The resulting mixture was stirred at 130 °C for 5 h. After cooling, the mixture was poured into water (50 mL) and extracted with CH2Cl2 (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc = 10 / 1) to give 4-(2-bromo-5-iodophenyl)but-2-one (488 mg, yield 81.3%).

[0366] Step C: 2-[2-(2-bromo-5-iodophenyl)ethyl]-2-methyl-1,3-benzodioxane

[0367] A mixture of 4-(2-bromo-5-iodophenyl)but-2-one (550 mg, 1.56 mmol), catechol (858 mg, 7.79 mmol), and PTSA (54 mg, 0.31 mmol) in toluene (10 mL) was stirred at 110 °C for 16 h. After cooling, the mixture was poured into water (50 mL) and extracted with CH2Cl2 (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 10:1) to give 2-[2-(2-bromo-5-iodophenyl)ethyl]-2-methyl-1,3-benzodioxane (110 mg, 15.9% yield).

[0368] 4-({3',5'-dimethoxy-4'-methyl-2-[2-(2-methyl-1,3-benzodioxacyclopenten-2-yl)ethyl]-[1,1'-biphenyl]-4-yl}amino)oxane-4-carboxylic acid (compound 132) was synthesized in step C using 2-[2-(2-bromo-5-iodophenyl)ethyl]-2-methyl-1,3-benzodioxacyclopentene, according to the procedure (steps C and D) described for the preparation of Example A3. LC-MS: m / z 534.1 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ6.90(d,J=8.3Hz,1H),6.74-6.71(s,4H),6.56(s,1H),6.46-6.42(m,3H),3.71(s,6H) ,3.63-3.62(m,3H),2.66-2.58(m,2H),2.29-2.14(m,2H),2.09-2.00(m,4H),1.86-1.84(m,2H),1.50(s,3H). Example A10 4-({2-[(cyclopentyloxy)methyl]-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl}amino)-oxane-4-

[0369] 4-({2-[(cyclopentyloxy)methyl]-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl}amino)-oxane-4-carboxylic acid (compound 134) was synthesized in step B using cyclopentanol according to the procedure (steps B to D) described for the preparation of Example A3. LC-MS: m / z 470.2 (M+H) + .1 H NMR(400MHz, DMSO-d6)δ6.98(d,J=8.3Hz,1H),6.75(d,J=2.4Hz,1H),6.54-6.52(m,3H),4.19(s,2H),3.91-3.90(m ,1H),3.76(s,6H),3.65-3.57(m,4H),2.04-2.00(m,5H),1.99-1.87(m,2H),1.69-1.53(m,6H),1.46-1.44(m,2H). Example A11 4-((2-((cyclopentyloxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (compound 140)

[0370] 1-(tert-butoxycarbonyl)-4-((2-((cyclopentyloxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)piperidine-4-carboxylic acid (11-1) was synthesized according to the procedure (steps B to D) described for the preparation of Example A3 by using cyclopentanol in step B and 4-amino-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid in step C. LC-MS: m / z 587.1 (M+H2O+H) + .

[0371] Step A: 4-((2-((cyclopentyloxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)piperidine-4-carboxylic acid

[0372] A mixture of 1-(tert-butoxycarbonyl)-4-((2-((cyclopentyloxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)piperidine-4-carboxylic acid (120 mg, 0.211 mmol) in TFA (2 mL) and CH2Cl2 (4 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: CH3CN; flow rate: 60mL / min; gradient: 5% B to 60% B over 10min) to give 4-((2-((cyclopentyloxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)piperidine-4-carboxylic acid (77 mg, yield 77.9%). LC-MS: m / z 469.1 (M+H) + .

[0373] Step B: 4-((2-((cyclopentyloxy)methyl)-3'-hydroxy-5'-methoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (compound 140)

[0374] At 0 °C, a solution of dimethyl dicarbonate (7.73 mg, 0.06 mmol) in CH₂Cl₂ (1 mL) was added dropwise to a solution of 4-((2-((cyclopentyloxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)piperidin-4-carboxylic acid (60 mg, 0.13 mmol) and Et₃N (38.87 mg, 0.39 mmol) in CH₂Cl₂ (3 mL). After the addition, the reaction mixture was stirred at 0 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150mm, 5μm; mobile phase A: water (10mM NH4HCO3), mobile phase B: CH3CN; flow rate: 60mL / min; gradient: 5% B to 60% B over 8 min) to give 4-((2-((cyclopentyloxy)methyl)-3'-hydroxy-5'-methoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (16.8 mg, yield 24.9%). LC-MS: m / z 527.2 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ6.96 (d, J = 8.4Hz, 1H), 6.79-6.70 (m, 1H), 6.57-6.44 (m, 3H), 4.19 (s, 2H), 3.96-3.86 (m, 1H), 3. 76(s,6H),3.68-3.50(m,5H),3.30-3.20(m,2H),2.00(s,3H),1.97-1.84(m,4H),1.68-1.53(m,6H),1.49-1.38(m,2H). Example A12 4-((2-((cyclopentyloxy)methyl)-3',5'-dimethoxy-4',6-dimethyl-[1,1'-biphenyl]-4-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (compound 141)

[0375] 4-((2-((cyclopentyloxy)methyl)-3',5'-dimethoxy-4',6-dimethyl-[1,1'-biphenyl]-4-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (compound 141) was synthesized according to the procedure (steps A to D) described for the preparation of Example A3 by using 2-bromo-5-iodo-1,3-dimethylbenzene in step A and cyclopentanol in step B. LC-MS: m / z 484.1 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ6.57(d,J=2.4Hz,1H),6.40(d,J=2.4Hz,1H),6.33(s,2H),3.96(s,2H),3.76-3.74(m,1 H),3.69(s,6H),3.68-3.54(m,4H),2.09-1.93(m,5H),1.88-1.80(m,5H),1.66-1.47(m,4H),1.47-1.33(m,4H). Example A13 4-((2-((cyclopentyloxy)methyl)-6-fluoro-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (compound 147)

[0376] Step A: 4-Bromo-3-fluoro-5-methylaniline

[0377] NBS (7.25 g, 40.8 mmol) was added to a mixture of 3-fluoro-5-methyl-aniline (5 g, 40.0 mmol) in DMF (40 mL) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. The reaction was quenched with H₂O (20 mL). The mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with H₂O (20 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was passed through a rapid silica gel column (…). 120g Purification was performed using a silica gel rapid column at 85 mL / min with an eluent gradient of 0%–20% EtOAc / PE to give 4-bromo-3-fluoro-5-methylaniline (8.0 g, 98.1% yield). 1 HNMR (400MHz, CDCl3): δ6.36 (s, 1H), 6.32-6.28 (m, 1H), 2.31 (s, 3H).

[0378] Step B: 2-Bromo-1-fluoro-5-iodo-3-methylbenzene

[0379] A solution of 4-bromo-3-fluoro-5-methylaniline (21.7 g, 106 mmol) in MeCN (500 mL) was added to a solution of H₂SO₄ (14.0 mL, 263 mmol) in H₂O (30 mL) at 0 °C. After stirring for 5 min, a solution of NaNO₂ (14.7 g, 213 mmol) in water (30 mL) was added dropwise, and the reaction mixture was stirred for an additional 15 min at 0 °C. Then, a solution of KI (70.6 g, 425 mmol) in water (60 mL) was added. After the addition, the ice bath was removed and the mixture was warmed to 25 °C, and the resulting reaction mixture was stirred for an additional 20 min. The mixture was quenched with a saturated aqueous solution of Na₂S₂O₃, diluted with water (300 mL), and extracted with EtOAc (160 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was passed through a rapid silica gel column (…). 220g Purification was performed using a silica gel rapid column at 100 mL / min with 0% EtOAc / PE gradient elution to give 2-bromo-1-fluoro-5-iodo-3-methylbenzene (31.6 g, 94.2% yield).

[0380] 4-((2-((cyclopentyloxy)methyl)-6-fluoro-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (compound 147) was synthesized according to the procedure (steps A and D) described for the preparation of Example A3 by using 2-bromo-1-fluoro-5-iodo-3-methylbenzene in step A and cyclopentanol in step B. LC-MS: m / z 488.4 (M+H) + . 1 H NMR (400MHz, CD3OD) δ6.65 (s, 1H), 6.46 (s, 2H), 6.39 (d, J = 12.0Hz, 1H), 4.18 (s, 2H), 3. 87-3.74(m,11H),2.28-2.20(m,2H),2.09(s,3H),2.06-2.01(m,2H),1.66-1.50(m,8H). Example A14 4-((2-((cyclopentyloxy)methyl)-3',5'-dimethoxy-2',4-dimethyl-[1,1'-biphenyl]-4-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (compound 148)

[0381] Step A: (3,5-Dimethoxy-4-methylphenyl) tert-butyl carbamate

[0382] TEA (39 mL, 280.20 mmol) and DPPA (38.10 g, 138.44 mmol) were added to a solution of 3,5-dimethoxy-4-methylbenzoic acid (25 g, 127.42 mmol) in toluene (70 mL) and t-BuOH (70 mL). After degassing and purging three times with nitrogen, the resulting mixture was stirred at 85 °C for 12 h under a nitrogen atmosphere. The reaction mixture was diluted with H₂O (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc = 9 / 2) to give tert-butyl (3,5-dimethoxy-4-methylphenyl)carbamate (28.86 g, 79.9% yield). LC-MS: m / z 268.1 (M+H) + .

[0383] Step B: 3,5-Dimethoxy-4-methylaniline

[0384] A mixture of tert-butyl (3,5-dimethoxy-4-methylphenyl)carbamate (28.86 g, 107.96 mmol) in 4 M HCl (gas) / EtOAc (258 mL) was stirred at 25 °C for 2 h. The pH was then adjusted to 8–9 with a saturated aqueous solution of NaHCO3, and the mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give 3,5-dimethoxy-4-methylaniline (18.03 g, 99.9% yield).

[0385] Step C: 2-Bromo-3,5-dimethoxy-4-methylaniline

[0386] NBS (5.32 g, 29.90 mmol) was added to a solution of 3,5-dimethoxy-4-methylaniline (5 g, 29.90 mmol) in AcOH (20 mL), and the mixture was stirred at 25 °C for 2 h. The pH was then adjusted to 8–9 with a saturated aqueous solution of NaHCO3, and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc = 9 / 1) to give 2-bromo-3,5-dimethoxy-4-methylaniline (4.59 g, yield 56.3%). LC-MS: m / z 246.1 (M+H) + .

[0387] Step D: 3,5-Dimethoxy-2,4-Dimethylaniline

[0388] Methylboric acid (2.79 g, 46.63 mmol), K3PO4 (15.84 g, 74.60 mmol), S-Phos (1.53 g, 3.73 mmol), and Pd2(dba)3 (1.71 g, 1.87 mmol) were added to a solution of 2-bromo-3,5-dimethoxy-4-methylaniline (4.59 g, 18.65 mmol) in toluene (30 mL) under nitrogen atmosphere. After degassing and purging with nitrogen three times, the mixture was stirred at 80 °C for 12 h under nitrogen atmosphere. After cooling and filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc = 9 / 1) to give 3,5-dimethoxy-2,4-dimethylaniline (2.45 g, 72.5% yield). LC-MS: m / z 182.2 (M+H) + .

[0389] Step E: 1-Iodo-3,5-dimethoxy-2,4-dimethylbenzene

[0390] A solution of NaNO2 (2.14 g, 31.04 mmol) in H2O (5 mL) was added to a solution of 3,5-dimethoxy-2,4-dimethylaniline (2.25 g, 12.42 mmol) in 37% HCl (12 mL, 124.15 mmol) and acetone (15 mL) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. A solution of NaI (7.44 g, 49.66 mmol) in H2O (5 mL) was added, and the mixture was stirred at 25 °C for 16 h. The reaction was quenched with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were concentrated and purified by silica gel column chromatography (100% PE) to give a red crude product. The crude product was dissolved in EtOAc (40 mL), and the mixture was washed with saturated aqueous Na2S2O3 solution (30 mL x 3). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated to give 1-iodo-3,5-dimethoxy-2,4-dimethylbenzene (2.64 g, yield 71.6%). LC-MS: m / z 292.9 (M+H) + .

[0391] Step F: 2-(3,5-dimethoxy-2,4-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane

[0392] To a solution of 1-iodo-3,5-dimethoxy-2,4-dimethylbenzene (1 g, 3.42 mmol) in 1,4-dioxane (20 mL), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane) (1.74 g, 6.85 mmol), KOAc (1.01 g, 10.27 mmol), and Pd(dppf)Cl2 (250.49 mg, 342.33 μmol) were added. After degassing and purging three times with nitrogen, the reaction mixture was stirred at 100 °C for 12 h under nitrogen. After cooling, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc = 32 / 1) to give 2-(3,5-dimethoxy-2,4-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane (404 mg, yield 40.4%). 1H NMR (400MHz, CDCl3) δ6.96(s,1H),3.77(s,3H),3.60(s,3H),2.35(s,3H),2.10(s,3H),1.27(s,12H).

[0393] 4-((2-((cyclopentyloxy)methyl)-3',5'-dimethoxy-2',4'-dimethyl-[1,1'-biphenyl]-4-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (compound 148) was synthesized according to the procedure (steps A and D) described for the preparation of Example A3 by using cyclopentanol in step B and 2-(3,5-dimethoxy-2,4-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane in step D. LC-MS: m / z 484.2 (M+H) + . 1 H NMR (400MHz, CD3OD) δ6.87-6.80(m,2H),6.68(dd,J=8.4Hz,2.4Hz,1H),6.47(s,1H),4.14-4.02(m,2H),3.88-3.77( m,5H),3.76(s,3H),3.71(s,3H),2.30-2.20(m,2H),2.16(s,3H),2.05-1.95(m,2H),1.90(s,3H),1.63-1.39(m,8H). Example A15 (S)-4-((3',5'-dimethoxy-4'-methyl-2-(2-(tetrahydrofuran-3-yl)ethyl)-[1,1'-biphenyl]-4-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid and (R)-4-((3',5'-dimethoxy-4'-methyl-2-(2-(tetrahydrofuran-3-yl)ethyl)-[1,1'-biphenyl]-4-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (compounds 185 and 186)

[0394] Step A: 3-Ethynyltetrahydrofuran

[0395] Dimethyl (1-diazo-2-oxopropyl)phosphonate (10.6 g, 54.9 mmol) was added to a mixture of tetrahydrofuran-3-carboxaldehyde (5.0 g, 49.9 mmol), K₂CO₃ (10.0 g, 72.4 mmol), and MeOH (60 mL). The reaction mixture was stirred at 20 °C for 3 h. The suspension was then subjected to… The mixture was filtered through a pad and washed with petroleum ether (30 mL). The filtrate was concentrated under vacuum (bath temperature below 15 °C) to give 3-ethynyltetrahydrofuran (10 g, crude product), which was used in the next step without further purification. 1 H NMR(400MHz, CDCl3)δ4.02(t,J=7.8Hz,1H),3.97-3.80(m,2H),3.67(dd,J=8.0Hz,7.2H z,1H),3.07-2.93(m,1H),2.30-2.16(m,1H),2.12(d,J=2.2Hz,1H),2.05-1.97(m,1H).

[0396] Step B: 3-((5-bromo-2-chlorophenyl)ethynyl)tetrahydrofuran

[0397] A mixture of CuI (50.0 mg, 263 μmol), Pd(PPh3)2Cl2 (92.2 mg, 131 μmol), and TEA (3.99 g, 39.4 mmol) in THF (100 mL) was degassed and purged three times with nitrogen. Then, 4-bromo-1-chloro-2-iodobenzene (5.00 g, 15.8 mmol) and 3-ethynyltetrahydrofuran (10.0 g, 104 mmol) were added. The resulting mixture was stirred at 20 °C for 6 h under a nitrogen atmosphere. The reaction mixture was diluted with saturated NH4Cl aqueous solution (40 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was subjected to rapid silica gel chromatography (…). 80g Purification was performed using a silica gel rapid column at 60 mL / min with an elution of 0%–15% EtOAc / PE gradient to give 3-((5-bromo-2-chlorophenyl)ethynyl)tetrahydrofuran (1.5 g, 40.0% yield). 1 H NMR (400MHz, CDCl3) δ7.57 (d, J=2.2Hz, 1H), 7.34 (dd, J=8.6Hz, 2.2Hz, 1H), 7.26 -7.22(m,1H),4.10(t,J=7.8Hz,1H),4.02-3.86(m,2H),3.78-3.76(m,1H),3.31-3.20(m,1H),2.37-2.25(m,1H),2.18-2.05(m,1H).

[0398] Step C: 4-((4-chloro-3-((tetrahydrofuran-3-yl)ethynyl)phenyl)amino)tetrahydro-2H-pyran-4-

[0399] A mixture of 3-((5-bromo-2-chlorophenyl)ethynyl)tetrahydrofuran (1 g, 3.50 mmol), 4-aminotetrahydro-2H-pyran-4-carboxylic acid (1.02 g, 7.00 mmol), CuI (133 mg, 700.37 μmol), and DBU (1.33 g, 8.75 mmol, 1.32 mL) in DMA (10 mL) was heated in a microwave oven at 120 °C for 60 min. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with brine (50 mL), extracted with EtOAc (50 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (fast silica gel column, 0%–50% EtOAc / PE gradient eluent) to give 4-((4-chloro-3-((tetrahydrofuran-3-yl)ethynyl)phenyl)amino)tetrahydro-2H-pyran-4-carboxylic acid (450 mg, 1.29 mmol). LC-MS: m / z 349.8 (M+H) + .

[0400] Step D: 4-((3',5'-dimethoxy-4'-methyl-2-((tetrahydrofuran-3-yl)ethynyl)-[1,1'-biphenyl]-4-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid

[0401] XPhos Pd G3 (96.8 mg, 114 μmol) and Cs2CO3 (745 mg, 2.29 mmol) were added to a solution of 4-((4-chloro-3-((tetrahydrofuran-3-yl)ethynyl)phenyl)amino)tetrahydro-2H-pyran-4-carboxylic acid (400 mg, 1.14 mmol) and 2-(3,5-dimethoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane-pentaborane (636 mg, 2.29 mmol) in THF (4 mL) and H2O (4 mL). The mixture was stirred at 120 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with brine (50 mL), acidified to pH 5 with 1 N HCl, extracted with EtOAc (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (fast silica gel column, 0%–50% EtOAc / PE gradient eluent) to give 4-((3',5'-dimethoxy-4'-methyl-2-((tetrahydrofuran-3-yl)ethynyl)-[1,1'-biphenyl]-4-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (470 mg, 1.01 mmol). LC-MS: m / z 465.9 (M+H) + .

[0402] Step E: 4-((3',5'-dimethoxy-4'-methyl-2-(2-(tetrahydrofuran-3-yl)ethyl)-[1,1'-biphenyl]-4-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid

[0403] Add 10% Pd / C (100 mg) to a solution of 4-((3',5'-dimethoxy-4'-methyl-2-((tetrahydrofuran-3-yl)ethynyl)-[1,1'-biphenyl]-4-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (470 mg, 1.01 mmol) in EtOAc (0.5 mL). Stir the reaction mixture at 25 °C for 5 h under a H2 atmosphere (15 psi). Dilute the mixture with EtOAc (20 mL), filter, and evaporate. The residue was purified by rapid silica gel chromatography (fast silica gel column, 0%–40% EtOAc / PE gradient eluent) to give 4-((3',5'-dimethoxy-4'-methyl-2-(2-(tetrahydrofuran-3-yl)ethyl)-[1,1'-biphenyl]-4-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (90 mg, yield 19.0%, purity 80%). LC-MS: m / z 470.3 (M+H) + .

[0404] Step F: (S)-4-((3',5'-dimethoxy-4'-methyl-2-(2-(tetrahydrofuran-3-yl)ethyl)-[1,1'-biphenyl]-4-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid and (R)-4-((3',5'-dimethoxy-4'-methyl-2-(2-(tetrahydrofuran-3-yl)ethyl)-[1,1'-biphenyl]-4-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (compounds 185 and 186)

[0405] A sample of 4-((3',5'-dimethoxy-4'-methyl-2-(2-(tetrahydrofuran-3-yl)ethyl)-[1,1'-biphenyl]-4-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid was subjected to SFC separation (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: A: CO2, B: [0.1% NH3H2O ​​in EtOH]; B%: 20%-20%). After solvent removal, the sample was lyophilized to obtain the title compound. The absolute stereochemistry of each product was not identified.

[0406] Enantiomer 1: 4-((3',5'-dimethoxy-4'-methyl-2-(2-(tetrahydrofuran-3-yl)ethyl)-[1,1'-biphenyl]-4-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (compound 185) SFC analytical conditions: Column: ChiralPak AD-3 150×4.6mm ID, 3µm; Mobile phase: A: CO2 B: ethanol (0.05% diethylamine); Isocratic rate: 15% B; Flow rate: 2.5 mL / min; Column temperature: 40℃; Retention time: 3.908 min. 1 H NMR(400MHz,DMSO-d6)δ6.84(d,J=8.2Hz,1H),6.55(s,1H),6.48-6.41(m,3H),3.73(s,6H),3.64-3.61(m,6H),3 .52-3.51(m,2H),3.09-3.04(m,1H),2.42-2.40(m,1H),2.05-1.97(m,7H),1.88-1.76(m,3H),1.49-1.44(m,2H). LC-MS:m / z 470.3(M+H) + .

[0407] Enantiomer 2: 4-((3',5'-dimethoxy-4'-methyl-2-(2-(tetrahydrofuran-3-yl)ethyl)-[1,1'-biphenyl]-4-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (compound 186) SFC analytical conditions: Column: ChiralPak AD-3 150×4.6mm ID, 3µm; Mobile phase: A: CO2 B: ethanol (0.05% diethylamine); Gradient: from 5% to 40% B over 4.5 min, then 5% B for 1.5 min; Flow rate: 2.5 mL / min; Column temperature: 40 °C; Retention time: 3.827 min. 1 HNMR(400MHz,DMSO-d6)δ6.86(d,J=8.4Hz,1H),6.54(s,1H),6.45-6.40(m,3H),3.73(s,6H),3.65-3.60(m,6H),3 .53-3.49(m,2H),3.09-3.04(m,1H),2.44-2.37(m,1H),2.06-1.94(m,7H),1.89-1.77(m,3H),1.50-1.44(m,2H). LC-MS:m / z 470.3(M+H) + . Example A16 4-((2'-chloro-2-((cyclopentyloxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)oxy)tetrahydro-2H-pyran-4-carboxylic acid (compound 192)

[0408] 1-Bromo-2-(cyclopentoxymethyl)-4-iodobenzene (16-1) was synthesized in step B using cyclopentanol according to the procedure (steps A to B) described in preparation for Example A3. 1 H NMR (400MHz, CDCl3) δ7.80 (d, J = 2.0Hz, 1H), 7.44 (dd, J = 8.4Hz, 2.2Hz, 1H), 7.23 (d, J = 8.4Hz, 1H), 4.45 (s, 2H), 4.10-4.02 (m, 1H), 1.85-1.52 (m, 8H).

[0409] Step A: (4-bromo-3-((cyclopentyloxy)methyl)phenyl)boronic acid

[0410] At -78 °C under a nitrogen atmosphere, n-BuLi (2.5 M, 1.3 mL) was added to a mixture of 1-bromo-2-(cyclopentoxymethyl)-4-iodobenzene (1.2 g, 3.2 mmol) in THF (10 mL). After stirring for 0.5 h, trimethyl borate (356 μL, 3.2 mmol) was added dropwise. The resulting mixture was stirred at -78 °C for 0.5 h and then at 15 °C for 0.5 h. It was then quenched with 2N HCl (15 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give crude [4-bromo-3-(cyclopentoxymethyl)phenyl]boronic acid (1 g, crude product) as a brown solid, which was used in the next step without purification.

[0411] Step B: 4-Bromo-3-((cyclopentyloxy)methyl)phenol

[0412] Add 30% H₂O₂ (10 mL, 104.1 mmol) to a mixture of [4-bromo-3-(cyclopentoxymethyl)phenyl]boronic acid (1 g, 3.3 mmol) in THF (10 mL). Stir the resulting mixture at 15 °C for 1 h. Carefully quench the reaction mixture with a saturated aqueous solution of Na₂SO₃ (50 mL) and extract with ethyl acetate (50 mL x 2). Dry the organic layer over anhydrous Na₂SO₄, filter, and concentrate under reduced pressure to obtain the residue. Separately analyze the residue by rapid silica gel chromatography (…). 20g Purification was performed using a silica gel rapid column at 40 mL / min with an eluent gradient of 0%–20% EtOAc / PE to give 4-bromo-3-(cyclopentoxymethyl)phenol (360 mg, yield 39.7%). LC-MS: m / z 269.1 (MH) - .

[0413] Step C: 4-(4-bromo-3-((cyclopentyloxy)methyl)phenoxy)tetrahydro-2H-pyran-4-carboxylic acid

[0414] At 0 °C, NaOH (266 mg, 6.6 mmol) and tetrahydropyran-4-one (399 mg, 4.0 mmol, 366 μL) were added to a mixture of 4-bromo-3-(cyclopentoxymethyl)phenol (360 mg, 1.3 mmol) in THF (6 mL). Subsequently, CHCl3 (536 μL, 6.6 mmol) was added dropwise. The resulting mixture was stirred at 15 °C for 16 h. The reaction mixture was acidified with 1N HCl (approximately 3 mL) and extracted with ethyl acetate (15 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to rapid silica gel chromatography (…). 12g Purification was performed using a silica gel rapid column at 40 mL / min with an elution of 0%–30% EtOAc / PE gradient to give 4-[4-bromo-3-(cyclopentoxymethyl)phenoxy]tetrahydropyran-4-carboxylic acid (280 mg, yield 52.8%). 1 H NMR (400MHz, CDCl3) δ7.37(d,J=8.8Hz,1H),7.08(d,J=2.8Hz,1H),6.68(dd,J=8.8,3.2Hz,1 H),4.44(s,2H),4.04-3.98(m,1H),3.82-3.76(m,4H),2.26-2.13(m,4H),1.77-1.53(m,8H).

[0415] Step D: 4-((2'-chloro-2-((cyclopentyloxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)oxy)tetrahydro-2H-pyran-4-carboxylic acid (compound 192)

[0416] XPhos Pd G3 (46.6 mg, 55.1 μmol) and Cs2CO3 (359 mg, 1.1 mmol) were added to a mixture of 4-[4-bromo-3-(cyclopentoxymethyl)phenoxy]tetrahydropyran-4-carboxylic acid (220 mg, 551 μmol) and 2-(2-chloro-3,5-dimethoxy-4-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane-189 mg, 606 μmol) in THF (3 mL) and H2O (3 mL). The resulting mixture was stirred at 80 °C for 16 h under nitrogen. After cooling, the reaction mixture was acidified to pH 4 with 1N HCl. The mixture was extracted with ethyl acetate (10 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to rapid silica gel chromatography (…). 12g Purification was performed using a silica gel fast column at 40 mL / min with an eluent gradient of 0%–40% EtOAc / PE and further by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (0.05% NH3·H2O + 10mM NH4HCO3)-CH3CN]; B%: 35%–65%, 7 min) to give 4-[4-(2-chloro-3,5-dimethoxy-4-methyl-phenyl)-3-(cyclopentoxymethyl)phenoxy]tetrahydropyran-4-carboxylic acid (70.3 mg, yield 25.3%). LC-MS: m / z 522.2 (M+NH3+H). + . 1 HNMR(400MHz,CD3OD)δ7.10(d,J=2.8Hz,1H),7.05(d,J=8.4Hz,1H),6.93(dd,J=8.4Hz,2.8Hz,1H),6.62(s, 1H), 4.92 (s, 14H), 4.20 (dd, J = 28.4Hz, 12Hz, 1H), 3.87-3.77 (m, 11H), 2.33-2.09 (m, 7H), 1.70-1.39 (m, 8H). Example A17 4-((3-((cyclopentyloxy)methyl)-4-(6-methoxy-7-methyl-2,3-benzodihydrofuran-4-yl)phenyl)amino)tetrahydro-2H-pyran-4-carboxylic acid (compound 193)

[0417] Step A: 1-Bromo-2-(2-Bromoethoxy)-4-methoxy-benzene

[0418] K₂CO₃ (7.45 g, 54 mmol) was added to a solution of 2-bromo-5-methoxyphenol (7.3 g, 36 mmol) and 1,2-dibromoethane (34 g, 180 mmol) in MeCN (150 mL). The mixture was stirred at 80 °C for 12 h. After cooling, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (120 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and evaporated to obtain the residue. The residue was subjected to rapid silica gel chromatography (…). 120g Purification was performed using a silica gel rapid column at 100 mL / min with 0%–2% EtOAc / PE gradient elution to give 1-bromo-2-(2-bromoethoxy)-4-methoxybenzene (7.2 g, yield 64.6%).1 H NMR (400MHz, CDCl3) δ7.42 (d, J = 8.6 Hz, 1H), 6.52-6.40 (m, 2H), 4.30 (t, J = 6.4 Hz, 2H), 3.79 (s, 3H), 3.67 (t, J = 6.4 Hz, 2H).

[0419] Step B: 6-Methoxy-2,3-benzodihydrofuran

[0420] n-BuLi (2.5 M, 10.22 mL) was added dropwise to a solution of 1-bromo-2-(2-bromoethoxy)-4-methoxybenzene (7.2 g, 23.2 mmol) in THF (60 mL) at -70 °C. The reaction mixture was stirred at -70 °C for 1 h and then at -50 °C for 2 h. The mixture was quenched with a saturated aqueous solution of NH4Cl (60 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated to give the residue. The residue was subjected to rapid silica gel chromatography (…). 120g Purification was performed using a silica gel rapid column at 100 mL / min with an elution of 0%–3% EtOAc / PE gradient to give 6-methoxy-2,3-benzodihydrofuran (1.08 g, 31.0% yield). 1 H NMR (400MHz, CDCl3) δ7.03-6.91 (m, 1H), 6.32-6.31 (m, 2H), 4.48 (t, J = 8.6Hz, 2H), 3.67 (s, 3H), 3.04 (t, J = 8.6Hz, 2H).

[0421] Step C: 6-Methoxy-7-methyl-2,3-benzodihydrofuran

[0422] n-BuLi (2.5 M, 3.16 mL) was added dropwise to a solution of 6-methoxy-2,3-benzodihydrofuran (1.08 g, 7.19 mmol) in THF (20 mL) at 80 °C. After stirring for 0.5 h, MeI (1.22 g, 8.63 mmol) was added dropwise. The resulting mixture was stirred at 25 °C for 1 h. The mixture was then diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and evaporated to obtain the residue. The residue was subjected to rapid silica gel chromatography (…). 20g Purification was performed using a silica gel rapid column at 80 mL / min with an elution rate of 0%–2% EtOAc / PE gradient to give 6-methoxy-7-methyl-2,3-benzodihydrofuran (192 mg, 16.3% yield). 1 H NMR (400MHz, CDCl3) δ6.87 (d, J = 8.0Hz, 1H), 6.28 (d, J = 8.4Hz, 2H), 4.49 (t, J = 8.6Hz, 2H), 3.72 (s, 3H), 3.08 (t, J = 8.6Hz, 2H), 2.01 (s, 3H).

[0423] Step D: 2-(6-methoxy-7-methyl-2,3-benzodihydrofuran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane

[0424] Add [Ir(COD)(OMe)]2 (3.88 mg, 5.85 μmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (dtbpy) (3.14 mg, 11.7 μmol) to a solution of 6-methoxy-7-methyl-2,3-benzodihydrofuran (192 mg, 1.17 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (dtbpy) in THF (5 mL) to a solution of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1,3,2-dioxane-2-yl) (267 mg, 1.05 mmol) in THF (5 mL). Stir the reaction mixture at 80 °C for 12 h. Evaporate the mixture to obtain the residue. Analyze the residue by rapid silica gel chromatography (…). 12g Purification was performed using a silica gel rapid column at 80 mL / min with 0%–3% EtOAc / PE gradient elution to give 2-(6-methoxy-7-methyl-2,3-benzodihydrofuran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane (129 mg, 38.0% yield). 1 H NMR (400MHz, CDCl3) δ6.69 (s, 1H), 4.48 (t, J = 8.8 Hz, 2H), 3.77 (s, 3H), 3.25 (t, J = 8.8 Hz, 2H), 2.03 (s, 3H), 1.25 (s, 12H).

[0425] 4-((3-((cyclopentyloxy)methyl)-4-(6-methoxy-7-methyl-2,3-benzodihydrofuran-4-yl)phenyl)amino)tetrahydro-2H-pyran-4-carboxylic acid (compound 193) was synthesized according to the procedure (steps A and D) described for the preparation of Example A3 by using cyclopentanol in step B and 2-(6-methoxy-7-methyl-2,3-benzodihydrofuran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane in step D. LC-MS: m / z 482.3 (M+H) + . 1 HNMR (400MHz, CD3OD) δ6.94(d,J=8.2Hz,1H),6.78(s,1H),6.67(d,J=8.2Hz,1H),6.23(s,1H),4.47(t,J=8.4Hz,2H),4.2 0(s,2H),3.89-3.75(m,5H),3.74(s,3H),2.89(t,J=8.0Hz,2H),2.27-2.16(m,2H),2.03-1.90(m,5H),1.65-1.47(m,8H). Example A18 4-((2-((bicyclo[3.1.0]hex-3-yloxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (compound 182)

[0426] 4-((2-((bicyclo[3.1.0]hex-3-yloxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (compound 182) was synthesized in step B using bicyclo[3.1.0]hex-3-ol according to the procedure (steps B to D) described for the preparation of Example A3. LC-MS: m / z 482.1 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ7.02(d,J=8.0Hz,1H),6.80(d,J=2.4Hz,1H),6.68(dd,J=8.4Hz,2.0Hz,1H),6.51(s,1H),4....

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein: A is for C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1 replace; 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 Alkyne or C 1-3 Heteroalkylene; wherein L 1 The C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkyne or C 1-3 The heteroalkylene group is optionally substituted by one to five independently selected groups: 1-9 Substitution of alkyl, halo, hydroxy and cyano groups; L 2 Yes key, C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkyne or C 1-3 Heteroalkylene; wherein L 2 The C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkyne or C 1-3 The heteroalkylene group is optionally substituted by one to five independently selected groups: 1-9 Substitution of alkyl, halo, hydroxy and cyano groups; X 1 Is N or CR 3 ; X 2 Is N or CR 5 ; X 3 Is N or CR 7 ; X 4 O or CHR 11 ; The condition is when A is C 1-6 When X is alkyl, 4 It is O; X 6 Is N or CR 6 ; n is 0, 1, or 2; m is 0, 1, 2, or 3; R 1 and R 2 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl or heterocyclic group; wherein R 1 and R 2 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl or heterocyclyl is optionally substituted by one to five Z 1 replace; or R 1 and R 2 Together with the atoms to which they are attached, they form C 3-10 Cycloalkyl or heterocyclic group; wherein the C 3-10 The cycloalkyl or heterocyclyl group is optionally substituted by one to five Z 1 replace; R 3 It is hydrogen, halide, cyano, nitro, -OH, -SH, -NH2, -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclic group; wherein R 3 The -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclyl is optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; R 4 It is a halide, 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 3-5 membered heterocyclic group; wherein R 4 The C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclic group is optionally substituted by one to five independently selected from halo, hydroxy, C 1-5 Substitution of alkoxy and cyano groups; or R 3 and R 4 together with the atoms to which they are attached form a cycloalkyl, aryl, heterocyclyl or heteroaryl; wherein the cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; R 5 is hydrogen, halide, cyano, nitro, -OR 15 、-N(R 15 )2. -SR 15 、-C(O)R 15 、-C(O)OR 15 , C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl, 3-5 membered heterocyclyl or 5 membered heteroaryl; wherein R 5 The C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl, 3-5 membered heterocyclyl or 5 membered heteroaryl are independently optionally substituted by one to five Z 1 replace; R 6 is hydrogen, halide, cyano, nitro, -OR 16 、-N(R 16 )2. -SR 16 , C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclic group; wherein R 6 The C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclyl is optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; R 7 It is hydrogen, halide, cyano, nitro, -OH, -SH, -NH2, -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclic group; wherein R 7 The -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclyl is optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; or R 6 and R 7 together with the atoms to which they are attached form a cycloalkyl, aryl, heterocyclyl or heteroaryl; wherein the cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; R 8 It is hydrogen, C 1-9 Alkyl, oxo, halo, hydroxy or cyano; R 9 It is hydrogen, C 1-9 Alkyl, oxo, halo, hydroxy or cyano; R 10 It is hydrogen, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclic group; wherein R 10 The C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclyl is optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; R 11 It 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 heterocyclic group; wherein R 13 Each -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-6 Cycloalkyl or 3 to 6 membered heterocyclyl is independently optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; R 14 It is hydrogen, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclic group; wherein R 14 The C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclyl is optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; R 15 It is hydrogen, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclic group; wherein R 15 The C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclyl is optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; R 16 It is hydrogen, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclic group; wherein R 16 The C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclyl is optionally substituted with one to five substituents independently selected from halo, hydroxy and cyano; 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; wherein Z 1 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1a replace; Each L is independently -O-, -S-, -NR 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -, -NR 20 C(O)-, -OC(O)NR 20 -, -NR 20 C(O)O-, -NR 20 C(O)NR 21 -, -S(O)-, -S(O)2-, -S(O)NR 20 -, -S(O)2NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR 20 S(O)NR 21 -, or -NR 20 S(O)2NR 21 -; Each R 20 and R 21 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein R 20 and R 21 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1a replace; or R 20 and R 21 Together with the atoms to which they are attached, they form independently optionally one to five Z 1a substituted heterocyclyl; and Each Z 1a are independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein Z 1a Each -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one to five independently selected 1-9 The substituents of the alkyl, oxo, halo, hydroxy and cyano groups are substituted.

2. The compound according to claim 1, wherein A is C1-6 alkyl.

3. The compound according to claim 1, which is represented by Formula IIA: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein Ring A is C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; and each C of ring A 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1 replace.

4. The compound according to claim 1 or 3, wherein A or ring A is optionally substituted by one to five Z 1 Substituted C 3-10 Cycloalkyl.

5. The compound according to claim 1 or 3, wherein A or ring A is optionally substituted by one to five Z 1 Substituted heterocyclic group.

6. The compound according to claim 1 or 3, wherein A or ring A is optionally substituted by one to five Z 1 Substituted aryl.

7. The compound according to claim 1 or 3, wherein A or ring A is optionally substituted by one to five Z 1 Substituted heteroaryl.

8. The compound according to claim 1 or 3, wherein A or ring A is C 3-10 Cycloalkyl or heteroaryl.

9. A compound according to any preceding claim, wherein L 1 is a bond, -O-, -NR 10 -、C 1-3 Alkylene or C 1-3 Heteroalkylene.

10. A compound according to any preceding claim, wherein L 2 is the key.

11. A compound according to any preceding claim, wherein X 1 Yes CR 3 .

12. A compound according to any preceding claim, wherein R 3 is hydrogen, halo or C 1-5 Alkyl, wherein the C 1-5 The alkyl group is optionally substituted with one to five halo groups.

13. A compound according to any one of claims 1 to 10, wherein X 1 It is N.

14. A compound according to any preceding claim, wherein R 4 Yes-OR 14 or C 1-5 Alkyl, wherein the C 1-5 The alkyl group is optionally replaced by a hydroxyl group or a C 1-5 Alkoxy substitution.

15. A compound according to any preceding claim, wherein R 4 It is hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, methyl, ethyl, n-propyl, isopropyl, 2-hydroxyethyl or methoxymethyl.

16. A compound according to any preceding claim, wherein X 2 Yes CR 5 .

17. A compound according to any preceding claim, wherein R 5 is hydrogen, halo, cyano, -C(O)-C 1-5 Alkyl or C 1-5 Alkyl, the C 1-5 The alkyl group is optionally substituted by one to three independently selected from halo, hydroxy and C 1-5 The substituents of the alkoxy group are substituted.

18. A compound according to any preceding claim, wherein R 6 It is hydrogen, cyano, hydroxyl, C 1-5 Alkoxy or C 1-5 alkyl.

19. A compound according to any one of claims 1 to 15, wherein X 2 It is N.

20. A compound according to any preceding claim, wherein X 3 Yes CR 7 .

21. A compound according to any preceding claim, wherein R 7 is hydrogen, halide, C 1-5 Alkyl or C 1-5 Halogenated alkyl.

22. A compound according to any one of claims 1 to 19, wherein X 3 It is N.

23. A compound according to any preceding claim, wherein X 4 It's O.

24. A compound according to any preceding claim, wherein R 8 It's hydrogen.

25. A compound according to any preceding claim, wherein n is 0.

26. A compound according to any preceding claim, wherein R1 and R 2 Each is independently C 1-9 alkyl.

27. A compound according to any one of claims 1 to 25, wherein R 1 and R 2 Together with the atoms to which they are attached, they form C 3-10 Cycloalkyl, the C 3-10 The cycloalkyl group is optionally substituted by one to five Z 1 replace.

28. A compound according to any one of claims 1 to 25, wherein R 1 and R 2 Together with the atoms to which they are attached, they form a heterocyclic group, which is optionally substituted by one to five Z 1 replace.

29. A compound according to any preceding claim, wherein R 13 is hydrogen, halo or C 1-9 alkyl.

30. The compound according to claim 1 or 3, which is represented by Formula IA: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

31. The compound according to claim 1 or 3, which is represented by Formula IF: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

32. The compound according to claim 1 or 3, which is represented by formula IH: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

33. The compound according to claim 1 or 3, which is represented by formula IK: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

34. The compound according to claim 1 or 3, which is represented by formula IM: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

35. The compound according to claim 1 or 3, which is represented by formula IIIA: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein: p is 0, 1, or 2; q is 0, 1, or 2; s is 0, 1, 2, or 3; X 5 Does not exist, or is O or NR 17 or C(R 18 )2; R 17 It is hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 、-C(O)OR 20 、-C(O)NR 20 、-S(O)R 20 、-S(O)2R 20 、-S(O)NR 20 R 21 or -S(O)2NR 20 R 21 ; where R 17 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1a replace; and Each R 18 are independently hydrogen or Z 1 .

36. The compound according to claim 1 or 3, which is represented by formula IIIC: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein: p is 0, 1, or 2; q is 0, 1, or 2; s is 0, 1, 2, or 3; X 5 Does not exist, or is O or NR 17 or C(R 18 )2; R 17 It is hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 、-C(O)OR 20 、-C(O)NR 20 、-S(O)R 20 、-S(O)2R 20 、-S(O)NR 20 R 21 or -S(O)2NR 20 R 21 ; where R 17 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1a replace; and Each R 18 are independently hydrogen or Z 1 .

37. The compound according to claim 1 or 3, which is represented by Formula IIID: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein: p is 0, 1, or 2; q is 0, 1, or 2; s is 0, 1, 2, or 3; X 5 Does not exist, or is O or NR 17 or C(R 18 )2; R 17 It is hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 、-C(O)OR 20 、-C(O)NR 20 、-S(O)R 20 、-S(O)2R 20 、-S(O)NR 20 R 21 or -S(O)2NR 20 R 21 ; where R 17 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1a replace; and Each R 18 are independently hydrogen or Z 1 .

38. The compound according to claim 1 or 3, which is represented by formula IIIF: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein: p is 0, 1, or 2; q is 0, 1, or 2; s is 0, 1, 2, or 3; X 5 Does not exist, or is O or NR 17 or C(R 18 )2; R 17 It is hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 、-C(O)OR 20 、-C(O)NR 20 、-S(O)R 20 、-S(O)2R 20 、-S(O)NR 20 R 21 or -S(O)2NR 20 R 21 ; where R 17 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1a replace; and Each R 18 are independently hydrogen or Z 1 .

39. A compound selected from Table 1 or Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

40. A pharmaceutical composition comprising a compound according to any preceding claim, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, and a pharmaceutically acceptable carrier.

41. 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 according to any one of claims 1-39, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, or a pharmaceutical composition according to claim 40.

42. The method of claim 41, wherein the LPA-associated disease, disorder or condition is an LPA1-associated disease.

43. The method of claim 41 or 42, wherein the LPA-associated disease, disorder or condition is fibrosis, transplant rejection, cancer, osteoporosis or an inflammatory disorder.

44. The method of claim 43, wherein the fibrosis is lung fibrosis, liver fibrosis, kidney fibrosis, heart fibrosis, skin fibrosis, eye fibrosis, or pancreatic fibrosis.

45. The method of claim 43, wherein the cancer is of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gallbladder, genitals, genitourinary tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral mucosa, nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testicles, or thyroid.

46. ​​The method of claim 41 or 42, wherein the LPA-related disease, disorder or condition is idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, systemic sclerosis, COVID-19, chronic obstructive pulmonary disease (COPD), neuroinflammation, or multiple sclerosis.

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