Compounds and compositions for the treatment of conditions associated with LPA receptor activity

Abstract

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

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of International Patent Application No. PCT / CN2022 / 077844, filed February 25, 2022, International Patent Application No. PCT / CN2022 / 094839, filed May 25, 2022, and International Patent Application No. PCT / CN2022 / 117690, filed September 8, 2022, each of which is incorporated herein by reference in its entirety.

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

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

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

[0005] In one embodiment, the present invention provides a compound of formula I: [ka] [During the ceremony: A is C 1-6 Alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1-6 Alkyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1 is replaced by; L 1 is a bond, -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -, C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene or C 1-3 heteroalkylene; 1 C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene or C 1-3 The heteroalkylene is independently optionally selected from C 1-9substituted with 1 to 5 substituents independently selected from alkyl, halo, hydroxy, and cyano; L 2 is a bond, C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene or C 1-3 heteroalkylene; 2 C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene or C 1-3 The heteroalkylene is independently optionally selected from C 1-9 substituted with 1 to 5 substituents independently selected from alkyl, halo, hydroxy, and cyano; X 1 is N or CR 3 and; X 2 is N or CR 5 and; X 3 is N or CR 7 and; X 4 is O or CHR 11 where A is C 1-6 If it is alkyl, then X 4 is O; X 6 is N or CR 6 and; 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 heterocyclyl; where R 1 and R 2 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl or heterocyclyl independently optionally has 1 to 5 Z1 is replaced by; or R 1 and R 2 are C together with the atoms to which they are bonded. 3-10 Forms a cycloalkyl or heterocyclyl; 3-10 The cycloalkyl or heterocyclyl optionally has 1 to 5 Z 1 is replaced by; R 3 are hydrogen, halo, cyano, nitro, -OH, -SH, -NH2, -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 3 -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 4 are halo, cyano, nitro, -OR 14 , -N(R 14 )2, -SR 14 , C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 4 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5The cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally selected from halo, hydroxy, C 1-5 substituted with 1 to 5 substituents independently selected from alkoxy and cyano; or R 3 and R 4 together with the atom to which they are attached form a cycloalkyl, aryl, heterocyclyl, or heteroaryl; wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 5 is hydrogen, halo, cyano, nitro, -OR 15 , -N(R 15 )2, -SR 15 , -C(O)R 15 , -C(O)OR 15 , C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl, 3- to 5-membered heterocyclyl, or 5-membered heteroaryl; where R 5 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 The cycloalkyl, 3- to 5-membered heterocyclyl, or 5-membered heteroaryl independently optionally has 1 to 5 Z 1 is replaced by; R 6 is hydrogen, halo, cyano, nitro, -OR 16 , -N(R 16 )2, -SR 16 , C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 6 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 7 are hydrogen, halo, cyano, nitro, -OH, -SH, -NH2, -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 7 -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; or R 6 and R 7 together with the atom to which they are attached form a cycloalkyl, aryl, heterocyclyl, or heteroaryl; wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 8 is hydrogen, C 1-9 alkyl, oxo, halo, hydroxy, or cyano; R 9 is hydrogen, C 1-9 alkyl, oxo, halo, hydroxy, or cyano; R 10 is hydrogen, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5cycloalkyl or 3- to 5-membered heterocyclyl; where R 10 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 11 is hydrogen, C 1-9 alkyl, oxo, halo, hydroxy, or cyano; Each R 13 are independently hydrogen, halo, cyano, nitro, -OH, -SH, -NH2, -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl; where R 13 Each of -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-6 the cycloalkyl or 3- to 6-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 14 is hydrogen, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 14 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 15 is hydrogen, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 15 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 16 is hydrogen, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 16 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; each Z 1 are independently halo, cyano, nitro, oxo, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LH, -LC 1-9 Alkyl, -LC 2-9 Alkenyl, -LC 2-9 Alkynyl, -LC 3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; 1 Each C 1-9 Alkyl, C 2-9Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; Each L is independently -O-, -S-, or -NR 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -, -NR 20 C(O)-, -OC(O)NR 20 -, -NR 20 C(O)O-, -NR 20 C(O)NR 21 -, -S(O)-, -S(O)2-, -S(O)NR 20 -, -S(O)NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR 20 S(O)NR 21 -or-NR 20 S(O)NR 21 - and; Each R 20 and R 21 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 20 and R 21 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a or R 20 and R 21 together with the atoms to which they are attached, independently optionally represent 1 to 5 Z 1a forming a heterocyclyl substituted with each Z 1aare independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1a Each of -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently optionally C 1-9 and substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy, and cyano. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0006] Also provided herein are 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] Also provided herein is a method for treating or preventing LPA-related diseases in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or its pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog or solvate) or a pharmaceutical composition thereof. In some embodiments, the LPA-related disease is an LPA1-related disease, such as, but not limited to, fibrosis, transplant rejection, cancer, osteoporosis or inflammatory disorders.

[0008] In some embodiments, the LPA-related disease is fibrosis, transplant rejection, cancer, osteoporosis or inflammatory disorder.In some of these embodiments, the fibrosis is lung, liver, kidney, heart, skin, eye or pancreatic fibrosis.In some embodiments, the cancer is bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gallbladder, genitals, urogenital tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testis or thyroid.

[0009] In certain embodiments, the LPA-associated disease is idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, systemic sclerosis, COVID-19, chronic obstructive pulmonary disease (COPD), neuroinflammation, or multiple sclerosis.

[0010] Also provided herein is a method of treating or preventing fibrosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of 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 embodiments, the fibrosis is idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), chronic kidney disease, diabetic nephropathy and systemic sclerosis.For example, the fibrosis can be IPF. DETAILED DESCRIPTION OF THE INVENTION

[0012] Detailed Description definition The following description sets forth exemplary embodiments of the present technology, however, it should be recognized that such description is not intended to limit the scope of the present invention, but is provided as a description of exemplary embodiments.

[0013] As used herein, the following words, phrases and symbols are intended to have the meanings indicated, unless otherwise indicated by the context of common usage:

[0014] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment of a substituent. For example, -C(O)NH2 is attached through a carbon atom. Dashes at the beginning or end of a chemical group are used for convenience; chemical groups may be written with or without one or more dashes without loss of normal meaning. A wavy line drawn through a line in a structure indicates the point of attachment of the group. Unless chemically or structurally necessary, no directionality is indicated or implied by the order in which chemical groups are written or named.

[0015] Prefix “C” u-v " means that the subsequent group has u to v carbon atoms. For example, "C 1-6 "Alkyl" means the alkyl group has from 1 to 6 carbon atoms.

[0016] Reference herein to "about" a value or parameter includes (and describes) embodiments relating to the value or parameter itself. In certain embodiments, the term "about" includes the recited amount ±10%. In other embodiments, the term "about" includes the recited amount ±5%. In certain other embodiments, the term "about" includes the recited amount ±1%. Also, the term "about X" includes reference to "X". Additionally, singular references include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "an assay" includes reference to one or more assays and equivalents thereof known to those of skill in the art.

[0017] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to a group having 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 12 carbon atoms (i.e., C 1-12 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl) or 1 to 4 carbon atoms (i.e., C 1-4 Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbon atoms is named by a chemical name or identified by a molecular formula, all positional isomers having that number of carbon atoms 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 an alkyl group containing at least one (e.g., 1 to 3 or 1) carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 12 carbon atoms (i.e., C 2-12 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl) or 2 to 4 carbon atoms (i.e., C 2-4 Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0019] "Alkynyl" refers to an alkyl group containing at least one (e.g., 1 to 3 or 1) carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), 2 to 12 carbon atoms (i.e., C 2-12 alkynyl), 2 to 8 carbon atoms (i.e., C 2-8alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl) or 2 to 4 carbon atoms (i.e., C 2-4 The term "alkynyl" refers to an alkyl group having one triple bond and one double bond.

[0020] Certain commonly used alternative chemical names may be used, for example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may also be referred to as "alkylene" or "alkylenyl" groups, "arylene" or "arylenyl" groups, respectively.

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

[0022] "Haloalkyl" refers to an unbranched or branched alkyl group, as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms have been replaced with halogen. For example, when a residue is substituted with more than one halogen, it can be described using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl may, but need not, be the same halogen. Examples of haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0023] "Haloalkoxy" refers to an alkoxy group, as defined above, in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms have been replaced with halogen.

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

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

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

[0027] An "amide" is the group -C(O)NR y R z refers to the "C-amido" group and the group -NR y C(O)R z An "N-amido" group (where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which is optionally substituted as defined herein, or R y and R z and together form a cycloalkyl or heterocyclyl, each of which may be optionally substituted as defined herein.

[0028] "Amino" is the group -NR y R z (where R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which is optionally substituted as defined herein.

[0029] "Amidino" is -C(NR y )(NR z 2) (where R y and R zare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which is optionally 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 refers to a group having 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl) or 6 to 10 carbon ring atoms (i.e., C 6-10 aryl). Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or overlap in any way with heteroaryl, as defined below. If one or more aryl groups are fused to a heteroaryl, the resulting ring system is a heteroaryl regardless of the point of attachment. If one or more aryl groups are fused to a heterocyclyl, the resulting ring system is a heterocyclyl regardless of the point of attachment. If one or more aryl groups are fused to a cycloalkyl, the resulting ring system is a cycloalkyl regardless of the point of attachment.

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

[0032] "Carboxyl ester" or "ester" is -OC(O)R x and -C(O)OR x (where R xis alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which is optionally substituted as defined herein.

[0033] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" refers to a cycloalkenyl group (i.e., a cyclic group having at least one double bond) and at least one sp 3 As used herein, cycloalkyl includes carbocyclic fused ring systems (i.e., at least one non-aromatic ring) having 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl) or 3 to 6 ring carbon atoms (i.e., C 3-6 cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Furthermore, the term cycloalkyl is intended to include any non-aromatic ring that may be fused to an aryl ring, regardless of the point of attachment to the rest of the molecule. Still further, cycloalkyl also includes "spirocycloalkyl" when there are two substitutions at the same carbon atom, such as spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0034] "Imino" is the group -C(NR y )R z (Here, R y and R zare each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which is optionally substituted as defined herein.

[0035] "Halogen" or "halo" refers to atoms occupying Group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodo.

[0036] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. By way of example, one, two, or three carbon atoms can be independently replaced with the same or different heteroatomic groups. Heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)-, and the like (where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted). Examples of heteroalkyl groups include -OCH, -CHOCH, -SCH, -CHSCH, -NRCH, and -CHNRCH (where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which is optionally substituted). As used herein, heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0037] "Heteroalkylene" refers to a divalent heteroalkyl group. A "heteroalkylene" group must have at least one carbon and at least one heteroatom group within the chain. The term "heteroalkylene" includes unbranched or branched saturated chains containing carbon and heteroatoms. For example, one, two, or three carbon atoms can be independently replaced with the same or different heteroatom groups. A heteroatom group can be -NR y-, -O-, -S-, -S(O)-, -S(O)2-, etc. (where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein. Examples of heteroalkylene groups include, for example, -CH2OCH2-, -CH(CH3)OCH2-, -CH2CH2OCH2-, -OCH2-, -CH(CH3)O-, -CH2CH2O-, -CH2CH2OCH2CH2OCH2-, -CH2CH2OCH2CH2O-, -CH2SCH2-, -CH(CH3)SCH2-, -CH2CH2SCH2-, -CH2CH2SCH2CH2SCH2-, -SCH2-, -CH(CH3)S-, -CH2CH2S-, -CH2CH2SCH2CH2S-, -CH2S(O)2CH2-, -CH(CH3)S(O)2CH2-, -CH2CH2S(O)2CH2CH2OCH2-, -CH2NR y CH2-, -CH(CH3)NR y CH2-, -CH2CH2NR y CH2-, -CH2CH2NR y CH2CH2NR y CH2- etc. (where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which is optionally substituted as defined herein. As used herein, heteroalkylene includes 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 amide or other functional groups where oxo is present at one or more carbon atoms.

[0038] "Heteroaryl" refers to an aromatic group having a single ring or multiple condensed rings and having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to a group having from 1 to 20 ring carbon atoms (i.e., C 1-20heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12 heteroaryl) or 3 to 8 carbon ring atoms (i.e., C 3-8Heteroaryl) and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. In certain examples, heteroaryl includes 5- to 10-membered, 5- to 7-membered, or 5- to 6-membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothienyl (dibenzothiophenyl), furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, and isoindolyl. , isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiophenyl (thienyl), thiazolyl, thiadiazolyl, 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), indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl (wherein the heteroaryl can be attached via any ring of the fused system). Any aromatic ring having single or multiple fused rings containing at least one heteroatom is considered heteroaryl, regardless of the point of attachment to the rest of the molecule (i.e., via any of the fused rings). Heteroaryl does not encompass or overlap with aryl, as defined above.

[0039] "Heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiro-heterocyclyl groups. Heterocyclyl may be monocyclic or polycyclic, which may be fused, bridged, or spiro, and may contain one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O) groups. - ) moiety. Any non-aromatic ring containing at least one heteroatom is considered heterocyclyl, regardless of the point of attachment (i.e., it may be attached via a carbon atom or a heteroatom). Additionally, the term heterocyclyl is intended to include any non-aromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, aryl, or heteroaryl ring, regardless of the point of attachment to the rest of the molecule. As used herein, heterocyclyl refers to a ring having 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclyl) or 3 to 6 ring carbon atoms (i.e., C 3-6and having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoinyl, and the like.

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

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

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

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

[0043] The terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. Also, the term "optionally substituted" means that any one or more hydrogen atoms of the specified atom or group may or may not be replaced with a non-hydrogen moiety.

[0044] As used herein, the term "compound" is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure. A compound identified herein by name or structure as a particular tautomeric form includes other tautomeric forms unless otherwise specified.

[0045] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and the nature of the equilibrium between the tautomers, those skilled in the art will understand that the compound includes both the amide and imidic acid tautomers. Thus, amide-containing compounds are understood to include imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include amide tautomers.

[0046] Any compound or structure depicted herein is also intended to represent unlabeled and isotopically labeled forms of the compound. These forms of the compound may be referred to as "isotopically enriched analogs." Isotopically labeled compounds have the structures depicted herein except that one or more atoms are replaced with an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 I. Various isotopically labeled compounds of the present invention, such as 3 H and 14 Those incorporating a radioactive isotope such as C. Such isotopically labeled compounds may be useful for metabolic studies including drug or substrate tissue distribution assays, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) or radioactive treatment of patients.

[0047] The term "isotopically enriched analog" includes "deuterated analogs" of compounds described herein in which one or more hydrogens, such as hydrogens on carbon atoms, have been replaced with deuterium. Such compounds are resistant to metabolism and are therefore useful for extending the half-life of a compound when administered to mammals, particularly humans. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds can be synthesized by means well known in the art, for example, using starting materials in which one or more hydrogens have been replaced with deuterium.

[0048] Deuterium-labeled or substituted therapeutic compounds of the invention may have improved DMPK (drug metabolism and pharmacokinetic) properties related to distribution, metabolism, and excretion (ADME). Substitution with heavy isotopes such as deuterium may confer certain therapeutic advantages due to greater metabolic stability, such as improved in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F, 3 H, 11 C-labeled compounds may be useful for PET or SPECT or other imaging studies. Isotopically labeled compounds of the present disclosure and their prodrugs may generally be prepared by practicing the methods disclosed in the following schemes or in the Examples and Preparations, substituting readily available isotopically labeled reagents for non-isotopically labeled reagents. It is understood that deuterium in this context is considered a substituent of the compounds described herein.

[0049] The concentration of such a heavy isotope, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," the position is understood to contain hydrogen at natural abundance isotopic composition. Thus, in the compounds of the present disclosure, an atom specifically designated as deuterium (D) is intended to represent deuterium.

[0050] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0051] Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other substances that are useful in the manufacture of pharmaceutical compositions suitable for animal or human pharmaceutical use.

[0052] The term "pharmaceutically acceptable salt" of a compound refers to a salt that retains the biological effectiveness and properties of the compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and organic acids. Furthermore, if a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with a suitable acid, according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include salts of NH or primary, secondary, and tertiary amines, e.g., from N-containing heterocycles, N-containing heteroaryls, or compounds of the formula N(R N ) 3 amines (e.g., HN + (R N )3 or (alkyl)N + (R N )3) (where each R Nare independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with one or more (e.g., 1 to 5 or 1 to 3) substituents (e.g., halo, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy). Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0053] The term "substituted" means that any one or more hydrogen atoms of the designated atom or group are replaced with one or more substituents other than hydrogen, provided that the normal valence of the designated atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonate, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.

[0054] Polymers or similar undefined structures resulting from substituents having infinitely more additional substituents (e.g., a substituted aryl with a substituted alkyl, which is itself substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.) are not intended to be encompassed herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is the limit for ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., a methyl substituted with five fluorines or a heteroaryl group with two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those of skill in the art. When used to modify a chemical group, the term "substituted" can refer to other chemical groups as defined herein. Unless otherwise specified, when a group is described as optionally substituted, any substituents of that group are themselves unsubstituted. For example, in certain embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, one or more of the substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0055] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable additive" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Except as long as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. Supplementary active ingredients may also be incorporated into the composition.

[0056] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0057] As used herein, the term "LPA-related disease" refers to diseases, disorders, or conditions in which activation of at least one LPA receptor by LPA contributes to the symptoms or progression of the disease, disorder, or condition, including, but not limited to, diseases, disorders, or conditions. These diseases, disorders, or conditions may be due to one or more of the following causes: genetic, iatrogenic, immunological, infectious, metabolic, oncological, toxic, surgical, and / or traumatic. Thus, inhibition of one or more lysophosphatidic acid (LPA) receptor (e.g., LPA1, LPA2, LPA3, LPA4, LPA5, or LPA6 receptor) signaling can alter the pathology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, the LPA-related disease is an LPA1-related disease, in which modulation of LPA1 receptor signaling 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, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and gastrointestinal tract.

[0059] As used herein, the term "pharmaceutically acceptable" indicates that a compound or salt or composition thereof is chemically and / or toxicologically compatible with other ingredients contained in the formulation and / or the subject being treated therewith.

[0060] The terms "administration" or "administering" refer to a method of providing a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, bird, fish, or amphibian. The method of administration 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 term "effective amount" or "effective dosage" or "pharmaceutically effective amount" or "therapeutically effective amount" refers to a sufficient quantity of an administered 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) to relieve to some extent one or more symptoms of the disease or condition being treated, and may include curing the disease. "Cure" means that the symptoms of active disease are eliminated. Results include reduction and / or alleviation of the signs, symptoms, or causes of disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. An appropriate "effective" amount in any individual case can be determined using any suitable technique, such as a dose escalation study. In certain embodiments, a "therapeutically effective amount" of a compound provided herein refers to the amount of the compound that is effective as a monotherapy or combination therapy.

[0062] The term "excipient" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In certain embodiments, each component is "pharmaceutically acceptable" in that it is compatible with the other components of the pharmaceutical formulation, is suitable for use in ingestion with human and animal tissues or organs without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and is compatible with a reasonable benefit / risk ratio. For example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical See Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

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

[0064] The terms "treat" and "treatment" in the context of treating a disease, disorder, or condition are meant to include alleviating or eliminating the disorder, disease, or condition or one or more symptoms of the disorder, disease, or condition; or slowing the progression, spread, or worsening of the disease, disorder, or condition or one or more symptoms of the disease, disorder, or condition.

[0065] As used herein, the term "prevention" refers to the complete or partial prevention of the onset, recurrence or spread of a disease or condition described herein or a symptom thereof.

[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, cows, sheep, horses, primates, and humans. In some embodiments, this term refers to a subject, particularly a mammalian subject, for whom diagnosis, prognosis, or treatment is desired or necessary. In some embodiments, the subject is a human. In some embodiments, the subject is experiencing / exhibiting at least one symptom of the disease, disorder, or condition to be treated and / or prevented.

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

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

[0069] As used herein, the term "combination therapy" refers to a dosing regimen of two different therapeutically active agents (i.e., components of a combination or combination partners), where the therapeutically active agents are administered simultaneously or separately as prescribed by a healthcare professional or in accordance with regulatory authorities as defined herein.

[0070] As used herein, the term "modulate" or "modulation" refers to regulation or modulation (e.g., increase or decrease) and can include, for example, agonism, partial agonism, or antagonism. compound

[0071] In some embodiments, provided herein are compounds of formula I: [ka] [During the ceremony: A is C 1-6 Alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1-6 Alkyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1 is replaced by; L 1 is a bond, -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -, C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene or C 1-3 heteroalkylene; 1 C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene or C 1-3 The heteroalkylene is independently optionally selected from C 1-9 substituted with 1 to 5 substituents independently selected from alkyl, halo, hydroxy, and cyano; L 2 is a bond, C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene or C 1-3 heteroalkylene; 2 C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene or C 1-3 The heteroalkylene is independently optionally selected from C1-9 substituted with 1 to 5 substituents independently selected from alkyl, halo, hydroxy, and cyano; X 1 is N or CR 3 and; X 2 is N or CR 5 and; X 3 is N or CR 7 and; X 4 is O or CHR 11 where A is C 1-6 If it is alkyl, then X 4 is O; X 6 is N or CR 6 and; 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 heterocyclyl; where R 1 and R 2 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl or heterocyclyl independently optionally has 1 to 5 Z 1 is replaced by; or R 1 and R 2 are C together with the atoms to which they are bonded. 3-10 Forms a cycloalkyl or heterocyclyl; 3-10 The cycloalkyl or heterocyclyl optionally has 1 to 5 Z 1 is replaced by; R 3 are hydrogen, halo, cyano, nitro, -OH, -SH, -NH2, -NH-C 1-5 Alkyl, -N(C 1-5Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 3 -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 4 are halo, cyano, nitro, -OR 14 , -N(R 14 )2, -SR 14 , C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 4 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 The cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally selected from halo, hydroxy, C 1-5 substituted with 1 to 5 substituents independently selected from alkoxy and cyano; or R 3 and R 4 together with the atom to which they are attached form a cycloalkyl, aryl, heterocyclyl, or heteroaryl; wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 5is hydrogen, halo, cyano, nitro, -OR 15 , -N(R 15 )2, -SR 15 , -C(O)R 15 , -C(O)OR 15 , C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl, 3- to 5-membered heterocyclyl, or 5-membered heteroaryl; where R 5 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 The cycloalkyl, 3- to 5-membered heterocyclyl, or 5-membered heteroaryl independently optionally has 1 to 5 Z 1 is replaced by; R 6 is hydrogen, halo, cyano, nitro, -OR 16 , -N(R 16 )2, -SR 16 , C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 6 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 7 are hydrogen, halo, cyano, nitro, -OH, -SH, -NH2, -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 7-NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; or R 6 and R 7 together with the atom to which they are attached form a cycloalkyl, aryl, heterocyclyl, or heteroaryl; wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 8 is hydrogen, C 1-9 alkyl, oxo, halo, hydroxy, or cyano; R 9 is hydrogen, C 1-9 alkyl, oxo, halo, hydroxy, or cyano; R 10 is hydrogen, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 10 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 11 is hydrogen, C 1-9 alkyl, oxo, halo, hydroxy, or cyano; Each R 13 are independently hydrogen, halo, cyano, nitro, -OH, -SH, -NH2, -NH-C1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl; where R 13 Each of -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-6 the cycloalkyl or 3- to 6-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 14 is hydrogen, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 14 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 15 is hydrogen, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 15 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 16 is hydrogen, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 16 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; each Z 1 are independently halo, cyano, nitro, oxo, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LH, -LC 1-9 Alkyl, -LC 2-9 Alkenyl, -LC 2-9 Alkynyl, -LC 3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; 1 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; Each L is independently -O-, -S-, or -NR 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -, -NR 20 C(O)-, -OC(O)NR 20 -, -NR 20 C(O)O-, -NR 20 C(O)NR21 -, -S(O)-, -S(O)2-, -S(O)NR 20 -, -S(O)NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR 20 S(O)NR 21 -or-NR 20 S(O)NR 21 - and; Each R 20 and R 21 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 20 and R 21 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a or R 20 and R 21 together with the atoms to which they are attached, independently optionally represent 1 to 5 Z 1a forming a heterocyclyl substituted with each Z 1a are independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1a Each of -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently optionally C 1-9 and substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy, and cyano. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0072] In some embodiments, provided herein is a compound of formula II: [ka] [In the formula, 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 L 2 each independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0073] In some embodiments, provided herein is a compound of formula II: [ka] [During the ceremony: A is C 1-6 Alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1-6 Alkyl, C 3-10The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1 is replaced by; L 1 is a bond, -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -, C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene or C 1-3 heteroalkylene; 1 C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene or C 1-3 The heteroalkylene is independently optionally selected from C 1-9 substituted with 1 to 5 substituents independently selected from alkyl, halo, hydroxy, and cyano; L 2 is a bond, C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene or C 1-3 heteroalkylene; 2 C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene or C 1-3 The heteroalkylene is independently optionally selected from C 1-9 substituted with 1 to 5 substituents independently selected from alkyl, halo, hydroxy, and cyano; X 1 is N or CR 3 and; X 2 is N or CR 5 and; X 3 is N or CR 7 and; X 4 is O or CHR 11 where A is C 1-6 If it is alkyl, then X 4 is O; 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 heterocyclyl; where R 1 and R 2 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl or heterocyclyl independently optionally has 1 to 5 Z 1 is replaced by; or R 1 and R 2 are C together with the atoms to which they are bonded. 3-10 Forms a cycloalkyl or heterocyclyl; 3-10 The cycloalkyl or heterocyclyl optionally has 1 to 5 Z 1 is replaced by; R 3 are hydrogen, halo, cyano, nitro, -OH, -SH, -NH2, -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 3 -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 4 are halo, cyano, nitro, -OR 14 , -N(R 14 )2, -SR 14 , C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 4 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 The cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally selected from halo, hydroxy, C 1-5 substituted with 1 to 5 substituents independently selected from alkoxy and cyano; or R 3 and R 4 together with the atom to which they are attached form a cycloalkyl, aryl, heterocyclyl, or heteroaryl; wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 5 is hydrogen, halo, cyano, nitro, -OR 15 , -N(R 15 )2, -SR 15 , -C(O)R 15 , -C(O)OR 15 , C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl, 3- to 5-membered heterocyclyl, or 5-membered heteroaryl; where R 5 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 The cycloalkyl, 3- to 5-membered heterocyclyl, or 5-membered heteroaryl independently optionally has 1 to 5 Z 1 is replaced by; R 6is hydrogen, halo, cyano, nitro, -OR 16 , -N(R 16 )2, -SR 16 , C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 6 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 7 are hydrogen, halo, cyano, nitro, -OH, -SH, -NH2, -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 7 -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; or R 6 and R 7together with the atom to which they are attached form a cycloalkyl, aryl, heterocyclyl, or heteroaryl; wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 8 is hydrogen, C 1-9 alkyl, oxo, halo, hydroxy, or cyano; R 9 is hydrogen, C 1-9 alkyl, oxo, halo, hydroxy, or cyano; R 10 is hydrogen, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 10 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 11 is hydrogen, C 1-9 alkyl, oxo, halo, hydroxy, or cyano; Each R 13 are independently hydrogen, halo, cyano, nitro, -OH, -SH, -NH2, -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl; where R 13 Each of -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-6 the cycloalkyl or 3- to 6-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 14 is hydrogen, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 14 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 15 is hydrogen, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 15 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 16 is hydrogen, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 16 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; each Z 1 are independently halo, cyano, nitro, oxo, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LH, -LC 1-9 Alkyl, -LC 2-9 Alkenyl, -LC 2-9 Alkynyl, -LC 3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; 1 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; Each L is independently -O-, -S-, or -NR 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -, -NR 20 C(O)-, -OC(O)NR 20 -, -NR 20 C(O)O-, -NR 20 C(O)NR 21 -, -S(O)-, -S(O)2-, -S(O)NR 20 -, -S(O)NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR 20 S(O)NR 21 -or-NR 20 S(O)NR 21 - and; Each R 20 and R 21 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 20 and R 21 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a or R 20 and R 21 together with the atoms to which they are attached, independently optionally represent 1 to 5 Z 1a forming a heterocyclyl substituted with each Z 1a are independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1a Each of -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently optionally C 1-9 and substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy, and cyano. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0074] In some embodiments, provided herein is a compound of formula IXA: [ka] [In the formula, 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 independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0075] In some embodiments, provided herein is a compound of formula IXB: [ka] [In the formula, A, R 1 , R 2 , R 4 , R 8 , R 9 , R 13 , X 1 , X 2 , X 3 , X 4 , n, L 1 and L 2 each independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

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

[0077] In some embodiments, provided herein are compounds of formula IIA: [ka] [In the formula, 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 independently as defined herein, and ring A is C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C of ring A 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1 is replaced by or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0078] In some embodiments, provided herein are compounds of formula IIA: [ka] [During the ceremony: Ring A is C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C of ring A 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1 is replaced by; L 1 is a bond, -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -, C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene or C1-3 heteroalkylene; 1 C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene or C 1-3 The heteroalkylene is independently optionally selected from C 1-9 substituted with 1 to 5 substituents independently selected from alkyl, halo, hydroxy, and cyano; L 2 is a bond, C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene or C 1-3 heteroalkylene; 2 C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene or C 1-3 The heteroalkylene is independently optionally selected from C 1-9 substituted with 1 to 5 substituents independently selected from alkyl, halo, hydroxy, and cyano; X 1 is N or CR 3 and; X 2 is N or CR 5 and; X 3 is N or CR 7 and; X 4 is O or CHR 11 and; 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 heterocyclyl; where R 1 and R 2 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C3-10 The cycloalkyl or heterocyclyl independently optionally has 1 to 5 Z 1 is replaced by; or R 1 and R 2 are C together with the atoms to which they are bonded. 3-10 Forms a cycloalkyl or heterocyclyl; 3-10 The cycloalkyl or heterocyclyl optionally has 1 to 5 Z 1 is replaced by; R 3 are hydrogen, halo, cyano, nitro, -OH, -SH, -NH2, -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 3 -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 4 are halo, cyano, nitro, -OR 14 , -N(R 14 )2, -SR 14 , C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 4 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; or R 3 and R 4 together with the atom to which they are attached form a cycloalkyl, aryl, heterocyclyl, or heteroaryl; wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 5 is hydrogen, halo, cyano, nitro, -OR 15 , -N(R 15 )2, -SR 15 , -C(O)R 15 , -C(O)OR 15 , C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl, 3- to 5-membered heterocyclyl, or 5-membered heteroaryl; where R 5 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 The cycloalkyl, 3- to 5-membered heterocyclyl, or 5-membered heteroaryl independently optionally has 1 to 5 Z 1 is replaced by; R 6 is hydrogen, halo, cyano, nitro, -OR 16 , -N(R 16 )2, -SR 16 , C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 6 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 7 are hydrogen, halo, cyano, nitro, -OH, -SH, -NH2, -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 7 -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; or R 6 and R 7 together with the atom to which they are attached form a cycloalkyl, aryl, heterocyclyl, or heteroaryl; wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 8 is hydrogen, C 1-9 alkyl, oxo, halo, hydroxy, or cyano; R 9 is hydrogen, C 1-9 alkyl, oxo, halo, hydroxy, or cyano; R 10 is hydrogen, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5cycloalkyl or 3- to 5-membered heterocyclyl; where R 10 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 11 is hydrogen, C 1-9 alkyl, oxo, halo, hydroxy, or cyano; Each R 13 are independently hydrogen, halo, cyano, nitro, -OH, -SH, -NH2, -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl; where R 13 Each of -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-6 the cycloalkyl or 3- to 6-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 14 is hydrogen, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 14 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 15 is hydrogen, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 15 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R 16 is hydrogen, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 16 C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; each Z 1 are independently halo, cyano, nitro, oxo, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LH, -LC 1-9 Alkyl, -LC 2-9 Alkenyl, -LC 2-9 Alkynyl, -LC 3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; 1 Each C 1-9 Alkyl, C 2-9Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; Each L is independently -O-, -S-, or -NR 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -, -NR 20 C(O)-, -OC(O)NR 20 -, -NR 20 C(O)O-, -NR 20 C(O)NR 21 -, -S(O)-, -S(O)2-, -S(O)NR 20 -, -S(O)NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR 20 S(O)NR 21 -or-NR 20 S(O)NR 21 - and; Each R 20 and R 21 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 20 and R 21 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a or R 20 and R 21 together with the atoms to which they are attached, independently optionally represent 1 to 5 Z 1a forming a heterocyclyl substituted with each Z 1aare independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1a Each of -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently optionally C 1-9 and substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy, and cyano. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0079] In some embodiments, provided herein are compounds of formula IIB: [ka] [In the formula, 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 independently as defined herein, and ring A is C 3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C of ring A 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1 is replaced by or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0080] In some embodiments, provided herein are compounds of formula IIC: [ka] [In the formula, 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 independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0081] In some embodiments, provided herein are compounds of formula IID: [ka] [In the formula, 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 independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0082] In some embodiments, provided herein are compounds of formula IIE: [ka] [In the formula, 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 independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0083] In some embodiments, provided herein are compounds of formula IIF: [ka] [In the formula, 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 independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0084] In certain embodiments, the compound of Formula I or II has Formula IA: [ka] [In the formula, 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 independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0085] In some embodiments, X 1 is N. In some embodiments, X 1 is CR 3 is.

[0086] In some embodiments, X 2 is N. In some embodiments, X 2 is CR 5 is.

[0087] In some embodiments, X 3 is N. In some embodiments, X 3 is CR 7 is.

[0088] In some embodiments, X 1 is N and X 2 is N and X 3 is N. In some embodiments, X 1 is N and X 2 is N and X 3 is CR 7 In one embodiment, X 1 is N and X 2 is CR 5 and X 3is N. In some embodiments, X 1 is CR 3 and X 2 is N and X 3 is N. In some embodiments, X 1 is CR 3 and X 2 is N and X 3 is CR 7 In one embodiment, X 1 is CR 3 and X 2 is CR 5 and X 3 is N. In some embodiments, X 1 is CR 3 and X 2 is CR 5 and X 3 is CR 7 In one embodiment, X 1 is N and X 2 is CR 5 and X 3 is CR 7 is.

[0089] In some embodiments, R 3 are hydrogen, halo, cyano, nitro, -OH, -SH, -NH2, -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 3 -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5The cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano.

[0090] In some embodiments, R 3 is hydrogen, halo or C 1-5 alkyl, where C 1-5 The alkyl is optionally substituted with 1 to 5 halo. In certain embodiments, R 3 is hydrogen, halo, C 1-5 Alkyl or C 1-5 In some embodiments, R 3 is hydrogen, fluoro, chloro, methyl, ethyl, or difluoromethyl. In certain embodiments, R 3 is hydrogen. In some embodiments, R 3 is halo. In certain embodiments, R 3 is C 1-5 In some embodiments, R 3 is C 1-5 It is haloalkyl.

[0091] In some embodiments, R 4 HA-OR 14 , -N(R 14 )2 or C 1-5 alkyl, where C 1-5 The alkyl is optionally hydroxy or C 1-5 In one embodiment, R 4 HA-OR 14 or C 1-5 alkyl, where C 1-5 The alkyl is optionally hydroxy or C 1-5 It is substituted with alkoxy.

[0092] In some embodiments, R 4 HA-OR 14 or -N(R 14 )2. In some embodiments, R 4 Ha-OC 1-5 Alkyl, -OC3-5 Cycloalkyl or -NH-C 1-5 In some embodiments, R 4 is methoxy, ethoxy, iso-butoxy, cyclopropoxy or ethylamino.

[0093] In some embodiments, R 4 HA-OR 14 In some embodiments, R 4 Ha-OC 1-5 In some embodiments, R 4 is hydroxy, methoxy, ethoxy, n-propoxy, iso-propoxy, cyclopropoxy, cyclobutoxy, methyl, ethyl, n-propyl, iso-propyl, 2-hydroxyethyl, or methoxymethyl. 4 HA-OR 14 and R 14 is C 1-5 Alkyl or C 3-5 In certain embodiments, R 4 is hydroxy, methoxy, ethoxy, n-propoxy, cyclopropoxy, cyclobutoxy, methyl, ethyl, n-propyl, 2-hydroxyethyl, or methoxymethyl. 4 is hydroxy, methoxy, ethoxy, or cyclopropyloxy. 4 is hydroxy, methoxy, or ethoxy. In some embodiments, R 4 is methoxy or ethoxy. In some embodiments, R 4 is methoxy. In some embodiments, R 4 is ethoxy. In some embodiments, R 4 is cyclopropyloxy.

[0094] In some embodiments, R 3 and R 4together with the atom to which they are attached form a cycloalkyl, aryl, heterocyclyl, or heteroaryl; wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano.

[0095] In some embodiments, R 3 and R 4 together with the atom to which they are attached form a cycloalkyl optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano. In certain embodiments, R 3 and R 4 together with the atom to which they are attached form a C6 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano. In some embodiments, R 3 and R 4 together with the atom to which they are attached form a C5 cycloalkyl, optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano. In some embodiments, the cycloalkyl is unsubstituted.

[0096] In some embodiments, R 3 and R 4 together with the atom to which they are attached form an aryl optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano. 3 and R 4 together with the atom to which they are attached form a C6 aryl, optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano. In some embodiments, the aryl is unsubstituted.

[0097] In some embodiments, R 3 and R 4together with the atom to which they are attached form a heterocyclyl optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano. In certain embodiments, R 3 and R 4 together with the atom to which they are attached form a 5- or 6-membered heterocyclyl optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano. In certain embodiments, R 3 and R 4 together with the atom to which they are attached form a 5-membered heterocyclyl optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano. In certain embodiments, R 3 and R 4 together with the atom to which they are attached form a 5-membered oxygen-containing heterocyclyl, optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano. In certain embodiments, the heterocyclyl is unsubstituted.

[0098] In some embodiments, R 3 and R 4 together with the atom to which they are attached form a heteroaryl optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano. In certain embodiments, R 3 and R 4 together with the atom to which they are attached form a 5- or 6-membered heteroaryl optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano. In certain embodiments, R 3 and R 4 together with the atom to which they are attached form a 6-membered heteroaryl, optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano. In some embodiments, the heteroaryl is unsubstituted.

[0099] In some embodiments, R 6is hydrogen, cyano, -OR 16 or C 1-5 In some embodiments, R 6 is hydrogen, cyano, -OC 1-5 Alkyl or C 1-5 In some embodiments, R 6 HA-OR 16 In some embodiments, R 6 Ha-OC 1-5 In some embodiments, R 6 is hydroxy, cyano, methoxy, or ethoxy. 6 is methoxy.

[0100] In some embodiments, R 4 HA-OR 14 or -N(R 14 )2 and R 6 is hydrogen, cyano, -OR 16 or C 1-5 In some embodiments, R 4 Ha-OC 1-5 Alkyl, -OC 3-5 Cycloalkyl or -NH-C 1-5 alkyl, and R 6 is hydrogen, cyano, -OC 1-5 Alkyl or C 1-5 In some embodiments, R 4 is methoxy, ethoxy, isobutyloxy, cyclopropoxy or ethylamino, and R 6 is hydroxy, cyano, methoxy or ethoxy.

[0101] In some embodiments, R 4 Ha-OC 1-5 alkyl, and R 6 is hydrogen, cyano, -OR 16 or C 1-5 In some embodiments, R 4 Ha-OC 1-5 alkyl, and R 6 is hydrogen, cyano, -OC 1-5Alkyl or C 1-5 In some embodiments, R 4 Ha-OC 1-5 alkyl, and R 6 HA-OR 16 In some embodiments, R 4 Ha-OC 1-5 alkyl, and R 6 Ha-OC 1-5 In some embodiments, R 4 Ha-OC 1-5 alkyl, and R 6 is hydroxy, cyano, methoxy, or ethoxy. 4 Ha-OC 1-5 alkyl, and R 6 is methoxy. In some embodiments, R 4 is methoxy and R 6 is hydrogen. In some embodiments, R 4 is methoxy and R 6 is methoxy.

[0102] In some embodiments, R 5 is hydrogen, halo, cyano, -C(O)-C 1-5 Alkyl or optionally halo, hydroxy and C 1-5 C substituted with 1 to 3 substituents independently selected from alkoxy 1-5 In some embodiments, R 5 is hydrogen, cyano, -C(O)-C 1-5 C substituted with 1 to 3 substituents independently selected from alkyl or halo and hydroxy 1-5 In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is cyano. In some embodiments, R 5 is halo. In certain embodiments, R 5 is fluoro. In some embodiments, R 5 is -C(O)-C 1-5 In some embodiments, R 5is substituted with 1 to 3 substituents independently selected from halo and hydroxy; 1-5 In some embodiments, R 5 is C 1-5 It is haloalkyl.

[0103] In some embodiments, R 4 Ha-OC 1-5 alkyl, and R 5 is hydrogen, cyano, -C(O)-C 1-5 C substituted with 1 to 3 substituents independently selected from alkyl or halo and hydroxy 1-5 alkyl, and R 6 is hydrogen, cyano, -OR 16 or C 1-5 It is alkyl.

[0104] In some embodiments, R 7 are hydrogen, halo, cyano, nitro, -OH, -SH, -NH2, -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl or 3- to 5-membered heterocyclyl; where R 7 -NH-C 1-5 Alkyl, -N(C 1-5 Alkyl)2, -SC 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 The cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano.

[0105] In some embodiments, R 7 is hydrogen, halo or C 1-5 Alkyl or C1-5 In some embodiments, R 7 is hydrogen, fluoro, chloro, methyl, ethyl, or difluoromethyl. In certain embodiments, R 7 is hydrogen or C 1-5 In some embodiments, R 7 is hydrogen, methyl, or ethyl. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is halo. In certain embodiments, R 7 is C 1-5 In some embodiments, R 7 is C 1-5 It is haloalkyl.

[0106] In some embodiments, R 3 is hydrogen and R 7 is hydrogen, halo or C 1-5 Alkyl or C 1-5 In some embodiments, R 3 is the halo and R 7 is hydrogen, halo or C 1-5 Alkyl or C 1-5 In some embodiments, R 3 is C 1-5 alkyl, and R 7 is hydrogen, halo or C 1-5 Alkyl or C 1-5 In some embodiments, R 3 is C 1-5 haloalkyl, and R 7 is hydrogen, halo or C 1-5 Alkyl or C 1-5 It is haloalkyl.

[0107] In some embodiments, R 3 is hydrogen and R 7 is hydrogen.

[0108] In some embodiments, R 7 is hydrogen and R 3 is hydrogen, halo or C1-5 Alkyl or C 1-5 In some embodiments, R 7 is the halo and R 3 is hydrogen, halo or C 1-5 Alkyl or C 1-5 In some embodiments, R 7 is C 1-5 alkyl, and R 3 is hydrogen, halo or C 1-5 Alkyl or C 1-5 In some embodiments, R 7 is C 1-5 haloalkyl, and R 3 is hydrogen, halo or C 1-5 Alkyl or C 1-5 It is haloalkyl.

[0109] In some embodiments, A or ring A is C 3-10 cycloalkyl or heterocyclyl, each independently optionally containing 1 to 5 Z 1 In some embodiments, A or ring A is substituted with C 3-10 It is cycloalkyl or heterocyclyl.

[0110] In some embodiments, A or ring A is C 3-10 cycloalkyl optionally 1 to 5 Z 1 In some embodiments, A or ring A is optionally substituted with halo, hydroxy, cyano, nitro, oxo, -SH, -NH, -NH-C 1-9 Alkyl, -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, C 3-10 C substituted with 1 to 5 substituents independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl 3-10cycloalkyl; 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, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently optionally C 1-9 In some embodiments, A or ring A is substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy, and cyano. 3-10 Cycloalkyl optionally C 1-9 It is substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy and cyano.

[0111] In some embodiments, A or ring A optionally has 1 to 5 Z 1 In some embodiments, A or ring A is optionally substituted with halo, hydroxy, cyano, nitro, oxo, -SH, -NH, -NH-C 1-9 Alkyl, -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, C 3-10 heterocyclyl substituted with 1 to 5 substituents independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl; 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 3-10Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently optionally C 1-9 In some embodiments, A or ring A is optionally substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy, and cyano. 1-9 Heterocyclyl substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy and cyano.

[0112] In some embodiments, A or ring A optionally has 1 to 5 Z 1 In some embodiments, A or ring A is optionally substituted with halo, hydroxy, cyano, nitro, oxo, -SH, -NH, -NH-C 1-9 Alkyl, -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, C 3-10 aryl substituted with 1 to 5 substituents independently selected from cycloalkyl, heterocyclyl, 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, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently optionally C 1-9 In some embodiments, A or ring A is optionally substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy, and cyano. 1-9 and aryl substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy, and cyano.

[0113] In some embodiments, A or ring A optionally has 1 to 5 Z 1 In some embodiments, A or ring A is optionally substituted with halo, hydroxy, cyano, nitro, oxo, -SH, -NH, -NH-C 1-9 Alkyl, -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, C 3-10 heteroaryl substituted with 1 to 5 substituents independently selected from cycloalkyl, heterocyclyl, 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, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently optionally C 1-9 In some embodiments, A or ring A is optionally substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy, and cyano. 1-9 Heteroaryl substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy, and cyano.

[0114] In any embodiment described herein, for groups having two or more substituents, the substituents may be the same or different. For example, —N(C 1-5 alkyl)2 or -N(C 1-9In alkyl), the alkyl groups may be the same or different, and when further substituted, the substituents may also be the same or different (e.g., -N(CH), -N(CH)CHCH, -N(CH)CHCF, -N(CHF)CHCHCN, etc.).

[0115] In some embodiments, X 4 is O. In some embodiments, X 4 is CHR 11 In one embodiment, X 4 is CH2.

[0116] In some embodiments, R 8 is hydrogen.

[0117] In some embodiments, R 9 is hydrogen.

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

[0119] In some embodiments, R 13 is hydrogen, halo, C 1-9 Alkyl, C 1-9 Haloalkyl or C 1-9 It is alkyl-CN.

[0120] In some embodiments, R 13 is hydrogen, halo or C 1-9 In some embodiments, R 13 is hydrogen.

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

[0122] In some embodiments, L 1 is a bond, -O-, -NR 10 -, C 1-3 Alkylene or C 1-3 In certain embodiments, L is heteroalkylene. 1 -O-, -NR 10 - or C 1-3 alkylene, and R 10 is hydrogen or C 1-9 In some embodiments, L 1 is a bond, -O-, -NH-, -NCH3-, C 1-3 Alkylene or C 1-3 In certain embodiments, L is heteroalkylene. 1 is a bond. In some embodiments, L 1 is —O—. In some embodiments, L 1 Ha-NR 10 In one embodiment, L 1 is -O- or -NR 10 In one embodiment, L 1 is -NH- or -NCH3-. In some embodiments, L 1 is -NH-. In some embodiments, L 1 is —O— or —NH—. In some embodiments, L 1 is C 1-3 In some embodiments, L is alkylene. 1 is C 1-3 In certain embodiments, L is heteroalkylene. 1 is -O-CH2-.

[0123] In some embodiments, L 2 is a bond.

[0124] In some embodiments, L 1 is a bond, -O-, -NR 10 -, C 1-3 Alkylene or C 1-3 is heteroalkylene, and L 2 is a bond. In some embodiments, L 1 is a bond, -O- or -NR10 - and L 2 is a bond. In some embodiments, L 1 is -O- or -NR 10 - and L 2 is a bond.

[0125] In some embodiments, provided is a compound of formula IB: [ka] [In the formula, m, R 1 , R 2 , R 4 , R 13 , X 1 , X 2 , X 3 , X 4 , X 6 , rings A and L 1 each independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0126] In some embodiments, provided is a compound of formula IC: [ka] [In the formula, R 1 , R 2 , R 4 , R 13 , X 1 , X 2 , X 3 , X 4 , X 6 , rings A and L 1 each independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0127] In some embodiments, provided is a compound of formula ID: [ka] [In the formula, m, R 1 , R 2 , R 6 , R 13 , R 14 , X 1 , X 2 , X 3 , X 4 , rings A and L 1 each independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0128] In some embodiments, provided are compounds of formula IE: [ka] [In the formula, R 1 , R 2 , R 6 , R 13 , R 14 , X 1 , X 2 , X 3 , X 4 , rings A and L 1 each independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0129] In some embodiments, provided is a compound of formula IF: [ka] [In the formula, m, R 1 , R 2 , R 4 , R 6 , R 13 , X 1 , X 2 , X 3 , X 4 , rings A and L 1 each independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0130] In some embodiments, provided is a compound of formula IG: [ka] [In the formula, m, R 1 , R 2 , R 4 , R 6 , R 13 , X 1 , X 2 , X 3 , X 4 , rings A and L 1 each independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0131] In some embodiments, provided is a compound of formula IH: [ka] [In the formula, R 1 , R 2 , R 4 , R 6 , R 13 , X 1 , X 2 , X 3 , X 4 , rings A and L 1 each independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0132] In some embodiments, provided is a compound of formula IJ: [ka] [In the formula, R 1 , R 2 , R4 , R 6 , R 13 , X 1 , X 2 , X 3 , X 4 , rings A and L 1 each independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0133] In some embodiments, provided is a compound of formula IK: [ka] [In the formula, m, R 1 , R 2 , R 6 , R 13 , R 14 , X 1 , X 2 , X 3 , X 4 , rings A and L 1 each independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0134] In some embodiments, provided are compounds of formula IL: [ka] [In the formula, m, R 1 , R 2 , R 6 , R 13 , R 14 , X 1 , X 2 , X 3 , X 4 , rings A and L 1 each independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0135] In some embodiments, provided is a compound of formula IM: [ka] [In the formula, R 1 , R 2 , R 6 , R 13 , R 14 , X 1 , X 2 , X 3 , X 4 , rings A and L 1 each independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0136] In some embodiments, provided is a compound of formula IN: [ka] [In the formula, R 1 , R 2 , R 6 , R 13 , R 14 , X 1 , X 2 , X 3 , X 4 , rings A and L 1 each independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

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

[0138] In some embodiments, R 14 is C3-5 In certain embodiments, R 14 is cyclopropyl. In certain embodiments, R 14 is cyclobutyl.

[0139] In some embodiments, R 14 is C 1-5 In some embodiments, R 14 is methyl or ethyl. In some embodiments, R 14 is methyl. In some embodiments, R 14 is ethyl.

[0140] In some embodiments, R 1 and R 2 are each independently C 1-9 In some embodiments, R 1 and R 2 Each R is methyl. 1 and R 2 are hydrogen atoms.

[0141] In some embodiments, R 1 and R 2 together with the atoms to which they are attached, optionally 1 to 5 Z 1 C is replaced by 3-10 In some embodiments, R 1 and R 2 together with the atoms to which they are attached, optionally 1 to 5 Z 1 C is replaced by 3-6 In some embodiments, R 1 and R 2 together with the atoms to which they are attached, optionally 1 to 5 Z 1 C is replaced by 3-4 In some embodiments, the cycloalkyl is unsubstituted. In some embodiments, the cycloalkyl is substituted with 1 to 5 halo, hydroxy, C 1-9 Alkyl, C 1-9Alkoxy, -CH2-OC 1-9 Alkyl or -NHC(O)OC 1-9 It is substituted with alkyl.

[0142] In some embodiments, R 1 and R 2 together with the atoms to which they are attached, optionally 1 to 5 Z 1 In certain embodiments, R 1 and R 2 together with the atoms to which they are attached, optionally 1 to 5 Z 1 In some embodiments, the heterocyclyl is unsubstituted. In some embodiments, the heterocyclyl is substituted with 1 to 5 C 1-9 Alkyl, -C(O)-C 1-9 Alkyl, -C(O)OC 1-9 Alkyl or -C(O)-CH2-OC 1-9 It is substituted with alkyl.

[0143] In some embodiments, R 1 and R 2 together with the atoms to which they are bonded, C 3-6 cycloalkyl or 4-6 membered heterocyclyl, each of which optionally contains 1-5 halo, hydroxy, C 1-9 Alkyl, C 1-9 Alkoxy, -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 It is substituted with alkyl.

[0144] In some embodiments, R 13 is hydrogen, halo or C 1-9 It is alkyl.

[0145] In certain embodiments, m is 0. In certain embodiments, m is 1.

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

[0147] In certain embodiments, provided are compounds of Formula III 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 and each ring A is independently as defined herein; p is 0, 1 or 2; q is 0, 1 or 2; s is 0, 1, 2 or 3; X 5 is non-existent, O, NR 17 or C(R 18 )2; R 17 is hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)NR 20 , -S(O)R20 , -S(O)2R 20 , -S(O)NR 20 R 21 or -S(O)NR 20 R 21 where R 17 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is substituted with; and Each R 18 are independently hydrogen or Z 1 is.

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

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

[0150] In some embodiments, provided is a compound of formula IIIA: [ka] [In the formula, m, R 4 , R 6 , R 13 , X 1 , X 2 , X 3 , X 4 and each ring A is independently as defined herein; p is 0, 1 or 2; q is 0, 1 or 2; s is 0, 1, 2 or 3; X 5 is non-existent, O, NR 17 or C(R 18 )2; R 17 is hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)NR 20 , -S(O)R 20 , -S(O)2R 20 , -S(O)NR 20 R 21 or -S(O)NR 20 R 21 where R 17 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is substituted with; and Each R 18 are independently hydrogen or Z1 It is. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

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

[0152] In some embodiments, provided is a compound of formula IIIC: [ka] [In the formula, R 4 , R 6 , R 13 , X 1 , X 2 , X 3 , X 4 and each ring A is independently as defined herein; p is 0, 1 or 2; q is 0, 1 or 2; s is 0, 1, 2 or 3; X 5 is non-existent, O, NR 17 or C(R 18 )2; R 17 is hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)NR 20 , -S(O)R 20 , -S(O)2R 20 , -S(O)NR 20 R 21 or -S(O)NR 20 R 21 where R 17 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is substituted with; and Each R 18 are independently hydrogen or Z 1 It is. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0153] In some embodiments, provided is a compound of formula IIID: [ka] [In the formula, m, R 6 , R 13 , R 14 , X 1 , X 2 , X 3 and each ring A is independently as defined herein; p is 0, 1 or 2; q is 0, 1 or 2; s is 0, 1, 2 or 3; X 5 is non-existent, O, NR 17 or C(R 18 )2; R 17 is hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)NR 20 , -S(O)R 20 , -S(O)2R 20 , -S(O)NR 20 R 21 or -S(O)NR 20 R 21 where R 17 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is substituted with; and Each R 18 are independently hydrogen or Z 1 It is. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0154] In some embodiments, provided is a compound of formula IIIE: [ka] [In the formula, R 6 , R 13 , R 14 , X 1 , X 2 , X 3 and each A is independently as defined herein; p is 0, 1 or 2; q is 0, 1 or 2; s is 0, 1, 2 or 3; X 5 is non-existent, O, NR 17 or C(R 18 )2; R 17 is hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)NR 20 , -S(O)R 20 , -S(O)2R 20 , -S(O)NR 20 R 21 or -S(O)NR 20 R 21 where R 17 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is substituted with; and Each R 18 are independently hydrogen or Z 1 It is. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0155] In some embodiments, provided is a compound of formula IIIF: [ka] [In the formula, R 6 , R 13 , R 14 , X 1 , X 2 , X 3 and each ring A is independently as defined herein; p is 0, 1 or 2; q is 0, 1 or 2; s is 0, 1, 2 or 3; X 5 is non-existent, O, NR 17 or C(R 18 )2; R 17 is hydrogen, C 1-9 Alkyl, C2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)NR 20 , -S(O)R 20 , -S(O)2R 20 , -S(O)NR 20 R 21 or -S(O)NR 20 R 21 where R 17 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is substituted with; and Each R 18 are independently hydrogen or Z 1 It is. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0156] In some embodiments, R 14 is C 1-5 In some embodiments, R 14 is methyl or ethyl. In some embodiments, R 14 is methyl. In some embodiments, R 14 is ethyl.

[0157] In some embodiments, X 5 is absent. In some embodiments, X 5 is O. In some embodiments, X 5 is NR 17 In one embodiment, X 5 is C(R 18 )2.

[0158] In certain embodiments, each R18 are independently hydrogen or Z 1 In some embodiments, each R 18 is hydrogen. In some embodiments, X 5 is CH. In some embodiments, each R 18 is independently Z 1 In some embodiments, each R 18 is independently halo. In certain embodiments, each R 18 is fluoro.

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

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

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

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

[0163] In some embodiments, provided is a compound of formula IIIG: [ka] [In the formula, R 4 , R 13 , X 1 , X 2 , X 3 , X 5 , X 6 and each A is independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0164] In some embodiments, X 6 is CR 6 and in some embodiments, X 6 is N, and in some embodiments, X 5 is O. In some embodiments, A is ring A.

[0165] In some embodiments, provided is a compound of formula IIIH: [ka] [In the formula, R 4 , R 6 , R 13 , X 1 , X 2 , X 3 and each A is independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0166] In some embodiments, R 13 is hydrogen. In some embodiments, A is C 1-6 In some embodiments, A is C 3-4 In some embodiments, A is C 3-10 cycloalkyl or heterocyclyl. In certain embodiments, R 4 HA-OR 14 is.

[0167] In some embodiments, provided is a compound of formula IIIJ: [ka] [In the formula, R 4 , R 13 , X 1 , X 2 , X 3 and each A is independently as defined herein. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

[0168] In some embodiments, R 13 is hydrogen. In some embodiments, A is C 1-6 In some embodiments, A is C 3-4 In some embodiments, A is C 3-10 cycloalkyl or heterocyclyl. In certain embodiments, R 4 HA-OR 14 is.

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

[0170] In some embodiments, R 13 is hydrogen. In some embodiments, ring A is C 3-10 cycloalkyl or heterocyclyl. In certain embodiments, R 4 HA-OR 14 is.

[0171] In certain embodiments, provided is a compound selected from Table 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof. [Table 1] Table 2 Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

Table 14

Table 15

Table 17

Table 19

Table 30

[0172] The compounds of Formula I provided herein encompass the stereochemical forms of the compounds, e.g., optical isomers, e.g., enantiomers, diastereomers, and mixtures thereof, e.g., enantiomeric and / or diastereomeric mixtures, including racemic mixtures, and equal or unequal mixtures of individual enantiomers and / or diastereomers. All stereochemical forms are contemplated in this disclosure. Unless otherwise specified, when a disclosed compound is named or described by structure without specifying stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Representative stereochemical forms are provided throughout the specification, including, but not limited to, those set forth in Table 2. In certain embodiments, provided is a compound selected from Table 2, or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof. [Table 66] [Table 67] [Table 68] [Table 69] [Table 70] [Table 71]

[0173] The compounds of Formula I include pharmaceutically acceptable salts thereof. Additionally, the compounds of Formula I also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts, but which may be useful as intermediates for the preparation and / or purification of the compounds of Formula I and / or the separation of enantiomers of the compounds of Formula I. Non-limiting examples of pharmaceutically acceptable salts of the compounds of Formula I include trifluoroacetate salts.

[0174] It is further recognized that the compounds of Formula I or their salts can be isolated in the form of a solvate, and therefore, all such solvates are included within the scope of the present invention. For example, the compounds of Formula I and their salts can exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

[0175] Treatment Methods and Uses The methods described herein can be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, such as an animal or human. In this context, the methods described herein can be used therapeutically on an individual. "Ex vivo" means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples can be obtained by methods well known in the art. Examples of biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used ex vivo to determine optimal schedules and / or dosages for administration of the compounds of the invention for a given indication, cell type, individual, and other parameters. Information gathered from such use can be used clinically for experimental purposes or to design protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suitable are described below or will become apparent to those skilled in the art. Selected compounds may be further characterized for testing in human or non-human subjects for safety or tolerable dosage. Such properties may be tested using methods commonly known to those skilled in the art.

[0176] The compounds provided herein, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions of such compounds, are useful as inhibitors of one or more LPA receptors. As further described herein, compounds that antagonize LPA receptors may be useful in the prevention and / or treatment of a variety of diseases, including, for example, fibrosis (e.g., renal fibrosis, pulmonary fibrosis, liver fibrosis, arterial fibrosis, systemic sclerosis), urinary system diseases, carcinoma-related diseases, proliferative diseases, inflammatory / immune diseases, diseases caused by secretory dysfunction, brain-related diseases, and chronic diseases.

[0177] In certain embodiments, the present invention provides methods of treating a subject (e.g., a human) having a disease, disorder, or condition (i.e., an LPA-associated disease) in which inhibition of one or more LPA receptors is beneficial in treating the pathology and / or symptoms and / or progression of the underlying disease, disorder, or condition. In certain embodiments, the methods provided herein can include, or further include, treatment of one or more concurrent or secondary conditions associated with any one or more of the conditions provided herein.

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

[0179] In certain embodiments, the LPA-related disease is fibrosis of organs (e.g., liver, kidney, lung, heart, and skin), liver diseases (acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative disorders, non-alcoholic steatohepatitis (NASH), decreased liver function, impaired liver blood flow, etc.), cell proliferative diseases (e.g., cancers and aggressive cancer cell metastases, including solid tumors, solid tumor metastases, angiofibromas, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, and chronic lymphocytic leukemia (CLL)), inflammatory diseases (e.g., psoriasis, nephropathy, and pneumonia), gastrointestinal diseases (e.g., irritable bowel syndrome (TBS), inflammatory bowel disease (IBD), and abnormal pancreas). secretion), kidney disease, urinary tract-related disease (e.g., symptoms associated with benign prostatic hyperplasia or neurogenic bladder disease), spinal cord tumors, herniated discs, spinal stenosis, symptoms from diabetes, lower urinary tract diseases (e.g., lower urinary tract obstruction), inflammatory diseases of the lower urinary tract, dysuria and frequent urination), pancreatic disease, diseases associated with abnormal angiogenesis (e.g., arterial occlusion), scleroderma, brain-related diseases (e.g., cerebral infarction and cerebral hemorrhage), neuropathic pain, peripheral neuropathy, eye disease (e.g., age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, and glaucoma filtration surgery scars).

[0180] In certain embodiments, provided herein is a method for treating or preventing fibrosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof) or a pharmaceutical composition disclosed herein. For example, the method may include treatment of renal fibrosis, pulmonary fibrosis, liver fibrosis, arterial fibrosis, or systemic sclerosis. In certain embodiments, provided herein is a method for treating pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis (IPF)), comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof) or a pharmaceutical composition provided herein.

[0181] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof) or a pharmaceutical composition provided herein is used to treat or prevent fibrosis in a subject. For example, a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof) or a pharmaceutical composition provided herein can be used to treat organ or tissue fibrosis in a subject. In certain embodiments, provided herein is a method for preventing a fibrotic condition 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, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof) or a pharmaceutical composition provided herein to a subject at risk of developing one or more fibrotic conditions. For example, the subject may be exposed to one or more environmental conditions known to increase the risk of organ or tissue fibrosis. In some embodiments, the subject is exposed to one or more environmental conditions known to increase the risk of lung, liver or kidney fibrosis. In some embodiments, the subject has a genetic predisposition to developing organ or tissue fibrosis. In some embodiments, the compound disclosed herein (e.g., a compound of Formula I or its pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotope-enriched analog or solvate) or the pharmaceutical composition provided herein is administered to the subject to prevent or minimize scarring after injury. For example, the injury may include surgery.

[0182] Examples of diseases, disorders, or conditions involving fibrosis include lung diseases associated with fibrosis, e.g., idiopathic pulmonary fibrosis, iatrogenic drug-induced, occupational / environmentally induced fibrosis (farmer's lung), granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases (e.g., scleroderma), pulmonary alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, genetic diseases (e.g., Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage diseases, and familial interstitial lung disease), and rheumatoid arthritis. Pulmonary fibrosis secondary to systemic inflammatory diseases such as pulmonary fibrosis, scleroderma, lupus, idiopathic interstitial pneumonia, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, bleomycin-induced pulmonary fibrosis, chronic asthma, silicosis, asbestos-induced pulmonary or pleural fibrosis, acute lung injury, acute respiratory distress syndrome (ARDS) and acute respiratory distress (including bacterial pneumonia-induced, trauma-induced, viral pneumonia-induced, ventilator-induced, non-pulmonary sepsis-induced and aspiration-induced); chronic nephropathy associated with injury / fibrosis, renal disease Fibrosis (renal fibrosis), glomerulonephritis secondary to systemic inflammatory diseases such as lupus and scleroderma, tubulointerstitial fibrosis, glomerulonephritis, glomerulosclerosis, focal segmental, diabetes, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allograft and Alport syndrome; skin disorders, intestinal fibrosis, e.g., scleroderma and radiation-induced intestinal fibrosis; liver fibrosis, e.g., cirrhosis, alcohol-induced liver fibrosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), toxic / drug-induced liver fibrosis (e.g., hemochromatosis), bile duct injury, primary biliary cirrhosis, infectious or virally induced liver fibrosis (e.g., chronic HCV infection), inflammatory / immune disorders and autoimmune hepatitis; head and neck fibrosis, e.g., corneal scarring, e.g., LASIK (laser in situ keratomileusis), corneal transplantation and trabeculectomy; hypertrophic scarring, Dupuytren's disease, skin fibrosis, cutaneous scleroderma, keloids, e.g., burn-induced or surgical;and other fibrotic diseases, including, but not limited to, sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, chronic lymphocytic leukemia, tumor metastasis, transplanted organ rejection (e.g., bronchiolitis obliterans), endometriosis, neonatal respiratory distress syndrome and neuropathic pain, fibromyalgia, mixed connective tissue disease, and Peyronie's disease;

[0183] Provided herein is a method for improving pulmonary function in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomer mixture, tautomer, isotopically enriched analog, or solvate thereof) or a pharmaceutical composition provided herein. In some embodiments, the subject has been diagnosed with pulmonary fibrosis. In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomer mixture, tautomer, isotopically enriched analog, or solvate thereof) or a pharmaceutical composition provided herein is used to treat idiopathic pulmonary fibrosis in a subject. In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomer mixture, tautomer, isotopically enriched analog, or solvate thereof) or a pharmaceutical composition provided herein is used to treat common interstitial pneumonia in a subject.

[0184] In certain embodiments, 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 provided herein is used to treat a generalized parenchymal interstitial lung disease, such as iatrogenic drug-induced, occupational / environmentally induced fibrosis (farmer's lung), granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases (such as scleroderma), pulmonary alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, genetic diseases (e.g., Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage diseases, and familial interstitial lung disease) in a subject.

[0185] In certain embodiments, 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 provided herein is useful for treating post-transplant fibrosis associated with chronic rejection, such as bronchiolitis obliterans after lung transplantation, in a subject.

[0186] In certain embodiments, 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 provided herein is useful for treating skin fibrosis, such as cutaneous scleroderma, Dupuytren's disease, and keloids, in a subject.

[0187] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, stereoisomeric mixtures, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions provided herein are useful for treating liver fibrosis with or without cirrhosis in subjects, such as toxic / drug-induced (hemochromatosis), alcoholic liver disease, viral hepatitis (hepatitis B virus, hepatitis C virus, HCV), non-alcoholic liver disease (NAFLD, NASH), and metabolic and autoimmune diseases.

[0188] In certain embodiments, 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 provided herein is useful for treating renal fibrosis in a subject (e.g., tubulointerstitial fibrosis and glomerulosclerosis).

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

[0190] In certain embodiments, 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 provided herein is administered to a subject having organ or tissue fibrosis or predisposed to developing organ or tissue fibrosis in combination with one or more other agents used to treat fibrosis. In certain embodiments, the one or more agents include a corticosteroid, an immunosuppressant, a B-cell antagonist, and a uteroglobin.

[0191] In some embodiments, 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 provided herein is used to treat a skin disorder in a subject. Such skin disorders include, but are not limited to, atopic dermatitis, bullous disorders, collagen diseases, psoriasis, scleroderma, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof) is used to treat systemic sclerosis.

[0192] In certain 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) are useful for treating or preventing inflammation 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) can be used to treat or prevent an inflammatory / immune disorder in a subject.

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

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

[0195] In some embodiments, 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 provided herein is used to treat fibromyalgia. Fibromyalgia is thought to originate from the formation of fibrous scar tissue in contractile (voluntary) muscles. Fibrosis binds tissue, restricts blood flow, and causes pain.

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

[0197] As used herein, the term "cancer" refers to an abnormal growth of cells that tends to grow uncontrolled and, in some cases, metastasize (spread). Types of cancer include, but are not limited to, solid tumors (e.g., of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (thyroid), prostate, skin (melanoma or basal cell carcinoma)) or hematological tumors (e.g., leukemia) at any stage of disease, with or without metastasis.

[0198] Further non-limiting examples of cancers include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal region cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdomyosarcoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumor, brain and spinal cord tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumor, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, tumors of the Ewing's sarcoma family, Eye cancer, retinoblastoma, gallbladder cancer, gastric (body of the stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor (endocrine pancreas), Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, 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's lymphoma, skin T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoma, Waldenstrom's macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, oral cancer, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal carcinoma, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papilloma, parathyroid cancer, penile cancer, pharyngeal cancer, intermediate pineal parenchymal tumor, pineoblastoma and primitive neuroectodermal tumor, pituitary tumor, thyroid tumor Includes stroma cell neoplasms / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing family of tumors, sarcoma, Kaposi-Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric (corpus) cancer, primitive neuroectodermal tumor, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, and Wilms' tumor.

[0199] In some embodiments, provided herein is a method for treating an allergic disorder in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof). In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof) is useful for treating a respiratory disease, disorder, or condition in a subject. For example, a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof) can treat asthma (e.g., chronic asthma) in a subject.

[0200] As used herein, the term "respiratory disease" refers to a disease affecting the organs involved in breathing, such as the nose, throat, larynx, Eustachian tube, trachea, bronchi, lungs, associated muscles (e.g., diaphragm and intercostal space), and nerves. Examples of respiratory diseases include asthma, adult respiratory distress syndrome, and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, childhood-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease including chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or airway inflammation, and cystic fibrosis and hypoxia.

[0201] As used herein, the term "asthma" refers to any disorder of the lung characterized by airway obstruction and associated alterations in pulmonary gas flow, regardless of cause (intrinsic, extrinsic, or both; allergic or non-allergic). The term asthma may be used with one or more adjectives indicating the cause.

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

[0203] In some embodiments, the compounds disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof) are useful for treating or preventing nervous system disorders in a subject. As used herein, the term "nervous system disorder" refers to conditions that alter 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, those seen after blunt or surgical trauma (including postoperative cognitive impairment and spinal cord or brainstem injury), and neurological disorders such as degenerative disc disease and sciatica.

[0204] In some embodiments, the present disclosure 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 / neuropathic pain, spinal cord injury, cerebral edema, and head injury.

[0205] Also provided herein are methods for treating or preventing cardiovascular disease in a subject. As used herein, the term "cardiovascular disease" refers to diseases affecting the heart or blood vessels, or both, including, but not limited to, arrhythmias (atrial or ventricular, or both); atherosclerosis and its sequelae; angina pectoris; cardiac rhythm disorders; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysms; vasculitis, stroke; peripheral occlusive arteriopathy of the limbs, organs, or tissues; reperfusion injury after ischemia of the brain, heart, or other organs or tissues; endotoxin, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including those associated with migraine); vascular abnormalities, inflammation, or failure limited to a single organ or tissue; vascular abnormalities, inflammation, or failure limited to a single organ or tissue. For example, provided herein are methods for treating or preventing vasoconstriction, atherosclerosis and its sequelae, myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis, and stroke, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof).

[0206] In certain embodiments, provided herein are methods for reducing cardiac reperfusion injury following myocardial ischemia and / or endotoxic shock, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof).

[0207] Also provided herein is a method of reducing vasoconstriction in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof). For example, provided herein is a method of lowering or preventing an increase in blood pressure in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a 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 by assays known in the art. The activity of the compounds and compositions provided herein as LGA receptor inhibitors can be assayed in vitro, in vivo, or in cell lines.

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

[0210] In another example, 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) is administered orally to CD-1 female mice 2 hours after LPA challenge. The mice are then administered 0.15 mL of LPA in 0.1% BSA / PBS (2 pg / pL) via the tail vein (IV). Exactly 2 minutes after LPA challenge, the mice are sacrificed by decapitation, and trunk blood is collected. These samples are pooled and centrifuged, and individual 75 pL samples are frozen at -20°C until histamine assays are performed. Plasma histamine analysis can be performed using standard enzyme immunoassay (EIA) methods. Plasma samples are thawed and diluted 1:30 with 0.1% BSA in PBS. The previously described EIA protocol for histamine analysis can be used for this assay.

[0211] LPA acts as a biological effector molecule and has a variety of physiological actions, including effects on blood pressure, platelet activation, and smooth muscle contraction, as well as a variety of cellular processes, including cell proliferation, cell rounding, neurite retraction, and actin stress fiber formation and cell migration. These actions are largely receptor-mediated.

[0212] Activation of LPA receptors (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) by LPA mediates a range of downstream signaling cascades. Non-limiting examples include mitogen-activated protein kinase (MAPK) activation, adenyl cyclase (AC) inhibition / activation, phospholipase C (PLC) activation / Ca 2+These include recruitment, arachidonic acid release, Akt / PKB activation and activation of the small GTPases Rho, ROCK, Rae and Ras. Additional pathways affected by LPA receptor activation include, for example, cyclic adenosine monophosphate (cAMP), cell division cycle 42 / GTP-binding protein (Cdc42), proto-oncogene serine / threonine-protein kinase Raf (c-RAF), proto-oncogene tyrosine-protein kinase Src (c-src), extracellular signal-regulated kinase (ERK), focal adhesion kinase (FAK), guanine nucleotide exchange factors (GEFs), glycogen synthase kinase 3b (GSK3b), c-jun amino-terminal kinase (JNK), MEK, myosin light chain II (MLC II), nuclear factor kB (NF-kB), N-methyl-D-aspartate (NMDA) receptor activation, phosphatidylinositol 3-kinase (PBK), protein kinase A (PKA), protein kinase C (PKC), and ms-related C3 botulinum toxin substrate 1 (RAC1). Nearly all mammalian cells, tissues, and organs co-express several LPA-receptor subtypes, indicating that LPA receptors signal in a coordinated manner. LPA1, LPA2, and LPA3 share high amino acid sequence similarity.

[0213] LPA1 (previously called VZG-1 / EDG-2 / mrecl.3) is a G protein of three types: G i / o , G q and G 12 / 13 Through the activation of these G proteins, LPA induces, for example, cell proliferation, serum response element (SRE) activation, mitogen-activated protein kinase (MAPK) activation, adenyl cyclase (AC) inhibition, phospholipase C (PLC) activation, and Ca 2+ A range of cellular responses are induced via LPA1, including recruitment, Akt activation and Rho activation.

[0214] LPA1 expression has been observed in mouse testis, brain, heart, lung, small intestine, stomach, spleen, thymus, and skeletal muscle. Similarly, LPA1 is expressed in human tissues such as brain, heart, lung, placenta, colon, small intestine, prostate, testis, ovary, pancreas, spleen, kidney, skeletal muscle, and thymus.

[0215] LPA2 (EDG-4) also binds to three types of G proteins, G i / o , G q and G 12 / 13 It binds to and mediates LPA-induced cell signaling. LPA2 expression is observed in the testis, kidney, lung, thymus, spleen, and stomach of adult mice, and in human testis, pancreas, prostate, thymus, spleen, and peripheral blood leukocytes. LPA2 expression is upregulated in various cancer cell lines, and several human LPA2 transcript variants with mutations in the 3' untranslated region have been observed.

[0216] LPA3 activates PLC, Ca 2+ It mediates pleiotropic LPA-induced signaling, including recruitment, AC inhibition / activation, and MAPK activation. Overexpression of LPA3 in neuroblastoma cells results in neurite outgrowth. LPA3 expression is observed in adult mouse testis, kidney, lung, small intestine, heart, thymus, and brain. In humans, it is found in the heart, pancreas, prostate, testis, lung, ovary, and brain (frontal cortex, hippocampus, and amygdala).

[0217] LPA4 (p2y9 / GPR23) is sequence-diverse compared to LPA1, LPA2, and LPA3, and shares considerable similarity with the platelet-activating factor (PAF) receptor. LPA4 mediates LPA-induced Ca2+ expression. 2+ It mediates the recruitment and accumulation of cAMP and is functionally coupled to the G protein G for AC activation, as well as to 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 purinoceptor cluster of GPCRs and is structurally most closely related to LPA4. LPA5 is expressed in human heart, placenta, spleen, brain, lung, and intestine. LPA also shows extremely high expression in the CD8+ lymphocyte compartment of the gastrointestinal tract.

[0219] LPA6 (p2y5), a member of the purino-cluster of GPCRs, is structurally most closely related to LPA4. LPA6 is an LPA receptor that couples to the Gl2 / l3-Rho signaling pathway and is expressed in the inner root sheath of human hair follicles.

[0220] Improvement in any of the above response criteria is specifically provided for by the methods of the present invention.

[0221] Combination therapy The compounds provided herein, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions of such compounds, are useful as inhibitors of one or more LPA receptors. As further described herein, compounds that antagonize LPA receptors may be useful in the prevention and / or treatment of a variety of diseases, including, for example, fibrosis (e.g., renal fibrosis, pulmonary fibrosis, liver fibrosis, arterial fibrosis, systemic sclerosis), urinary system diseases, carcinoma-related diseases, proliferative diseases, inflammatory / immune diseases, diseases caused by secretory dysfunction, brain-related diseases, and chronic diseases.

[0222] In certain embodiments, the present invention provides methods of treating a subject (e.g., a human) having a disease, disorder, or condition (i.e., an LPA-associated disease) in which inhibition of one or more LPA receptors is beneficial in treating the pathology and / or symptoms and / or progression of the underlying disease, disorder, or condition. In certain embodiments, the methods provided herein can include, or further include, treatment of one or more concurrent or secondary conditions associated with any one or more of the conditions provided herein.

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

[0224] In certain embodiments, the LPA-related disease is fibrosis of organs (e.g., liver, kidney, lung, heart, and skin), liver diseases (acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative disorders, non-alcoholic steatohepatitis (NASH), decreased liver function, impaired liver blood flow, etc.), cell proliferative diseases (e.g., cancers and aggressive cancer cell metastases, including solid tumors, solid tumor metastases, angiofibromas, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, and chronic lymphocytic leukemia (CLL)), inflammatory diseases (e.g., psoriasis, nephropathy, and pneumonia), gastrointestinal diseases (e.g., irritable bowel syndrome (TBS), inflammatory bowel disease (IBD), and abnormal pancreas). secretion), kidney disease, urinary tract-related disease (e.g., symptoms associated with benign prostatic hyperplasia or neurogenic bladder disease), spinal cord tumors, herniated discs, spinal stenosis, symptoms from diabetes, lower urinary tract diseases (e.g., lower urinary tract obstruction), inflammatory diseases of the lower urinary tract, dysuria and frequent urination), pancreatic disease, diseases associated with abnormal angiogenesis (e.g., arterial occlusion), scleroderma, brain-related diseases (e.g., cerebral infarction and cerebral hemorrhage), neuropathic pain, peripheral neuropathy, eye disease (e.g., age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, and glaucoma filtration surgery scars).

[0225] In certain embodiments, a method for treating or preventing fibrosis is provided herein, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof) or a pharmaceutical composition disclosed herein. For example, the method may include treating renal fibrosis, pulmonary fibrosis, liver fibrosis, arterial fibrosis, or systemic sclerosis. In certain embodiments, a method for treating pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis (IPF)) is provided herein, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof) or a pharmaceutical composition provided herein.

[0226] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof) or a pharmaceutical composition provided herein is used to treat or prevent fibrosis in a subject. For example, a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof) or a pharmaceutical composition provided herein can be used to treat organ or tissue fibrosis in a subject. In certain embodiments, provided herein is a method for preventing a fibrotic condition 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, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof) or a pharmaceutical composition provided herein to a subject at risk of developing one or more fibrotic conditions. For example, the subject may be exposed to one or more environmental conditions known to increase the risk of organ or tissue fibrosis. In some embodiments, the subject is exposed to one or more environmental conditions known to increase the risk of lung, liver or kidney fibrosis. In some embodiments, the subject has a genetic predisposition to developing organ or tissue fibrosis. In some embodiments, the compound disclosed herein (e.g., a compound of Formula I or its pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotope-enriched analog or solvate) or the pharmaceutical composition provided herein is administered to the subject to prevent or minimize scarring after injury. For example, the injury may include surgery.

[0227] Examples of diseases, disorders, or conditions involving fibrosis include lung diseases associated with fibrosis, e.g., idiopathic pulmonary fibrosis, iatrogenic drug-induced, occupational / environmental induced fibrosis (farmer's lung), granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases (scleroderma and others), pulmonary alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, genetic disorders (e.g., Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage diseases, and familial interstitial lung disease), joint disorders, and pulmonary diseases. These include, but are not limited to, pulmonary fibrosis secondary to systemic inflammatory diseases such as rheumatoid arthritis, scleroderma, lupus, idiopathic interstitial pneumonia, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, bleomycin-induced pulmonary fibrosis, chronic asthma, silicosis, asbestos-induced pulmonary or pleural fibrosis, acute lung injury, acute respiratory distress syndrome (ARDS) and acute respiratory distress (including bacterial pneumonia-induced, trauma-induced, viral pneumonia-induced, ventilator-induced, non-pulmonary sepsis-induced and aspiration-induced).Chronic nephropathy associated with injury / fibrosis, renal fibrosis (nephrofibrosis), glomerulonephritis secondary to systemic inflammatory diseases such as lupus and scleroderma, tubulointerstitial fibrosis, glomerulonephritis, glomerulosclerosis, focal segmental, diabetes, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allograft and Alport syndrome; skin disorders, intestinal fibrosis, e.g., scleroderma and radiation-induced intestinal fibrosis; liver fibrosis, e.g., cirrhosis, alcohol-induced liver fibrosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), toxic / drug-induced liver fibrosis (e.g., hemochromatosis), bile duct injury, primary biliary cirrhosis, infection- or virus-induced liver fibrosis (e.g., chronic HCV). V infection), inflammatory / immune disorders and autoimmune hepatitis; head and neck fibrosis, e.g., corneal scarring, e.g., LASIK (laser in situ keratomileusis), keratoplasty and trabeculectomy; hypertrophic scarring, Dupuytren's disease, skin fibrosis, cutaneous scleroderma, keloids, e.g., burn-induced or surgical; and other fibrotic diseases, e.g., sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, chronic lymphocytic leukemia, tumor metastasis, transplanted organ rejection (e.g., bronchiolitis obliterans), endometriosis, neonatal respiratory distress syndrome and neuropathic pain, fibromyalgia, mixed connective tissue disease and Peyronie's disease.

[0228] Provided herein is a method for improving pulmonary function in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomer mixture, tautomer, isotopically enriched analog, or solvate thereof) or a pharmaceutical composition provided herein. In some embodiments, the subject has been diagnosed with pulmonary fibrosis. In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomer mixture, tautomer, isotopically enriched analog, or solvate thereof) or a pharmaceutical composition provided herein is used to treat idiopathic pulmonary fibrosis in a subject. In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomer mixture, tautomer, isotopically enriched analog, or solvate thereof) or a pharmaceutical composition provided herein is used to treat common interstitial pneumonia in a subject.

[0229] In certain embodiments, 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 provided herein is used to treat a generalized parenchymal interstitial lung disease, such as iatrogenic drug-induced, occupational / environmentally induced fibrosis (farmer's lung), granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases (scleroderma and others), pulmonary alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, genetic diseases (e.g., Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage diseases, and familial interstitial lung disease) in a subject.

[0230] In certain embodiments, 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 provided herein is useful for treating post-transplant fibrosis associated with chronic rejection, such as bronchiolitis obliterans after lung transplantation, in a subject.

[0231] In certain embodiments, 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 provided herein is useful for treating skin fibrosis, such as cutaneous scleroderma, Dupuytren's disease, and keloids, in a subject.

[0232] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, stereoisomeric mixtures, tautomers, isotopically enriched analogs or solvates thereof) or pharmaceutical compositions provided herein are useful for treating liver fibrosis with or without cirrhosis in subjects. For example, 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 certain embodiments, 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 provided herein is useful for treating renal fibrosis in a subject (e.g., tubulointerstitial fibrosis and glomerulosclerosis).

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

[0235] In certain embodiments, 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 provided herein is useful for treating one or more symptoms of COVID-19.

[0236] In certain embodiments, 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 provided herein is useful for treating chronic obstructive pulmonary disease (COPD).

[0237] In certain embodiments, 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 provided herein is useful for treating neuroinflammation.

[0238] In certain embodiments, 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 provided herein is useful for treating multiple sclerosis.

[0239] In certain embodiments, 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 provided herein is administered to a subject having organ or tissue fibrosis or predisposed to developing organ or tissue fibrosis in combination with one or more other agents used to treat fibrosis. In certain embodiments, the one or more agents include a corticosteroid, an immunosuppressant, a B-cell antagonist, and a uteroglobin.

[0240] In some embodiments, 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 provided herein is used to treat a skin disorder in a subject. Such skin disorders include, but are not limited to, atopic dermatitis, bullous disorders, collagen diseases, psoriasis, scleroderma, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof) is used to treat systemic sclerosis.

[0241] In certain 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) are useful for treating or preventing inflammation 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) can be used to treat or prevent an inflammatory / immune disorder in a subject.

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

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

[0244] In some embodiments, 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 provided herein is used to treat fibromyalgia. Fibromyalgia is thought to originate from the formation of fibrous scar tissue in contractile (voluntary) muscles. Fibrosis binds tissue, restricts blood flow, and causes pain.

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

[0246] As used herein, the term "cancer" refers to an abnormal growth of cells that tends to grow uncontrolled and, in some cases, metastasize (spread). Types of cancer include, but are not limited to, solid tumors (e.g., of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (thyroid), prostate, skin (melanoma or basal cell carcinoma)) or hematological tumors (e.g., leukemia) at any stage of disease, with or without metastasis.

[0247] Further non-limiting examples of cancers include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal region cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdomyosarcoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumor, brain and spinal cord tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumor, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing's sarcoma family of tumors, eye cancer, Cancer, retinoblastoma, gallbladder cancer, gastric (body of the stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor (endocrine pancreas), Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, 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's lymphoma, skin T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoma, Waldenstrom's macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, oral cancer, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal carcinoma, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papilloma, parathyroid cancer, penile cancer, pharyngeal cancer, intermediate pineal parenchymal tumor, pineoblastoma and primitive neuroectodermal tumor, pituitary tumor, thyroid tumor Includes stroma cell neoplasms / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing family of tumors, sarcoma, Kaposi-Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric (corpus) cancer, primitive neuroectodermal tumor, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, and Wilms' tumor.

[0248] In some embodiments, provided herein is a method for treating an allergic disorder in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof). In some embodiments, a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof) is useful for treating a respiratory disease, disorder, or condition in a subject. For example, a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof) can treat asthma (e.g., chronic asthma) in a subject.

[0249] As used herein, the term "respiratory disease" refers to a disease affecting the organs involved in breathing, such as the nose, throat, larynx, Eustachian tube, trachea, bronchi, lungs, associated muscles (e.g., diaphragm and intercostal space), and nerves. Examples of respiratory diseases include asthma, adult respiratory distress syndrome, and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, childhood-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease including chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or airway inflammation, and cystic fibrosis and hypoxia.

[0250] As used herein, the term "asthma" refers to any disorder of the lung characterized by airway obstruction and associated alterations in pulmonary gas flow, regardless of cause (intrinsic, extrinsic, or both; allergic or non-allergic). The term asthma may be used with one or more adjectives indicating the cause.

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

[0252] In some embodiments, the compounds disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof) are useful for treating or preventing nervous system disorders in a subject. As used herein, the term "nervous system disorder" refers to conditions that alter 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, those seen after blunt or surgical trauma (including postoperative cognitive impairment and spinal cord or brainstem injury), and neurological disorders such as degenerative disc disease and sciatica.

[0253] In some embodiments, the present disclosure 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 / neuropathic pain, spinal cord injury, cerebral edema, and head injury.

[0254] Also provided herein are methods for treating or preventing cardiovascular disease in a subject. As used herein, the term "cardiovascular disease" refers to diseases affecting the heart or blood vessels, or both, including, but not limited to, arrhythmias (atrial or ventricular, or both); atherosclerosis and its sequelae; angina pectoris; cardiac rhythm disorders; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysms; vasculitis, stroke; peripheral occlusive arteriopathy of the limbs, organs, or tissues; reperfusion injury after ischemia of the brain, heart, or other organs or tissues; endotoxin, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including those associated with migraine); vascular abnormalities, inflammation, or failure limited to a single organ or tissue; vascular abnormalities, inflammation, or failure limited to a single organ or tissue. For example, provided herein are methods for treating or preventing vasoconstriction, atherosclerosis and its sequelae, myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis, and stroke, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof).

[0255] In certain embodiments, provided herein are methods for reducing cardiac reperfusion injury following myocardial ischemia and / or endotoxic shock, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof).

[0256] Also provided herein is a method of reducing vasoconstriction in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof). For example, provided herein is a method of lowering or preventing an increase in blood pressure in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof).

[0257] Pharmaceutical Compositions and Methods of Administration The compounds provided herein are typically administered in the form of a pharmaceutical composition.

[0258] When used as pharmaceuticals, 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, can be administered in the form of pharmaceutical compositions. These compositions can be prepared by methods well known in the pharmaceutical arts and can be administered by a variety of routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epithelial, ocular, and mucosal membranes, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Oral administration can include dosage forms prepared for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracranial, e.g., intrathecal or intracerebroventricular, administration. Parenteral administration can be in the form of a single bolus dose or, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, and the like may be necessary or desirable.

[0259] Also provided herein are pharmaceutical compositions comprising, as an active ingredient, a compound disclosed herein or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof) in combination with one or more pharmaceutically acceptable excipients (carriers). For example, a pharmaceutical composition is prepared using a compound disclosed herein or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof). In certain embodiments, the composition is suitable for topical administration. When preparing the compositions provided herein, the active ingredient is typically mixed with an additive, diluted with an additive, or enclosed in such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When an additive acts as a diluent, it can be a solid, semi-solid, or liquid substance, and acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is a solid oral formulation. In some embodiments, the composition is formulated as a tablet or capsule.

[0260] Further provided herein is a pharmaceutical composition 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 comprising a compound disclosed herein or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof) as an active ingredient can be prepared by intimately mixing a compound disclosed herein or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof) with a pharmaceutical carrier by conventional pharmaceutical compounding techniques. The carrier can take a variety of forms depending on the desired route of administration (e.g., oral, parenteral). In certain embodiments, the composition is a solid oral composition.

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

[0262] Methods for preparing pharmaceutical compositions are described in numerous publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al.; published by Marcel Dekker, Inc.

[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 polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances, such as phosphate, Tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylic acid, waxes, polyethylene-polyoxypropylene block polymers and wool fat. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives, can also be used to enhance delivery of the compounds provided herein. Dosage forms or compositions containing 0.005% to 100% of the chemicals provided herein, with the remainder consisting of non-toxic additives, can be prepared. Contemplated compositions include 0.001% to 100% of the chemicals provided herein, 0.1% to 95% in some embodiments, 75% to 85% in other embodiments, and 20% to 80% in further embodiments. Actual methods for preparing such dosage forms will be known or apparent to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, UK. 2012).

[0264] In certain embodiments, 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), or a pharmaceutical composition provided herein, may be administered to a subject in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, intracervical, intrasinus, intratracheal, enteral, epidural, intrasystemic, intraperitoneal, intraarterial, intrabronchial, intravesical, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepithelial, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intraspinal, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intrathecal, intrasynovial, intratesticular, intrathecal, intraductal, intratumoral, intrauterine, intravascular, intravenous, intranasal (e.g., intranasal), nasogastric, oral, parenteral, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal. In certain embodiments, the preferred route of administration is parenteral (eg, intratumoral).

[0265] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, stereoisomeric mixtures, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions thereof provided herein can be formulated for parenteral administration, for example, for injection via intraarterial, intrasternal, intracranial, intravenous, intramuscular, subcutaneous, or intraperitoneal routes. For example, such compositions can be prepared as liquid solutions or suspensions for injection; solid forms suitable for preparing solutions or suspensions by adding liquids before injection can also be prepared; and formulations can also be emulsified. The preparation of such formulations is known to those skilled in the art in light of the present invention. In some embodiments, a device is used for parenteral administration. For example, such devices can include needle injectors, microneedle injectors, needleless injectors, and infusion techniques.

[0266] In some embodiments, pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.In some embodiments, the form must be sterile and fluid enough to be easily squirted.In some embodiments, the form must be stable under the conditions of manufacture and storage, and must be protected from contamination by microorganisms such as bacteria and fungi.

[0267] In some embodiments, the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In some embodiments, proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. In some embodiments, the prevention of microbial activity can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In some embodiments, isotonic agents, such as sugars or sodium chloride, are included. In some embodiments, prolonged absorption of injectable compositions can be achieved by using absorption-delaying agents, for example, aluminum monostearate and gelatin, in the compositions.

[0268] In some embodiments, sterile injectable solutions are prepared by dissolving the required 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) in an appropriate solvent containing various other ingredients as listed above, as needed, followed by filter sterilization. In some embodiments, dispersions are prepared by dissolving the various sterilized active ingredients in a sterile vehicle containing the basic dispersion medium and the required other ingredients listed above. In some embodiments, sterile powders are used to prepare sterile injectable solutions. In some embodiments, the preparation method is vacuum drying and freeze-drying techniques, which produce powders of the active ingredient and any additional desired ingredients from a previously sterilized solution.

[0269] In certain embodiments, pharmaceutically acceptable excipients useful in rectal compositions as gels, creams, enemas, or rectal suppositories include cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-hydroxybenzoate, sodium propyl p-hydroxybenzoate, diethylamine, carbomer, carbopol, methyl hydroxybenzoate, macrogol cetostearyl The inactive ingredients may include, but are not limited to, one or more of: glycerin, methylparaben, sorbitan stearate, sorbitan isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, disodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0270] In some embodiments, suppositories 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 provided herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax, which is solid at ambient temperature but liquid at body temperature and thus melts in the rectum and releases the active compound. In some embodiments, a composition for rectal administration is in the form of an enema.

[0271] In certain embodiments, 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 provided herein may be formulated for local delivery to the digestive or GI tract by oral administration (e.g., in solid or liquid dosage form).

[0272] In some embodiments, the solid dosage form for oral administration includes capsules, tablets, pills, powders and granules.In some embodiments, the compound disclosed herein or its pharmaceutically acceptable salt, stereoisomer, stereoisomer mixture, tautomer, isotopically enriched analog or solvate (e.g., the compound of Formula I or its pharmaceutically acceptable salt, stereoisomer, stereoisomer mixture, tautomer, isotopically enriched analog or solvate) is mixed with one or more pharmaceutically acceptable additives, such as sodium citrate or dicalcium phosphate, and / or: a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) for example, carboxymethylcellulose, alginate, gelatin, polyvinyl alcohol, hydroxybenzoates ... Binders such as pyrrolidinone, sucrose and acacia, c) wetting agents such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, some silicic acid and sodium carbonate, e) dissolution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and their mixtures.For example, in the case of capsules, tablets and pills, these dosage forms can also contain buffering agents.In some embodiments, similar type solid compositions can also be used as fillers in soft and hard-filled gelatin capsules, using additives such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0273] In some embodiments, the pharmaceutical composition is in the form of a unit dosage form such as a pill or tablet, and thus the composition may contain 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) as provided herein, along with a diluent such as lactose, sucrose, or dicalcium phosphate; a lubricant such as magnesium stearate; and a binder such as starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, or a cellulose derivative. In some embodiments, other solid dosage forms, such as powders, quince, solutions, or suspensions (e.g., propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglyceride injections) may be filled into capsules (gelatin or cellulose-based capsules). In some embodiments, unit dosage forms in which one or more compounds and the pharmaceutical compositions provided herein or additional active agents are physically separated are also contemplated; for example, capsules (or tablets in capsules) with granules of each drug; bilayer tablets; bicompartment gelcaps, etc. In certain embodiments, enteric coated or delayed release oral dosage forms are also contemplated.

[0274] In certain embodiments, other physiologically acceptable compounds are wetting agents, emulsifying agents, dispersing agents, or preservatives that are particularly useful for preventing the growth or action of microorganisms. For example, various preservatives are well known and include, for example, phenol and ascorbic acid.

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

[0276] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, stereoisomeric mixtures, tautomers, isotopically enriched analogs, or solvates thereof) or pharmaceutical compositions thereof may be formulated for ocular administration. In some embodiments, the ocular compositions may include, but are not limited to, one or more of the following: viscogen (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymer), cyclodextrin); preservatives (e.g., benzalkonium chloride, EDTA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychlorocomplex; Allergan, Inc.)).

[0277] In certain 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 thereof provided herein are formulated for topical administration to the skin or mucosa (e.g., dermal or transdermal). In certain embodiments, topical compositions can include ointments and creams. In certain embodiments, ointments are semi-solid formulations typically based on petrolatum or other petroleum derivatives. In certain embodiments, creams containing the selected active agent are typically viscous liquids or semi-solid emulsions, often oil-in-water or water-in-oil. For example, cream bases are typically water-washable and contain an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase, sometimes referred to as the "internal" phase, is generally composed of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume and generally contains a humectant. In some embodiments, the emulsifier in a cream formulation is generally a nonionic, anionic, cationic, or amphiphilic surfactant. In some embodiments, the ointment base, like other carriers or vehicles, must be inert, stable, non-irritating, and non-sensitizing.

[0278] In any of the above embodiments, the pharmaceutical compositions provided herein can include one or more of lipids, interbilayer-crosslinked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0279] In some embodiments, the dosage of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof) is determined based on multiple factors, including, but not limited to, the type of subject, body weight, sex, medical condition, the severity of the subject's medical condition, the route of administration, and the activity of the compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the appropriate dosage for a particular situation can be determined by those skilled in the medical field. In some embodiments, the total daily dosage can be divided and administered throughout the day in small doses or by a means that provides continuous delivery.

[0280] In certain embodiments, 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) is administered at a dose of about 0.01 to about 1000 mg, e.g., about 0.1 to about 30 mg, about 10 to about 80 mg, about 0.5 to about 15 mg, about 50 mg to about 200 mg, about 100 mg to about 300 mg, about 200 to about 400 mg, about 300 mg to about 500 mg, about 400 mg to about 600 mg, about 500 mg to about 800 mg, about 600 mg to about 900 mg, or about 700 mg to about 1000 mg. In certain embodiments, the dose is a therapeutically effective amount.

[0281] In certain embodiments, 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) provided herein is administered at a dose of about 0.0002 mg / Kg to about 100 mg / Kg (e.g., about 0.0002 mg / Kg to about 50 mg / Kg; about 0.0002 mg / Kg to about 25 mg / Kg; about 0.0002 mg / Kg to about 100 mg / Kg). 002mg / Kg~about 10mg / Kg;about 0.0002mg / Kg~about 5mg / Kg;about 0.0002mg / Kg~about 1mg / Kg;about 0.0002mg / Kg~about 0.5mg / Kg;about 0. 0002mg / Kg ~ approx. 0.1mg / Kg; approx. 0.001mg / Kg ~ approx. 50mg / Kg; approx. 0.001mg / Kg ~ approx. 25mg / Kg; approx. 0.001mg / Kg ~ approx. 10mg / Kg; approx. 0. 001mg / Kg~about 5mg / Kg;about 0.001mg / Kg~about 1mg / Kg;about 0.001mg / Kg~about 0.5mg / Kg;about 0.001mg / Kg~about 0.1mg / Kg;about 0.01 mg / Kg~about 50mg / Kg;about 0.01mg / Kg~about 25mg / Kg;about 0.01mg / Kg~about 10mg / Kg;about 0.01mg / Kg~about 5mg / Kg;about 0.01mg / Kg~about 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 at a dosage of about 100 mg / kg.

[0282] In certain embodiments, the dosages 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) can be administered daily (e.g., in a single dose or in two or more divided doses) or on a non-daily basis (e.g., every other day, every two days, every three days, weekly, twice weekly, biweekly, monthly).

[0283] In some embodiments, the administration period 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) provided herein is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In some embodiments, the period for which administration is suspended is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In certain embodiments, 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) is administered to a subject for a period of time, followed by another period of time during which administration of 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) is discontinued. In certain embodiments, a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof) is administered for a first period of time, followed by a second period of time during which administration is stopped, followed by a third period of time during which administration of a compound disclosed herein or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof (e.g., a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, tautomer, isotopically enriched analog, or solvate thereof) is initiated, and then the third period of time is followed by a fourth period of time during which administration is stopped.For example, a period of administration 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) followed by a period during which administration is discontinued is repeated for a determined or undetermined period of time. In some embodiments, the period of administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In some embodiments, the period for which administration is suspended is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more.

[0284] In certain embodiments, 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) is orally administered to a subject one or more times daily (e.g., once daily, twice daily, three times daily, four times daily, or once daily administration).

[0285] In certain embodiments, 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) is parenterally administered to a subject one or more times daily (e.g., 1 to 4 times once daily, twice daily, three times daily, four times daily, or once daily).

[0286] In certain embodiments, 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) is parenterally administered to a subject weekly.

[0287] Compound synthesis The compounds of the present disclosure can be prepared, for example, from readily available starting materials using the following general methods and procedures. Where certain process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are described, it is recognized that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the reactants or solvents used, but such conditions can be determined by one skilled in the art by routine 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 undesired reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting certain functional groups are well known in the art. For example, numerous protecting groups are described in TW Greene and GM Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein.

[0289] Furthermore, compounds of the present disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., individual enantiomers or diastereomers, or stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present invention, unless otherwise specified. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, etc.

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

[0291] Scheme I shows the 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 2are each independently as defined herein; LG and LG′ are suitable leaving groups such as halo (e.g., Cl, Br, or I), where LG and LG′ are not the same; PG is a suitable carboxyl protecting group such as alkyl or benzyl; B is a boronic ester (e.g., —B(R 50 )2 (where each R 50 are independently alkyl or substituted alkyl, or two R 50 is a suitable coupling functional group, including, but not limited to, a boronic acid or derivative thereof, such as boronic acid (e.g., pinacol boronic acid ester), which together form an optionally substituted cyclic boronic ester (e.g., pinacol boronic acid ester). [ka]

[0292] A compound of Formula I can be prepared by first coupling compound I-1, followed by deprotection to give the free acid of Formula I, where B is a suitable coupling functional group, such as a boronic acid or derivative thereof, such as a boronic ester (cyclic or annular), a zinc or magnesium halide, an organotin compound, such as tributylstannane or trimethylstannane, a fluorosulfonyl ester, tin, sodium, etc. Such reactions are commonly used for aromatic functionalizations and are typically carried out in the presence of a suitable catalyst, such as, but not limited to, a palladium catalyst, including, for example, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, Pd(OAc)2, Pd(PPh3)4, PdCl2(PPh3)2, or tris(dibenzylideneacetone)dipalladium(0), or a copper catalyst, such as CuCl or CuI, using a suitable solvent / solvent mixture, and if necessary, a suitable mediator, co-catalyst, and / or base known to those skilled in the art. After the reaction is complete, the compound of Formula I can be recovered by conventional techniques, such as neutralization, extraction, precipitation, chromatography, filtration, and the like. In certain embodiments, when control of stereochemistry is desired, appropriate control of the reaction conditions and selection of substituents on the reactants can lead to or maintain, at least in part, the formation of various stereoisomers. Compounds I-1 and I-2 can be obtained commercially or synthesized de novo. For example, as shown in Scheme I above, compound I-1 can be prepared by coupling compound I-3 with compound I-4 under standard nucleophilic aromatic substitution conditions.

[0293] Scheme II shows the 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 2are each independently as defined herein; LG and LG′ are suitable leaving groups such as halo (e.g., Cl, Br, or I), where LG and LG′ are not the same; PG is a suitable carboxyl protecting group such as alkyl or benzyl; B is a boronic ester (e.g., —B(R 50 )2 (where each R 50 are independently alkyl or substituted alkyl, or two R 50 is a suitable coupling functional group, including, but not limited to, a boronic acid or derivative thereof, such as boronic acid (e.g., pinacol boronic acid ester), which together form an optionally substituted cyclic boronic ester (e.g., pinacol boronic acid ester). [ka]

[0294] Compound II can be prepared by first coupling compound II-1, followed by deprotection to give the free acid of formula II, where B is a suitable functional group, such as, but not limited to, a boronic acid or derivative thereof, such as a boronic ester (cyclic or annular), a zinc or magnesium halide, an organotin compound, e.g., tributylstannane or trimethylstannane, a fluorosulfonyl ester, tin, sodium, hydrogen, etc. Such reactions are commonly used for aromatic functionalizations and are typically carried out in the presence of a suitable catalyst, such as, but not limited to, a palladium catalyst, including, for example, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, Pd(OAc)2, Pd(PPh3)4, PdCl2(PPh3)2, or tris(dibenzylideneacetone)dipalladium(0), or a copper catalyst, such as CuCl or CuI, using a suitable solvent / solvent mixture, and, if necessary, a suitable mediator, co-catalyst, and / or base known to those skilled in the art. After the reaction is complete, the compound of formula II can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, etc. In certain embodiments, when control of stereochemistry is desired, appropriate control of reaction conditions and selection of reagent substituents can lead to or maintain, at least in part, the formation of various stereoisomers. Compounds I-1 and II-2 can be obtained commercially or synthesized de novo.

[0295] Scheme III shows the 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 are each independently as defined herein; LG and LG′ are suitable leaving groups such as halo (e.g., Cl, Br, or I), where LG and LG′ are not the same; PG is a suitable carboxyl protecting group such as alkyl or benzyl; B is a boronic ester (e.g., —B(R50 )2 (where each R 50 are independently alkyl or substituted alkyl, or two R 50 is a suitable coupling functional group, including, but not limited to, a boronic acid or derivative thereof, such as boronic acid (e.g., pinacol boronic acid ester), which together form an optionally substituted cyclic boronic ester (e.g., pinacol boronic acid ester). [ka]

[0296] A compound of Formula IIA can be prepared by first coupling compound IIA-1, followed by deprotection to give the free acid of Formula IIA, where B is a suitable functional group such as, but not limited to, a boronic acid or derivative thereof, such as a boronic ester (cyclic or annular), a zinc or magnesium halide, an organotin compound, e.g., tributylstannane or trimethylstannane, a fluorosulfonyl ester, tin, sodium, hydrogen, etc. Such reactions are commonly used for aromatic functionalizations and are typically carried out in the presence of a suitable catalyst, such as, but not limited to, a palladium catalyst, including, for example, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, Pd(OAc)2, Pd(PPh3)4, PdCl2(PPh3)2, or tris(dibenzylideneacetone)dipalladium(0), or a copper catalyst, such as CuCl or CuI, using a suitable solvent / solvent mixture, and if necessary, a suitable mediator, co-catalyst, and / or base known to those skilled in the art. After the reaction is complete, the compound of formula IIA can be recovered by conventional techniques, such as neutralization, extraction, precipitation, chromatography, filtration, and the like. In certain embodiments, when control of stereochemistry is desired, appropriate control of the reaction conditions and selection of substituents on the reagents can lead to or maintain, at least in part, the formation of various stereoisomers. Compounds IIA-1 and II-2 can be obtained commercially or synthesized de novo. For example, as shown in Scheme III above, compound IIA-1 can be prepared by coupling compound IIA-3 with compound I-4 under standard nucleophilic aromatic substitution conditions.

[0297] It is recognized that various substituents of 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 II). For example, A or ring A can be added before or after the steps shown in the schemes above. The A or ring A moiety can be added to X 4 It can be combined with the precursor under substitution reaction conditions.

[0298] It should be understood that for any compound shown in Scheme I, Scheme II, or Scheme II, various derivatives can be provided by functional group interconversion at any step. In certain embodiments, various substituents (e.g., A, ring A, R) of Formula I-1, II-1, IIA-1, I-2, II-2, I-3, II-3, IIA-3, or I-4 can be provided by functional group interconversion at any step. 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 ) are 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 of the reactions and / or further derivatization of the resulting reaction products will provide various compounds of Formula I, Formula II, or Formula IIA. Suitable starting materials and reagents can be purchased or prepared by methods known to those skilled in the art. After completion of each reaction, each intermediate or final compound can be recovered by conventional techniques, such as neutralization, extraction, precipitation, chromatography, filtration, and the like, and purified, if desired. Other modifications to arrive at compounds of the present disclosure are within the skill of those in the art.

[0299] general synthesis Compounds of exemplary embodiments described herein can be synthesized using the following general reaction schemes. It is understood that, in light of the description herein, the general schemes can be modified by replacing starting materials with other materials having similar structures, resulting in correspondingly different products. Following the description of the synthesis, numerous examples are provided of how the starting materials can be modified to yield the corresponding products. In light of the desired product, where the substituents are defined, the necessary starting materials can generally be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. For the synthesis of compounds that are embodiments described herein, inspection of the structure of the compound to be synthesized provides the identity of each substituent. The identity of the final product will generally reveal the identity of the necessary starting materials by simple procedures of inspection, in light of the examples herein. In general, the compounds described herein are typically stable and isolatable at room temperature and atmospheric pressure. [Example]

[0300] The following examples are provided to demonstrate specific embodiments of the present invention. Those skilled in the art will recognize that the techniques disclosed in the following examples represent fully functional techniques for the practice of the invention and, therefore, can be considered to constitute specific modes of practice thereof. However, those skilled in the art will recognize in light of the present invention that many changes can be made to the disclosed embodiments and still obtain like or similar results without departing from the spirit and scope of the present disclosure.

[0301] Abbreviations (used here): [Table 72] [Table 73]

[0302] General information: Total evaporation or concentration was performed using a rotary evaporator under reduced pressure. Analytical samples were dried under reduced pressure (1-5 mmHg) at room temperature. Thin-layer chromatography (TLC) was performed on silica gel plates, and spots were visualized with UV light (214 nm and 254 nm). Purification by column and flash chromatography was performed using silica gel (100-200 mesh). Solvent systems are listed as mixtures by volume. NMR spectra were recorded on a Bruker 400 or Varian (400 MHz) spectrometer. 1 H chemical shifts were recorded in δ values ​​(ppm) with deuterated solvent as internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant (Hz), and integral diagram. LCMS spectra were performed on a SHIMADZU LC20-MS2020 or Agilent 1260 Series 6125B mass spectrometer or Agilent 1200 Series, 6110, or 6120 mass spectrometer using electrospray ionization, except where otherwise noted.

[0303] Example A1 3-((2-(((2,3-dihydro-1H-inden-2-yl)oxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)oxy)propanoic acid (Compound 105) [ka] Step A: Ethyl 3-(4-bromo-3-methylphenoxy)propanoate [ka]

[0304] To a mixture of 4-bromo-3-methylphenol (3.20 g, 17.10 mmol) in ethyl acrylate (14 mL) was added DMAP (522 mg, 4.28 mmol) at room temperature. The mixture was stirred at 120 °C for 5 hours under microwave irradiation. The reaction mixture was then concentrated under reduced pressure. The residue was purified on a silica gel column (PE / EtOAc = 20:1) to give ethyl 3-(4-bromo-3-methylphenoxy)propanoate (1.20 g, 24% yield). 1 H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.8 Hz, 1H), 6.80 (d, J = 2.8 Hz, 1H), 6.62 (dd, J = 8.8 Hz, 3.2 Hz, 1H), 4.25 - 4.13 (m, 4H), 2.77 (t, J = 6.4 Hz, 2H), 2.35 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H).

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

[0306] To a mixture of ethyl 3-(4-bromo-3-methylphenoxy)propanoate (300 mg, 1.04 mmol) in CCl4 (8 mL) was added NBS (222 mg, 1.25 mmol), AIBN (7 mg, 0.042 mmol), and AcOH (0.15 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 × 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)propanoate (200 mg, 52% yield). 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 3.2 Hz, 1H), 6.74 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 4.54 (s, 2H), 4.28 - 4.13 (m, 4H), 2.78 (t, J = 6.4 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H).

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

[0308] To a mixture of ethyl 3-(4-bromo-3-(bromomethyl)phenoxy)propanoate (220 mg, 0.60 mmol) and 2,3-dihydro-1H-inden-2-ol (139 mg, 1.05 mmol) in DCE (8 mL) was added 2,6-di-tert-butylpyridine (197 mg, 1.80 mmol) and AgOTf (269 mg, 1.05 mmol) at room temperature. The mixture was stirred at 25 °C for 16 hours. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column (PE / EtOAc = 10:1) to give ethyl 3-(4-bromo-3-(((2,3-dihydro-1H-inden-2-yl)oxy)methyl)phenoxy)propanoate (100 mg, 40% yield). 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.4 Hz, 1H), 7.25 - 7.20 (m, 2H), 7.19 - 7.14 (m, 2H), 7.04 (d, J = 3.2 Hz, 1H), 6.70 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 4.59 (s, 2H), 4.54 - 4.47 (m, 1H), 4.28 - 4.12 (m, 4H), 3.23 (dd, J = 16.4 Hz, 6.4 Hz, 2H), 3.10 (dd, J = 16.0 Hz, 4.8 Hz, 2H), 2.76 (t, J = 6.4 Hz, 2H), 1.27 (t, J = 6.8 Hz, 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)propanoate [ka]

[0310] To a mixture of ethyl 3-(4-bromo-3-(((2,3-dihydro-1H-inden-2-yl)oxy)methyl)phenoxy)propanoate (20.0 mg, 0.048 mmol) in 1,4-dioxane / HO (1 mL / 0.2 mL), 2-(3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (20.0 mg, 0.072 mmol), NaCO (15.2 mg, 0.144 mmol), and Pd(dppf)Cl.CHCl (2.00 mg, 0.0024 mmol) were added at room temperature. The reaction mixture was stirred at 90 °C under microwave irradiation for 1 hour. After cooling, the reaction mixture was filtered, and the filter cake was washed with EtOAc (10 mL). The filtrate was dried over NaSO and concentrated. The residue was purified by preparative TLC (PE / EtOAc=5 / 1) to give ethyl 3-((2-(((2,3-dihydro-1H-inden-2-yl)oxy)methyl)-3′,5′-dimethoxy-4′-methyl-[1,1′-biphenyl]-yl)oxy)propanoate (13.0 mg, 56% yield). 1 H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 8.4 Hz, 1H), 7.17 - 7.12 (m, 4H), 7.09 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 6.51 (s, 2H), 4.44 (s, 2H), 4.42 - 4.35 (m, 1H), 4.28 (t, J = 6.4 Hz, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.77 (s, 6H), 3.12 (dd, J = 16.0 Hz, 6.4 Hz, 2H), 2.97 (dd, J = 16.0 Hz, 4.4 Hz, 2H), 2.80 (t, J = 6.4 Hz, 2H), 2.14 (s, 3H), 1.29 (d, J = 7.2 Hz, 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)propanoic acid (Compound 105) [ka]

[0312] A mixture of ethyl 3-((2-(((2,3-dihydro-1H-inden-2-yl)oxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-yl)oxy)propanoate (50.0 mg, 0.102 mmol) in AcOH (2 mL) and 5 M aqueous HCl (2 mL) was stirred at 60° C. for 4 hours. The reaction mixture was concentrated. The residue was purified by preparative TLC (PE / EtOAc=1 / 2) and further by preparative HPLC (HO and 0.1% formic acid in MeOH) to give 3-((2-(((2,3-dihydro-1H-inden-2-yl)oxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)oxy)propanoic acid (12.0 mg, 32% yield). LC-MS: m / z 485.3 (M+Na) + . 1 H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 8.4 Hz, 1H), 7.19 - 7.11 (m, 4H), 7.09 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 8.4 Hz, 2.8 Hz, 1H), 6.50 (s, 2H), 4.45 (s, 2H), 4.41 - 4.36 (m, 1H), 4.29 (t, J = 6.4 Hz, 2H), 3.77 (s, 6H), 3.12 (dd, J = 16.0 Hz, 6.4 Hz, 2H), 2.97 (dd, J = 16.4 Hz, 4.4 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.14 (s, 3H).

[0313] Example A2 3-((2-(((2,3-dihydro-1H-inden-2-yl)oxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)propanoic acid (Compound 101) [ka] Step A: (3',5'-dimethoxy-4'-methyl-4-nitro-[1,1'-biphenyl]-2-yl)methanol [ka]

[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-dioxaborolane (2.40 g, 8.62 mmol) in dioxane (30 mL) and HO (10 mL) was added NaCO (2.74 g, 25.86 mmol) and Pd(dppf)Cl (631 mg, 861.95 μmol). The mixture was stirred under nitrogen at 85 °C for 16 h. After cooling, the mixture was diluted with HO (15 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column (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 (400 MHz, CD3OD) δ 8.50 (d, J = 2.4 Hz, 1H), 8.20 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 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)methyl methanesulfonate [ka]

[0316] 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) was added TEA (1.47 g, 14.51 mmol) and MsCl (1.25 g, 10.88 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The mixture was then diluted with HO (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified on a silica gel column (PE / EtOAc = 10 / 1) to give (3',5'-dimethoxy-4'-methyl-4-nitro-[1,1'-biphenyl]-2-yl)methyl methanesulfonate (2.50 g, 90% yield). 1 H NMR (400MHz, DMSO-d6) δ 8.49 (d, J = 2.4 Hz, 1H), 8.32 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.70 (d, J = 8.4 Hz, 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 [ka]

[0318] To a solution of indan-2-ol (1.42 g, 10.62 mmol) in THF (20 mL) was added NaH (424.71 mg, 10.62 mmol, 60% wt in mineral oil) at 0 °C. After stirring for 30 min, a solution of (3',5'-dimethoxy-4'-methyl-4-nitro-[1,1'-biphenyl]-2-yl)methyl methanesulfonate (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 HO (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column (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 [ka]

[0320] 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 5 mL of EtOAc was added 10% Pd / C (100 mg) under nitrogen. The suspension was degassed under reduced pressure and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 25 °C for 1 h. The mixture was filtered and the filtrate was concentrated to give 4-(3,5-dimethoxy-4-methyl-phenyl)-3-(indan-2-yloxymethyl)aniline (170 mg, 91% yield), which was used in the next step without further purification. 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)propanoate [ka]

[0322] 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-dimethoxypropanoate (64.67 mg, 436.47 μmol) in DCE (5 mL) was added TFA (3.23 g, 28.37 mmol) and EtSiH (167 mg, 1.44 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. The mixture was diluted with HO (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified on a silica gel column (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)propanoate (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)propanoic acid (Compound 101) [ka]

[0324] To a solution of methyl 3-[4-(3,5-dimethoxy-4-methyl-phenyl)-3-(indan-2-yloxymethyl)anilino]propanoate (50 mg, 105.14 μmol) in MeOH (1 mL), THF (1 mL), and HO (1 mL) was added LiOH.HO (22 mg, 525.68 μmol). 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 × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM NH4HCO3)-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)propanoic acid (43 mg, 87% yield). LC-MS: m / z 462.0 (M+H) + . 1 H NMR (400 MHz, CD3OD) δ 7.18 - 7.06 (m, 5H), 6.81 (d, J = 2.4 Hz, 1H), 6.67 (dd, J = 8.0 Hz, 2.4 Hz, 1H), 6.54 (s, 2H), 4.43 (s, 2H), 4.41 - 4.36 (m, 1H), 3.73 (s, 6H), 3.43 (t, J = 6.8 Hz, 2H), 3.09 (dd, J = 16.0 Hz, 8.0 Hz, 2H), 2.89 (dd, J = 16.0 Hz, 4.0 Hz, 2H), 2.59 (t, J = 6.8 Hz, 2H), 2.09 (s, 3H).

[0325] Example A3 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) [ka] Step A: 1-Bromo-2-(bromomethyl)-4-iodobenzene [ka]

[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 reduced pressure. The residue was purified on a silica gel column (100% PE) to give 1-bromo-2-(bromomethyl)-4-iodobenzene (8.0 g, 31.6% yield). Alternatively, 1-bromo-2-(bromomethyl)-4-iodobenzene was obtained from (2-bromo-5-iodophenyl)methanol using PPh3 and CBr4 at 25 °C.

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

[0328] To a solution of 2,3-dihydro-1H-inden-2-ol (0.86 g, 6.39 mmol) in DMF (40 mL) was added NaH (319 mg, 7.98 mmol, 60% wt in mineral oil) 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 saturated aqueous NH Cl (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na SO , filtered, and concentrated. The residue was purified by silica gel column (0-10% EtOAc in PE) to give 2-[(2-bromo-5-iodophenyl)methoxy]-2,3-dihydro-1H-indene (450 mg, 19.7% yield).

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

[0330] To a solution of 2-[(2-bromo-5-iodophenyl)methoxy]-2,3-dihydro-1H-indene (450 mg, 1.05 mmol) in DMAc (10 mL) was added CuI (40 mg, 0.21 mmol), 4-aminotetrahydro-2H-pyran-4-carboxylic acid (304 mg, 2.10 mmol), and DBU (93.13 mg, 0.61 mmol). 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 CHCl (20 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified on a silica gel column (0-10% MeOH in CHCl) to give 4-({4-bromo-3-[(2,3-dihydro-1H-inden-2-yloxy)methyl]phenyl}amino)oxane-4-carboxylic acid (35 mg, 44.9% yield). 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) [ka]

[0332] A mixture of 4-({4-bromo-3-[(2,3-dihydro-1H-inden-2-yloxy)methyl]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-dioxaborolane (118 mg, 0.43 mmol), NaCO (135 mg, 1.28 mmol), and Pd(dppf)Cl.CHCl (69.35 mg, 0.09 mmol) in 1,4-dioxane (4 mL) / water (1 mL) was stirred at 100 °C for 3 h 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 C18 OBD column 30*150 mm*5 μm; mobile phase A: water (0.05% FA), mobile phase B: CH3CN; flow rate: 60 mL / min; gradient: 30% B → 81% B in 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, 45.9% yield). LC-MS: m / z 518.4 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.20 - 7.18 (m, 2H), 7.16 - 7.08 (m, 2H), 7.02 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 2.6 Hz, 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 = 16.4 Hz, 6.3 Hz, 2H), 2.87 (dd, J = 16.4 Hz, 3.7 Hz, 2H), 2.08 - 1.97 (m, 2H), 1.91 - 1.89 (m, 2H).

[0333] 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) [ka] 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 according to the procedure described for the preparation of Example A3 (Steps C and D), using 1-aminocyclopropane-1-carboxylic acid in Step C. LC-MS: m / z 496.2 (M+Na). + . 1 H NMR (400MHz, CDCl3) δ 12.29 (brs, 1H), 7.21 - 7.16 (m, 2H), 7.15 - 7.09 (m, 2H), 7.04 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.58 - 6.56 (m, 2H), 6.54 (s, 2H), 4.38 - 4.30 (m, 3H), 3.73 (s, 6H), 3.08 (dd, J = 16.4 Hz, 6.0 Hz, 2H), 2.85 (dd, J = 16.4 Hz, 3.6 Hz, 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-inden-2-yloxy)methyl]-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl}oxy)cyclopropane-1-carboxylic acid (Compound 117) [ka]

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

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

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

[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 minutes under a nitrogen atmosphere. 2-[(2-bromo-5-methoxyphenyl)methoxy]-2,3-dihydro-1H-indene (9.00 g, 27.01 mmol) was then added to the mixture. The resulting mixture was stirred at 120 °C for 2 hours under a nitrogen atmosphere. After cooling, the reaction mixture was diluted with water (200 mL) and neutralized to pH 7 with saturated aqueous NH4Cl. The resulting mixture was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by reverse flash column chromatography (30% to 80% CHCN in water) to give 4-bromo-3-[(2,3-dihydro-1H-inden-2-yloxy)methyl]phenol (4.0 g, 11.6% yield). LC-MS: m / z 318.9 (M−H). - .

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

[0339] A mixture of 4-bromo-3-[(2,3-dihydro-1H-inden-2-yloxy)methyl]phenol (500 mg, 1.57 mmol), methyl 2,4-dibromobutanoate (489 mg, 1.88 mmol), and KCO (432.98 mg, 3.13 mmol) in DMF (10 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to give crude methyl 4-bromo-2-{4-bromo-3-[(2,3-dihydro-1H-inden-2-yloxy)methyl]phenoxy}butanoate (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 [ka]

[0341] A mixture of methyl 4-bromo-2-{4-bromo-3-[(2,3-dihydro-1H-inden-2-yloxy)methyl]phenoxy}butanoate (710 mg, 1.43 mmol) and potassium tert-butoxide (320 mg, 2.85 mmol) in THF (10 mL) was stirred at room temperature for 2.5 hours. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL × 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-inden-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) [ka]

[0343] To a mixture of 1-{4-bromo-3-[(2,3-dihydro-1H-inden-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-dioxaborolane (400 mg, 1.44 mmol), and NaCO (370.58 mg, 3.50 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was added Pd(dppf)Cl.CHCl (190 mg, 0.23 mmol). The reaction mixture was heated to 90 °C and stirred under nitrogen at 90 °C for 1 h under microwave irradiation. After cooling, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (30 mL × 3). The combined organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. 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, 1.5% yield). LC-MS: m / z 497.2 (M+Na). + . 1 H NMR (400 MHz, DMSO-d6) δ 7.21 - 7.07 (m, 5H), 6.97 (d, J = 2.6 Hz, 1H), 6.86 (dd, J = 8.4 Hz, 2.7 Hz, 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).

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

[0345] To a solution of 2-(4-bromo-3-methylphenyl)acetonitrile (6.00 g, 28.56 mmol) in THF (120 mL) was added sodium hydride (1.14 g, 28.56 mmol, 60% wt in mineral oil) at 0 °C. After stirring for 15 min, dibromoethane (5.37 g, 28.56 mmol) was added to the reaction mixture. The resulting reaction mixture was 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 × 3). The combined organic layers were washed with brine (200 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified on a silica gel column (10% to 20% EtOAc in PE) to give 1-(4-bromo-3-methylphenyl)cyclopropane-1-carbonitrile (800 mg, 11.9% yield).

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

[0347] To a mixture of 1-(4-bromo-3-methylphenyl)cyclopropane-1-carbonitrile (800 mg, 3.39 mmol) and NBS (1.21 g, 6.78 mmol) in CCl4 (16 mL) was added AIBN (278 mg, 1.70 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at reflux for 16 h. After cooling, the reaction mixture was diluted with water (100 mL) and extracted with CHCl2 (20 mL × 3). The combined organic layers were washed with water (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified on a silica gel column (10%-20% EtOAc in PE) to give 1-[4-bromo-3-(bromomethyl)phenyl]cyclopropane-1-carbonitrile (550 mg, 51.5% yield).

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

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

[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-carbonitrile [ka]

[0351] To a stirred solution of 1-{4-bromo-3-[(2,3-dihydro-1H-inden-2-yloxy)methyl]phenyl}cyclopropane-1-carbonitrile (220 mg, 0.60 mmol), 2-(3,5-dimethoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (199 mg, 0.716 mmol), and NaCO (190 mg, 1.79 mmol) in 1,4-dioxane (4 mL) and water (0.8 mL) was added Pd(dppf)Cl.CHCl (49 mg, 0.06 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified on a silica gel column (10% to 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-carbonitrile (220 mg, 83.8% yield). 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) [ka]

[0353] To a stirred solution of 1-{2-[(2,3-dihydro-1H-inden-2-yloxy)methyl]-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl}cyclopropane-1-carbonitrile (100 mg, 0.29 mmol) in EtOH (5 mL) was added a solution of NaOH (500 mg, 12.5 mmol) in water (1 mL). The reaction mixture was stirred at 100 °C for 2 hours 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 × 3). The combined organic layers were washed with brine (30 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Xselect CSH C18 OBD column 30*150 mm 5 μm, n; mobile phase A: water (0.05% HCl), mobile phase B: CH3CN; flow rate: 60 mL / min; gradient: 50% B → 90% B in 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, 38.9% yield). LC-MS: m / z 457.0 (MH) - . 1 H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 7.41 (d, J = 1.9 Hz, 1H), 7.30 (dd, J = 7.8 Hz, 1.9 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.20 - 7.16 (m, 2H), 7.14 - 7.09 (m, 2H), 6.61 (s, 2H), 4.43 - 4.31 (m, 3H), 3.73 (s, 6H), 3.08 (dd, J = 16.4 Hz, 6.3 Hz, 2H), 2.86 (dd, J = 16.4 Hz, 3.7 Hz, 2H), 2.03 (s, 3H), 1.46 - 1.44 (m, 2H), 1.14 - 1.12 (m, 2H).

[0354] Example A7 (2S)-1-((2-(((2,3-dihydro-1H-inden-2-yl)oxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)-2-methylcyclopropane-1-carboxylic acid (Compound 119) [ka] Step A: Ethyl (2S)-1-((diphenylmethylene)amino)-2-methylcyclopropane-1-carboxylate [ka]

[0355] To a solution of ethyl 2-[(diphenylmethylidene)amino]acetate (5 g, 18.70 mmol) in THF (50 mL) was added NaH (1.35 g, 56.11 mmol, 60% wt in mineral oil) at 0 °C. After stirring for 15 min, (R)-(-)-4-methyl-2,2-dioxo-1,3,2-dioxathiolane (2.28 g, 14.30 mmol) was added to the above solution. The resulting reaction 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 × 3). The combined filtrate was concentrated under reduced pressure to give ethyl (2S)-1-[(diphenylmethylidene)amino]-2-methylcyclopropane-1-carboxylate (3.4 g, crude). LC-MS: m / z 308.0 (M+H) + .

[0356] Step B: Ethyl (2S)-1-amino-2-methylcyclopropane-1-carboxylate hydrochloride [ka]

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

[0358] [ka] (2S)-1-((2-(((2,3-Dihydro-1H-inden-2-yl)oxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)-2-methylcyclopropane-1-carboxylic acid (compound 119) was synthesized according to the procedure described for the preparation of Example A3 (Steps C and D), using ethyl (2S)-1-amino-2-methylcyclopropane-1-carboxylate hydrochloride in Step C. LC-MS: m / z 488.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.22 - 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), 6.39 (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).

[0359] Example A8 1-({4'-acetyl-2-[(2,3-dihydro-1H-inden-2-yloxy)methyl]-3',5'-dimethoxy-[1,1'-biphenyl]-4-yl}amino)cyclopropane-1-carboxylic acid (Compound 121) [ka] Step A: 1-[2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone [ka]

[0360] To a stirred mixture of 2',6'-dimethoxyacetophenone (1.00 g, 5.55 mmol), bis(pinacolato)diboron (1.69 g, 6.66 mmol), and 4,4'-di-tert-butyl-2,2'-dipyridyl (dtbpy) (0.30 g, 1.11 mmol) in THF (10 mL) was added [Ir(COD)(OMe)] (0.18 g, 0.28 mmol) 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 × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified on a silica gel column (3%-7% MeOH in CHCl) to give 1-[2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone (600 mg, 35.3%). LC-MS: m / z 306.9 (M+H). + .

[0361] [ka] 1-({4'-acetyl-2-[(2,3-dihydro-1H-inden-2-yloxy)methyl]-3',5'-dimethoxy-[1,1'-biphenyl]-4-yl}amino)cyclopropane-1-carboxylic acid (compound 121) was synthesized according to the procedure described for the preparation of Example A3 (Steps C and D), using 1-aminocyclopropane-1-carboxylic acid in Step C and 1-[2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone in Step D. LC-MS: m / z 502.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.20 - 7.18 (m, 2H), 7.13 - 7.10 (m, 2H), 7.06 (d, J = 8.3 Hz, 1H), 6.74 (d, J = 2.0 Hz, 1H), 6.63 - 6.61 (m, 3H), 6.54 (s, 1H), 4.36 - 4.35 (m, 3H), 3.71 (s, 6H), 3.09 (dd, J = 16.4 Hz, 6.3 Hz, 2H), 2.85 (dd, J = 16.3 Hz, 3.7 Hz, 2H), 2.38 (s, 3H), 1.39 - 1.37 (m, 2H), 0.94 - 0.90 (m, 2H).

[0362] Example A9 4-({3',5'-dimethoxy-4'-methyl-2-[2-(2-methyl-1,3-benzodioxol-2-yl)ethyl]-[1,1'-biphenyl]-4-yl}amino)oxane-4-carboxylic acid (Compound 132) [ka] Step A: Methyl 2-[(2-bromo-5-iodophenyl)methyl]-3-oxobutanoate [ka]

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

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

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

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

[0367] A mixture of 4-(2-bromo-5-iodophenyl)butan-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 CHCl (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified on a silica gel column (PE / EA = 10:1) to give 2-[2-(2-bromo-5-iodophenyl)ethyl]-2-methyl-1,3-benzodioxole (110 mg, 15.9% yield).

[0368] [ka] 4-({3',5'-Dimethoxy-4'-methyl-2-[2-(2-methyl-1,3-benzodioxol-2-yl)ethyl]-[1,1'-biphenyl]-4-yl}amino)oxane-4-carboxylic acid (compound 132) was synthesized according to the procedure described for the preparation of Example A3 (Steps C and D), using 2-[2-(2-bromo-5-iodophenyl)ethyl]-2-methyl-1,3-benzodioxole in Step C. LC-MS: m / z 534.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 6.90 (d, J = 8.3 Hz, 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).

[0369] Example A10 4-({2-[(cyclopentyloxy)methyl]-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl}amino)-oxane-4-carboxylic acid (Compound 134) [ka] 4-({2-[(cyclopentyloxy)methyl]-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl}amino)-oxane-4-carboxylic acid (compound 134) was synthesized according to the procedure described for the preparation of Example A3 (Steps B to D), using cyclopentanol in Step B. LC-MS: m / z 470.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 6.98 (d, J = 8.3 Hz, 1H), 6.75 (d, J = 2.4 Hz, 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).

[0370] 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) [ka] 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 described for the preparation of Example A3 (Steps B-D), 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+HO+H). + .

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

[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 CHCl (4 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: CH3CN; flow rate: 60 mL / min; gradient: 5% B → 60% B in 10 min) to give 4-((2-((cyclopentyloxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)piperidine-4-carboxylic acid (77 mg, 77.9% yield). 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) [ka]

[0374] To a solution of 4-((2-((cyclopentyloxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)piperidine-4-carboxylic acid (60 mg, 0.13 mmol) and EtN (38.87 mg, 0.39 mmol) in CHCl (3 mL) was added dropwise a solution of dimethyl dicarbonate (7.73 mg, 0.06 mmol) in CHCl (1 mL) at 0 °C. After the addition, the reaction mixture was stirred at 0 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The crude material was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3), mobile phase B: CH3CN; flow rate: 60 mL / min; gradient: 5% B → 60% B in 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, 24.9% yield). LC-MS: m / z 527.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 6.96 (d, J = 8.4 Hz, 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).

[0375] 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) [ka] 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 described for the preparation of Example A3 (Steps A-D), 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 (400 MHz, DMSO-d6) δ 6.57 (d, J = 2.4 Hz, 1H), 6.40 (d, J = 2.4 Hz, 1H), 6.33 (s, 2H), 3.96 (s, 2H), 3.76 - 3.74 (m, 1H), 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).

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

[0377] To a mixture of 3-fluoro-5-methyl-aniline (5 g, 40.0 mmol) in DMF (40 mL) was added NBS (7.25 g, 40.8 mmol) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. The reaction was quenched with HO (20 mL). The mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with HO (20 mL × 3), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified on a flash silica gel column (ISCO®; 120 g SepaFlash® Silica Flash column, eluent: 0–20% EtOAc / PE gradient at 85 mL / min) to give 4-bromo-3-fluoro-5-methyl-aniline (8.0 g, 98.1% yield). 1 H NMR (400 MHz, CDCl3): δ 6.36 (s, 1H), 6.32 - 6.28 (m, 1H), 2.31 (s, 3H).

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

[0379] To a solution of 4-bromo-3-fluoro-5-methyl-aniline (21.7 g, 106 mmol) in MeCN (500 mL) was added a solution of HSO (14.0 mL, 263 mmol) in HO (30 mL) at 0 °C. After stirring for 5 min, a solution of NaNO (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, the mixture was allowed to warm to 25 °C, and the resulting reaction mixture was stirred for an additional 20 min. The mixture was quenched with saturated aqueous NaSO, diluted with water (300 mL), and extracted with EtOAc (160 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified on a flash silica gel column (ISCO®; 220 g SepaFlash® Silica Flash column, eluent of 0% EtOAc / PE gradient at 100 mL / min) to give 2-bromo-1-fluoro-5-iodo-3-methyl-benzene (31.6 g, 94.2% yield). 1 H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.30 - 7.26 (m, 1H), 2.38 (s, 3H).

[0380] [ka] 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 described for the preparation of Example A3 (Steps A and D), 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) + . 1H NMR (400 MHz, CD3OD) δ 6.65 (s, 1H), 6.46 (s, 2H), 6.39 (d, J = 12.0 Hz, 1H), 4.18 (s, 2H), 3.87 - 3.74 (m, 11H), 2.28 - 2.20 (m, 2 H), 2.09 (s, 3H), 2.06 - 2.01 (m, 2H), 1.66 - 1.50 (m, 8H).

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

[0382] To a solution of 3,5-dimethoxy-4-methylbenzoic acid (25 g, 127.42 mmol) in toluene (70 mL) and t-BuOH (70 mL) was added TEA (39 mL, 280.20 mmol) and DPPA (38.10 g, 138.44 mmol). After degassing and purging with nitrogen three times, the resulting mixture was stirred at 85 °C for 12 h under a nitrogen atmosphere. The reaction mixture was diluted with HO (200 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified on a silica gel column (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 [ka]

[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. Then, the pH value was adjusted to 8-9 with saturated aqueous NaHCO3, and the mixture was extracted with EtOAc (200 mL × 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 [ka]

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

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

[0388] To a solution of 2-bromo-3,5-dimethoxy-4-methylaniline (4.59 g, 18.65 mmol) in toluene (30 mL), methylboronic acid (2.79 g, 46.63 mmol), KPO (15.84 g, 74.60 mmol), S-Phos (1.53 g, 3.73 mmol), and Pd(dba) (1.71 g, 1.87 mmol) were added under nitrogen. The mixture was degassed and purged with nitrogen three times. The mixture was then stirred at 80 °C for 12 h under a nitrogen atmosphere. After cooling, it was filtered, and the filtrate was concentrated. The residue was purified on a silica gel column (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 [ka]

[0390] 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) was added a solution of NaNO (2.14 g, 31.04 mmol) in HO (5 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 HO (5 mL) was added, and the mixture was stirred at 25 °C for 16 h. The reaction was quenched with HO (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were concentrated and purified on a silica gel column (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 NaSO (30 mL × 3). The organic layer was dried over anhydrous NaSO, filtered and concentrated to give 1-iodo-3,5-dimethoxy-2,4-dimethylbenzene (2.64 g, 71.6% yield). 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-dioxaborolane [ka]

[0392] To a solution of 1-iodo-3,5-dimethoxy-2,4-dimethylbenzene (1 g, 3.42 mmol) in 1,4-dioxane (20 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.74 g, 6.85 mmol), KOAc (1.01 g, 10.27 mmol), and Pd(dppf)Cl2 (250.49 mg, 342.33 μmol). After degassing and purging with nitrogen three times, the reaction mixture was stirred at 100 °C under nitrogen for 12 h. After cooling, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column (PE / EtOAc=32 / 1) to give 2-(3,5-dimethoxy-2,4-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (404 mg, 40.4% yield). 1 H NMR (400 MHz, CDCl3) δ 6.96 (s, 1H), 3.77 (s, 3H), 3.60 (s, 3H), 2.35 (s, 3H), 2.10 (s, 3H), 1.27(s, 12H).

[0393] [ka] 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 described for the preparation of Example A3 (Steps A and D), using cyclopentanol in Step B and 2-(3,5-dimethoxy-2,4-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in Step D. LC-MS: m / z 484.2 (M+H) + .1 H NMR (400 MHz, CD3OD) δ 6.87 - 6.80 (m, 2H), 6.68 (dd, J = 8.4 Hz, 2.4 Hz, 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).

[0394] 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) [ka] Step A: 3-Ethynyltetrahydrofuran [ka]

[0395] To a mixture of tetrahydrofuran-3-carbaldehyde (5.0 g, 49.9 mmol), KCO (10.0 g, 72.4 mmol) in MeOH (60 mL) was added dimethyl (1-diazo-2-oxopropyl)phosphonate (10.6 g, 54.9 mmol). The reaction mixture was stirred at 20 °C for 3 h. The suspension was filtered through a Celite® pad, the pad was washed with petroleum ether (30 mL), and the filtrate was concentrated under reduced pressure (bath temperature <15 °C) to give 3-ethynyltetrahydrofuran (10 g, crude), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 4.02 (t, J = 7.8 Hz, 1H), 3.97 - 3.80 (m, 2H), 3.67 (dd, J = 8.0 Hz, 7.2 Hz, 1H), 3.07 - 2.93 (m, 1H), 2.30 - 2.16 (m, 1H), 2.12 (d, J = 2.2 Hz, 1H), 2.05 - 1.97 (m, 1H).

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

[0397] A mixture of CuI (50.0 mg, 263 μmol), Pd(PPh)Cl (92.2 mg, 131 μmol), and TEA (3.99 g, 39.4 mmol) in THF (100 mL) was degassed and purged with nitrogen three times, and 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 aqueous NHCl (40 mL) and extracted with ethyl acetate (40 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash column, eluent: 0-15% EtOAc / PE gradient at 60 mL / min) to give 3-((5-bromo-2-chlorophenyl)ethynyl)tetrahydrofuran (1.5 g, 40.0% yield). 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 2.2 Hz, 1H), 7.34 (dd, J = 8.6 Hz, 2.2 Hz, 1H), 7.26 -7.22 (m, 1H), 4.10 (t, J = 7.8 Hz, 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-carboxylic acid [ka]

[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 at 120° C. for 60 minutes under microwave irradiation. 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×2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Silica Flash column, eluent: 0-50% EtOAc / PE gradient) 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 [ka]

[0401] 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-dioxaborolane (636 mg, 2.29 mmol) in THF (4 mL) and HO (4 mL) was added XPhos Pd G (96.8 mg, 114 μmol) and CsCO (745 mg, 2.29 mmol). 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 × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Silica Flash column, eluent: 0-50% EtOAc / PE gradient) 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 [ka]

[0403] 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) was added 10% Pd / C (100 mg). The reaction mixture was stirred under a H atmosphere (15 psi) at 25 °C for 5 h. The mixture was diluted with EtOAc (20 mL), filtered, and evaporated. The residue was purified by flash silica gel chromatography (Silica Flash column, elution with a 0-40% EtOAc / PE gradient) 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, 19.0% yield, 80% purity). 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) [ka]

[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 is CO2, B is [0.1% NH3H2O ​​in EtOH]; B%: 20%-20%). After solvent removal, the sample was lyophilized to give 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 x 4.6 mm ID, 3 μm; Mobile phase: A:CO2 B:ethanol (0.05% diethylamine); Isocratic: 15% B, Flow rate: 2.5 mL / min; Column temperature: 40 °C, Retention time: 3.908 min. 1 H NMR (400 MHz, DMSO-d6) δ 6.84 (d, J = 8.2 Hz, 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 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 analysis conditions: Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 μm; Mobile phase: A:CO₂B:ethanol (0.05% diethylamine); Gradient: 5% to 40% B in 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 H NMR (400 MHz, DMSO-d6) δ 6.86 (d, J = 8.4 Hz, 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 LC-MS: m / z 470.3 (M+H) + .

[0408] 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) [ka] [ka] 1-Bromo-2-(cyclopentoxymethyl)-4-iodo-benzene (16-1) was synthesized according to the procedure described for the preparation of Example A3 (Steps A-B), using cyclopentanol in Step B. 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 8.4 Hz, 2.2 Hz, 1H), 7.23 (d, J = 8.4 Hz, 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 [ka]

[0410] At −78° C., n-BuLi (2.5 M, 1.3 mL) was added to a mixture of 1-bromo-2-(cyclopentoxymethyl)-4-iodo-benzene (1.2 g, 3.2 mmol) in THF (10 mL) under a nitrogen atmosphere. 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 at 15° C. for 0.5 h. It was then quenched with 2 N HCl (15 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give crude [4-bromo-3-(cyclopentoxymethyl)phenyl]boronic acid (1 g, crude) as a brown solid, which was used in the next step without further purification.

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

[0412] To a mixture of [4-bromo-3-(cyclopentoxymethyl)phenyl]boronic acid (1 g, 3.3 mmol) in THF (10 mL) was added 30% HO (10 mL, 104.1 mmol). The resulting mixture was stirred at 15 °C for 1 h. The reaction mixture was carefully quenched with saturated aqueous NaSO (50 mL) and extracted with ethyl acetate (50 mL × 2). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash column, eluent: 0-20% EtOAc / PE gradient at 40 mL / min) to give 4-bromo-3-(cyclopentoxymethyl)phenol (360 mg, 39.7% yield). LC-MS: m / z 269.1 (MH) - .

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

[0414] To a mixture of 4-bromo-3-(cyclopentoxymethyl)phenol (360 mg, 1.3 mmol) in THF (6 mL) was added NaOH (266 mg, 6.6 mmol) and tetrahydropyran-4-one (399 mg, 4.0 mmol, 366 μL) at 0 °C. Subsequently, CHCl (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 1 N HCl (approximately 3 mL) and extracted with ethyl acetate (15 mL × 3). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash column, eluent: 0-30% EtOAc / PE gradient at 40 mL / min) to give 4-[4-bromo-3-(cyclopentoxymethyl)phenoxy]tetrahydropyran-4-carboxylic acid (280 mg, 52.8% yield).1 H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 2.8 Hz, 1H), 6.68 (dd, J = 8.8, 3.2 Hz, 1H), 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) [ka]

[0416] 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-dioxaborolane (189 mg, 606 μmol) in THF (3 mL) and HO (3 mL) was added XPhos Pd G3 (46.6 mg, 55.1 μmol) and Cs2CO3 (359 mg, 1.1 mmol). The resulting mixture was stirred at 80 °C under nitrogen for 16 h. After cooling, the reaction mixture was acidified to pH 4 with 1 N HCl, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash column, eluting with a 0-40% EtOAc / PE gradient at 40 mL / min) and further purified by preparative HPLC (column: Welch Xtimate C18 150*25 mm*5 μm; mobile phase: [water (0.05% NH₃·H₂O + 10 mM 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, 25.3% yield). LC-MS: m / z 522.2 (M+NH₃+H). + . 1 H NMR (400 MHz, CD3OD) δ 7.10 (d, J = 2.8 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.93 (dd, J = 8.4 Hz, 2.8 Hz, 1H), 6.62 (s, 1H), 4.92 (s, 14H), 4.20 (dd, J = 28.4 Hz, 12 Hz, 1H), 3.87 - 3.77 (m, 11H), 2.33 - 2.09 (m, 7H), 1.70 - 1.39 (m, 8H).

[0417] Example A17 4-((3-((cyclopentyloxy)methyl)-4-(6-methoxy-7-methyl-2,3-dihydrobenzofuran-4-yl)phenyl)amino)tetrahydro-2H-pyran-4-carboxylic acid (Compound 193) [ka] Step A: 1-Bromo-2-(2-bromoethoxy)-4-methoxy-benzene [ka]

[0418] 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) was added KCO (7.45 g, 54 mmol). 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 × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and evaporated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash column, eluent: 0–2% EtOAc / PE gradient at 100 mL / min) to give 1-bromo-2-(2-bromoethoxy)-4-methoxy-benzene (7.2 g, 64.6% yield). 1 H NMR (400 MHz, CDCl3) δ 7.42 (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-dihydrobenzofuran [ka]

[0420] To a solution of 1-bromo-2-(2-bromoethoxy)-4-methoxy-benzene (7.2 g, 23.2 mmol) in THF (60 mL) was added n-BuLi (2.5 M, 10.22 mL) dropwise 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 saturated aqueous NH4Cl (60 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash column, eluent: 0–3% EtOAc / PE gradient at 100 mL / min) to give 6-methoxy-2,3-dihydrobenzofuran (1.08 g, 31.0% yield). 1 H NMR (400 MHz, CDCl3) δ 7.03 - 6.91 (m, 1H), 6.32 - 6.31 (m, 2H), 4.48 (t, J = 8.6 Hz, 2H), 3.67 (s, 3H), 3.04 (t, J = 8.6 Hz, 2H).

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

[0422] To a solution of 6-methoxy-2,3-dihydrobenzofuran (1.08 g, 7.19 mmol) in THF (20 mL) was added n-BuLi (2.5 M, 3.16 mL) dropwise 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 × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and evaporated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash column, eluent: 0–2% EtOAc / PE gradient at 80 mL / min) to give 6-methoxy-7-methyl-2,3-dihydrobenzofuran (192 mg, 16.3% yield). 1 H NMR (400 MHz, CDCl3) δ 6.87 (d, J = 8.0 Hz, 1H), 6.28 (d, J = 8.4 Hz, 2H), 4.49 (t, J = 8.6 Hz, 2H), 3.72 (s, 3H), 3.08 (t, J = 8.6 Hz, 2H), 2.01 (s, 3H).

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

[0424] To a solution of 6-methoxy-7-methyl-2,3-dihydrobenzofuran (192 mg, 1.17 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (267 mg, 1.05 mmol) in THF (5 mL) was added [Ir(COD)(OMe)] (3.88 mg, 5.85 μmol) and 4,4'-di-tert-butyl-2,2'-dipyridyl (dtbpy) (3.14 mg, 11.7 μmol). The reaction mixture was stirred at 80 °C for 12 hours. The mixture was evaporated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash column, eluent: 0-3% EtOAc / PE gradient at 80 mL / min) to give 2-(6-methoxy-7-methyl-2,3-dihydrobenzofuran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (129 mg, 38.0% yield). 1 H NMR (400 MHz, CDCl3) δ 6.69 (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] [ka] 4-((3-((cyclopentyloxy)methyl)-4-(6-methoxy-7-methyl-2,3-dihydrobenzofuran-4-yl)phenyl)amino)tetrahydro-2H-pyran-4-carboxylic acid (compound 193) was synthesized according to the procedure described for the preparation of Example A3 (Steps A and D), using cyclopentanol in Step B and 2-(6-methoxy-7-methyl-2,3-dihydrobenzofuran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in Step D. LC-MS: m / z 482.3 (M+H) + . 1H NMR (400 MHz, CD3OD) δ 6.94 (d, J = 8.2 Hz, 1H), 6.78 (s, 1H), 6.67 (d, J = 8.2 Hz, 1H), 6.23 (s, 1H), 4.47 (t, J = 8.4 Hz, 2H), 4.20 (s, 2H), 3.89 - 3.75 (m, 5H), 3.74 (s, 3H), 2.89 (t, J = 8.0 Hz, 2H), 2.27 - 2.16 (m, 2H), 2.03 - 1.90 (m, 5H), 1.65 - 1.47 (m, 8H).

[0426] Example A18 4-((2-((bicyclo[3.1.0]hexan-3-yloxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (Compound 182) [ka] 4-((2-((bicyclo[3.1.0]hexan-3-yloxy)methyl)-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)amino)tetrahydro-2H-pyran-4-carboxylic acid (compound 182) was synthesized according to the procedure described for the preparation of Example A3 (Steps B to D), using bicyclo[3.1.0]hexan-3-ol in Step B. LC-MS: m / z 482.1 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 7.02 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H), 6.68 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 6.51 (s, 1H), 4.20 (s, 2H), 3.99 - 3.95 (m, 1H), 3.82 - 3.76 (m, 10H), 2.28 - 2.21 (m, 2H), 2.07 (s, 3H), 2.00 - 1.94 (m, 2H), 1.85 - 1.82 (m, 2H), 1.23 - 1.21 (m, 2H), 0.49 - 0.46 (m, 1H), 0.38 - 0.37 (m, 1H).

[0427] Example A19 4-((4-(3-chloro-2,6-dimethoxypyridin-4-yl)-3-((cyclopentyloxy)methyl)phenyl)amino)tetrahydro-2H-pyran-4-carboxylic acid (Compound 207) [ka] [ka] Step A: 3-chloro-2,6-dimethoxypyridin-4-amine [ka]

[0428] To a mixture of 2,6-dimethoxypyridin-4-amine (1 g, 6.5 mmol) in MeCN (8 mL) was added NCS (866 mg, 6.5 mmol). The reaction mixture was stirred at 10 °C for 3 h. The reaction mixture was quenched with HO (10 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was dried over anhydrous NaSO and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash column, eluent: 0–18% EtOAc / PE gradient at 40 mL / min) to give 3-chloro-2,6-dimethoxy-pyridin-4-amine (1.22 g, 99% yield). 1 H NMR (400 MHz, CDCl3) δ 5.72 (s, 1H), 4.48 (brs, 2H), 3.96 (s, 3H), 3.84 (s, 3H).

[0429] Step B: 3-chloro-4-iodo-2,6-dimethoxypyridine [ka]

[0430] To a suspension of CuI (2.49 g, 13.1 mmol) in CHCN (10 mL) was added tert-butyl nitrite (3.37 g, 32.7 mmol, 3.9 mL) at 80 °C under nitrogen. After stirring for 0.5 h, a solution of 3-chloro-2,6-dimethoxy-pyridin-4-amine (1.23 g, 6.5 mmol) in CHCN (10 mL) was added dropwise. The resulting mixture was stirred at 80 °C for 2 h. After cooling, the reaction was quenched with HO (20 mL) and extracted with ethyl acetate (50 mL × 3). The organic layer was dried over NaSO and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash column, eluent: 0-7% EtOAc / PE gradient at 100 mL / min) to give 3-chloro-4-iodo-2,6-dimethoxy-pyridine (1.23 g, 62.8% yield). 1H NMR (400 MHz, CDCl3) δ 6.84 (s, 1H), 3.98 (s, 3H), 3.90 (s, 3H).

[0431] Step C: 3-chloro-2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [ka]

[0432] To a mixture of 3-chloro-4-iodo-2,6-dimethoxy-pyridine (1.23 g, 4.1 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.25 g, 4.9 mmol) in DMF (8 mL) was added Pd(dppf)Cl. CHCl (335 mg, 411 μmol) and KOAc (1.21 g, 12.3 mmol). The reaction mixture was stirred at 90 °C for 3 h. After cooling, the reaction solution was poured into water (10 mL) and extracted with ethyl acetate (25 mL × 3). The organic layer was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash column, eluent: 0-10% EtOAc / PE gradient at 40 mL / min) to give 3-chloro-2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (300 mg, 24.4% yield). 1 H NMR (400 MHz, CDCl3) δ 6.52 (s, 1H), 3.99 (s, 3H), 3.89 (s, 3H), 1.34 (s, 12H). [ka]

[0433] 4-((4-(3-chloro-2,6-dimethoxypyridin-4-yl)-3-((cyclopentyloxy)methyl)phenyl)amino)tetrahydro-2H-pyran-4-carboxylic acid (compound 207) was synthesized according to the procedure described for the preparation of Example A3 (Steps A and D), using cyclopentanol in Step B and 3-chloro-2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in Step D. LC-MS: m / z 491.2 (M+H) + . 1 H NMR (400 MHz, CD3OD) δ 6.87 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 6.64 (dd, J = 8.4, 2.4 Hz, 1H), 6.25 (s, 1H), 4.17 (dd, J = 32.0 Hz, 11.6 Hz, 1H), 4.03 (s, 3H), 3.94 (s, 3H), 3.86 - 3.75 (m, 5H), 2.27 - 2.21 (m, 2H), 2.05 - 2.02 (m, 2H), 1.60 - 1.47 (m, 8H).

[0434] Example A20 4-((2-((cyclopentyloxy)methyl)-2'-fluoro-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)oxy)tetrahydro-2H-pyran-4-carboxylic acid (Compound 209) [ka] Step A: 2-(2-fluoro-3,5-dimethoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka]

[0435] To a solution of 2-(3,5-dimethoxy-4-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.2 g, 43.9 mmol) in THF (100 mL) was added NFSI (20.8 g, 65.8 mmol). The resulting mixture was stirred at 90° C. for 12 hours. Then, additional NFSI (20.8 g, 65.8 mmol) was added and stirred at 90° C. for an additional 12 hours. After cooling, the solvent was removed under reduced pressure to provide a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash column, eluent: 0-4% EtOAc / PE gradient at 100 mL / min) to give 2-(2-fluoro-3,5-dimethoxy-4-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.7 g, 36.2% yield). 1 H NMR (400 MHz, CDCl3) δ 6.84 (s, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 2.16 (s, 3H), 1.37 (s, 12H).

[0436] Step B: 4-((2-((cyclopentyloxy)methyl)-2'-fluoro-3',5'-dimethoxy-4'-methyl-[1,1'-biphenyl]-4-yl)oxy)tetrahydro-2H-pyran-4-carboxylic acid (Compound 209) [ka]

[0437] To a mixture of 4-[4-bromo-3-(cyclopentoxymethyl)phenoxy]tetrahydropyran-4-carboxylic acid (70 mg, 175 μmol) and 2-(2-fluoro-3,5-dimethoxy-4-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (130 mg, 438 μmol) in THF (2 mL) and HO (2 mL) was added XPhos Pd G3 (14.8 mg, 17.5 μmol) and Cs2CO3 (114 mg, 351 μmol). The reaction mixture was stirred at 80 °C under nitrogen for 16 h. After cooling, the reaction mixture was acidified to pH 3 with 1 N HCl. The mixture was extracted with ethyl acetate (10 mL × 3). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash column, eluting with a 0-36% EtOAc / PE gradient at 40 mL / min) and further purified by preparative HPLC (column: Welch Xtimate C18 150*25 mm*5 μm; mobile phase: [water (0.05% NH₃·H₂O + 10 mM NH₄HCO₃)—CH₃CN]; B%: 35%-65%, 7 min) to give 4-[3-(cyclopentoxymethyl)-4-(2-fluoro-3,5-dimethoxy-4-methyl-phenyl)phenoxy]tetrahydropyran-4-carboxylic acid (21.3 mg, 24.9% yield). LC-MS: m / z 506.3 (M+H). + . 1 H NMR (400 MHz, CD3OD) δ 7.15-7.09 (m, 2H), 6.96 (dd, J = 8.4, 2.6 Hz, 1H), 6.51 (d, J = 8.0 Hz, 1H), 4.28 (s, 2H), 3.89 - 3.79 (m, 11H), 2.26 -2.20 (m, 2H), 2.18 - 2.10 (m, 5H), 1.67-1.47 (m, 8H).

[0438] Example A21 (2R,6S)-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 225) [ka] Step A: N-[4-bromo-3-(cyclopentoxymethyl)phenyl]-1,1-diphenyl-methanimine [ka]

[0439] To a solution of 1-bromo-2-(cyclopentoxymethyl)-4-iodo-benzene (600 mg, 1.57 mmol) and diphenylmethanimine (285 mg, 1.57 mmol) in toluene (10 mL) was added Pd(dba) (72.1 mg, 78.7 μmol), t-BuONa (303 mg, 3.15 mmol), and [1-(2-diphenylphosphanyl-1-naphthyl)-2-naphthyl]-diphenyl-phosphane (BINAP) (98.1 mg, 157 μmol). The mixture was stirred at 100 °C for 2 h. After cooling, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and evaporated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash column, eluent: 0-2% EtOAc / PE gradient at 40 mL / min) to give N-[4-bromo-3-(cyclopentoxymethyl)phenyl]-1,1-diphenyl-methanimine (653 mg, 95.5% yield). LC-MS: m / z 434.2 (M+H) + .

[0440] Step B: 4-Bromo-3-((cyclopentyloxy)methyl)aniline [ka]

[0441] To a solution of N-[4-bromo-3-(cyclopentoxymethyl)phenyl]-1,1-diphenylmethanimine (653 mg, 1.50 mmol) in THF (10 mL) was added 2 M HCl (752 μL). The reaction mixture was stirred at 25 °C for 2 h. The mixture was diluted with water (40 mL), basified with saturated aqueous NaHCO (20 mL), and extracted with ethyl acetate (25 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and evaporated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash column, eluent: 0–50% EtOAc / PE gradient at 40 mL / min) to give 4-bromo-3-(cyclopentoxymethyl)aniline (323 mg, 79.5% yield). 1 H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 3.2 Hz, 1H), 6.39 (dd, J = 8.4, 3.2 Hz, 1H), 4.32 (s, 2H), 4.06 - 3.89 (m, 1H), 3.61 (s, 2H), 1.80 - 1.36 (m, 8H).

[0442] Step C: (2R,4S,6S)-2,6-dimethyltetrahydro-2H-pyran-4-ol [ka]

[0443] To a solution of 2,6-dimethyl-4H-pyran-4-one (10.0 g, 80.6 mmol) in EtOH (150 mL) was added 10% Pd / C (4 g) under a N atmosphere. The suspension was degassed and purged with H thre...

Claims

1. Formula I: 【Chemistry 1】 [In the ceremony: A is C １－６ Alkyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl; １－６ Alkyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z １ is substituted with; L １ is a bond, -O-, -S-, -S(O)-, -S(O) ２ -, -NR １０ -, C １－３ Alkylene, C ２－３ Alkenylene, C ２－３ Alkynylene or C １－３ heteroalkylene; １ C １－３ Alkylene, C ２－３ Alkenylene, C ２－３ Alkynylene or C １－３ The heteroalkylene is independently optionally C １－９ substituted with 1 to 5 substituents independently selected from alkyl, halo, hydroxy, and cyano; L ２ is a bond, C １－３ Alkylene, C ２－３ Alkenylene, C ２－３ Alkynylene or C １－３ heteroalkylene; ２ C １－３ Alkylene, C ２－３ Alkenylene, C ２－３ Alkynylene or C １－３ The heteroalkylene is independently optionally C １－９ substituted with 1 to 5 substituents independently selected from alkyl, halo, hydroxy, and cyano; X １ is N or CR ３ and X ２ is N or CR ５ and X ３ is N or CR ７ and X ４ is O or CHR １１ and A is C. １－６ If it is alkyl, X ４ is O; X ６ is N or CR ６ and n is 0, 1 or 2; m is 0, 1, 2 or 3; R １ and R ２ are each independently hydrogen, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ cycloalkyl or heterocyclyl; where R １ and R ２ Each C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ The cycloalkyl or heterocyclyl independently optionally has 1 to 5 Z １ is substituted with; or R １ and R ２ are C together with the atoms to which they are bonded. ３－１０ forms a cycloalkyl or heterocyclyl; ３－１０ The cycloalkyl or heterocyclyl optionally has 1 to 5 Z １ is substituted with; R ３ is hydrogen, halo, cyano, nitro, -OH, -SH, -NH ２ , —NH—C １－５ Alkyl, -N(C １－５ alkyl) ２ , -S-C １－５ Alkyl, C １－５ Alkoxy, C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ cycloalkyl or 3- to 5-membered heterocyclyl; ３ -NH-C １－５ Alkyl, -N(C １－５ alkyl) ２ , -S-C １－５ Alkyl, C １－５ Alkoxy, C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R ４ is halo, cyano, nitro, -OR １４ , -N(R １４ ) ２ , -SR １４ , C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ cycloalkyl or 3- to 5-membered heterocyclyl; ４ C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ The cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally selected from halo, hydroxy, C １－５ substituted with 1 to 5 substituents independently selected from alkoxy and cyano; or R ３ and R ４ together with the atom to which they are attached form a cycloalkyl, aryl, heterocyclyl, or heteroaryl; wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R ５ is hydrogen, halo, cyano, nitro, -OR １５ , -N(R １５ ) ２ , -SR １５ , -C(O)R １５ , -C(O)OR １５ , C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ cycloalkyl, 3- to 5-membered heterocyclyl, or 5-membered heteroaryl; where R ５ C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ The cycloalkyl, 3- to 5-membered heterocyclyl, or 5-membered heteroaryl independently optionally has 1 to 5 Z １ is substituted with; R ６ is hydrogen, halo, cyano, nitro, -OR １６ , -N(R １６ ) ２ , -SR １６ , C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ cycloalkyl or 3- to 5-membered heterocyclyl; ６ C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R ７ is hydrogen, halo, cyano, nitro, -OH, -SH, -NH ２ , —NH—C １－５ Alkyl, -N(C １－５ alkyl) ２ , -S-C １－５ Alkyl, C １－５ Alkoxy, C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ cycloalkyl or 3- to 5-membered heterocyclyl; ７ -NH-C １－５ Alkyl, -N(C １－５ alkyl) ２ , -S-C １－５ Alkyl, C １－５ Alkoxy, C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; or R ６ and R ７ together with the atom to which they are attached form a cycloalkyl, aryl, heterocyclyl, or heteroaryl; wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R ８ is hydrogen, C １－９ alkyl, oxo, halo, hydroxy, or cyano; R ９ is hydrogen, C １－９ alkyl, oxo, halo, hydroxy, or cyano; R １０ is hydrogen, C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ cycloalkyl or 3- to 5-membered heterocyclyl; １０ C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R １１ is hydrogen, C １－９ alkyl, oxo, halo, hydroxy, or cyano; Each R １３ are independently hydrogen, halo, cyano, nitro, —OH, —SH, —NH ２ , —NH—C １－９ Alkyl, -N(C １－９ alkyl) ２ , -S-C １－９ Alkyl, C １－９ Alkoxy, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－６ cycloalkyl or 3- to 6-membered heterocyclyl; １３ Each of -NH-C １－９ Alkyl, -N(C １－９ alkyl) ２ , -S-C １－９ Alkyl, C １－９ Alkoxy, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－６ the cycloalkyl or 3- to 6-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R １４ is hydrogen, C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ cycloalkyl or 3- to 5-membered heterocyclyl; １４ C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R １５ is hydrogen, C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ cycloalkyl or 3- to 5-membered heterocyclyl; １５ C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; R １６ is hydrogen, C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ cycloalkyl or 3- to 5-membered heterocyclyl; １６ C １－５ Alkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ the cycloalkyl or 3- to 5-membered heterocyclyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; Each Z １ are independently halo, cyano, nitro, oxo, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-H, -L-C １－９ Alkyl, -L-C ２－９ alkenyl, -L-C ２－９ Alkynyl, -L-C ３－１０ cycloalkyl, -L-heterocyclyl, -L-aryl or -L-heteroaryl; １ Each C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z １ａ is substituted with; Each L is independently —O—, —S—, or —NR ２０ -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR ２０ -, -NR ２０ C(O)-, -OC(O)NR ２０ -, -NR ２０ C(O)O-, -NR ２０ C(O)NR ２１ -, -S(O)-, -S(O) ２ -, -S(O)NR ２０ -, -S(O) ２ NR ２０ -, -NR ２０ S(O)-, -NR ２０ S(O) ２ -, -NR ２０ S(O)NR ２１ -or-NR ２０ S(O) ２ NR ２１ - and; Each R ２０ and R ２１ are independently hydrogen, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R ２０ and R ２１ Each C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z １ａ or R ２０ and R ２１ together with the atoms to which they are attached, independently and optionally, 1 to 5 Z １ａ forming a heterocyclyl substituted with Each Z １ａ are independently halo, hydroxy, cyano, nitro, oxo, —SH, —NH ２ , —NH—C １－９ Alkyl, -N(C １－９ alkyl) ２ , -S-C １－９ Alkyl, C １－９ Alkoxy, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl; １ａ Each of -NH-C １－９ Alkyl, -N(C １－９ alkyl) ２ , -S-C １－９ Alkyl, C １－９ Alkoxy, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently optionally C １－９ and substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy, and cyano. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

2. A is C １－６ 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof, wherein:

3. Formula IIA: 【Chemistry 2】 wherein ring A is C ３－１０ cycloalkyl, heterocyclyl, aryl or heteroaryl, and each C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl in ring A is independently optionally substituted by 1 to 5 Z １ is replaced by 10. The compound of claim 1, which is represented by: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof.

4. A or ring A optionally has 1 to 5 Z １ 2. The compound of claim 1, wherein R is C 3-10 cycloalkyl substituted with R or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof.

5. A or ring A optionally has 1 to 5 Z １ 2. The compound of claim 1, wherein R is a heterocyclyl substituted with R, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof.

6. A or ring A optionally has 1 to 5 Z １ 10. The compound of claim 1, wherein R is aryl substituted with R, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof.

7. A or ring A optionally has 1 to 5 Z １ 10. The compound of claim 1, wherein R is a heteroaryl substituted with R, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof.

8. A or ring A is C ３－１０ 2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof, wherein:

9. L １ is a bond, —O—, —NR １０ -, C １－３ Alkylene or C １－３ 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof, which is heteroalkylene.

10. L ２ 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof, wherein: is a bond.

11. X １ is CR ３ 2. The compound of claim 1, wherein:

12. R ３ is hydrogen, halo or C １－５ alkyl, where C １－５ 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof, wherein alkyl is optionally substituted with 1 to 5 halo.

13. X １ is N, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof.

14. R ４ Ga-OR １４ or C １－５ alkyl, where C １－５ alkyl is optionally hydroxy or C １－５ 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof, which is substituted with alkoxy.

15. R ４ is hydroxy, methoxy, ethoxy, n-propoxy, iso-propoxy, cyclopropoxy, cyclobutoxy, methyl, ethyl, n-propyl, iso-propyl, 2-hydroxyethyl, or methoxymethyl, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof.

16. X ２ is CR ５ 2. The compound of claim 1, wherein:

17. R ５ is hydrogen, halo, cyano, -C(O)-C １－５ Alkyl or optionally halo, hydroxy and C １－５ C substituted with 1 to 3 substituents independently selected from alkoxy １－５ 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof, wherein:

18. R ６ is hydrogen, cyano, hydroxy, C １－５ Alkoxy or C １－５ 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof, wherein:

19. X ２ is N, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof.

20. X ３ is CR ７ 2. The compound of claim 1, wherein:

21. R ７ is hydrogen, halo, C １－５ Alkyl or C １－５ 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof, which is haloalkyl.

22. X ３ is N, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof.

23. X ４ is O, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof.

24. R ８ 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof, wherein is hydrogen.

25. 2. The compound of claim 1, wherein n is 0, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof.

26. R １ and R ２ are each independently C １－９ 10. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof.

27. R １ and R ２ together with the atoms to which they are attached, optionally 1 to 5 Z １ C substituted with ３－１０ 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, which forms a cycloalkyl.

28. R １ and R ２ together with the atoms to which they are attached, optionally 1 to 5 Z １ 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof, wherein R is a substituted heterocyclyl;

29. R １３ is hydrogen, halo or C １－９ 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof, wherein:

30. Formula IA: 【Transformation 3】 10. The compound of claim 1, represented by: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof.

31. Formula IF: 【Chemistry 4】 10. The compound of claim 1, represented by: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof.

32. Formula IH: 【Transformation 5】 10. The compound of claim 1, represented by: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof.

33. Formula IK: 【Transformation 6】 10. The compound of claim 1, represented by: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof.

34. Formula IM: 【Transformation 7】 10. The compound of claim 1, represented by: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof.

35. Formula IIIA: 【Transformation 8】 [During the ceremony, p is 0, 1 or 2; q is 0, 1 or 2; s is 0, 1, 2 or 3; X ５ is absent, O, NR １７ or C(R １８ ) ２ and R １７ is hydrogen, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R ２０ , -C(O)OR ２０ , —C(O)NR ２０ , -S(O)R ２０ , -S(O) ２ R ２０ , -S(O)NR ２０ R ２１ or -S(O) ２ NR ２０ R ２１ where R １７ Each C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally substituted with 1 to 5 Z １ａ is substituted with; and Each R １８ are independently hydrogen or Z １ It is.

10. The compound of claim 1, represented by: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof.

36. Formula IIIC: 【Chemistry 9】 [During the ceremony, p is 0, 1 or 2; q is 0, 1 or 2; s is 0, 1, 2 or 3; X ５ is absent, O, NR １７ or C(R １８ ) ２ and R １７ is hydrogen, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R ２０ , -C(O)OR ２０ , —C(O)NR ２０ , -S(O)R ２０ , -S(O) ２ R ２０ , -S(O)NR ２０ R ２１ or -S(O) ２ NR ２０ R ２１ where R １７ Each C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally substituted with 1 to 5 Z １ａ is substituted with; and Each R １８ are independently hydrogen or Z １ It is.

10. The compound of claim 1, represented by: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof.

37. Formula IIID: 【Chemistry 10】 [During the ceremony, p is 0, 1 or 2; q is 0, 1 or 2; s is 0, 1, 2 or 3; X ５ is absent, O, NR １７ or C(R １８ ) ２ and R １７ is hydrogen, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R ２０ , -C(O)OR ２０ , —C(O)NR ２０ , -S(O)R ２０ , -S(O) ２ R ２０ , -S(O)NR ２０ R ２１ or -S(O) ２ NR ２０ R ２１ where R １７ Each C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally substituted with 1 to 5 Z １ａ is substituted with; and Each R １８ are independently hydrogen or Z １ It is.

10. The compound of claim 1, represented by: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof.

38. Formula IIIF: 【Chemistry 11】 [During the ceremony, p is 0, 1 or 2; q is 0, 1 or 2; s is 0, 1, 2 or 3; X ５ is absent, O, NR １７ or C(R １８ ) ２ and R １７ is hydrogen, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R ２０ , -C(O)OR ２０ , —C(O)NR ２０ , -S(O)R ２０ , -S(O) ２ R ２０ , -S(O)NR ２０ R ２１ or -S(O) ２ NR ２０ R ２１ where R １７ Each C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally substituted with 1 to 5 Z １ａ is substituted with; and Each R １８ are independently hydrogen or Z １ It is.

10. The compound of claim 1, represented by: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog, or solvate thereof.

39. A compound selected from Table 1 or Table 2 below, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof. Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 Table 33 Table 34 Table 35 Table 36 Table 37 Table 38 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 Table 45 Table 46 Table 47 Table 48 Table 49 Table 50 Table 51 Table 52 Table 53 Table 54 Table 55 Table 56 Table 57 Table 58 Table 59 Table 60 Table 61 Table 62 Table 63 Table 64 Table 65 Table 66 Table 67 Table 68 Table 69 Table 70 Table 71

40. 40. A pharmaceutical composition comprising a compound of any of claims 1 to 39 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, isotopically enriched analog or solvate thereof and a pharmaceutically acceptable carrier.

41. 41. The pharmaceutical composition of claim 40 for treating an LPA-related disease, disorder or condition.

42. LPA-related disease, disorder or condition is LPA １ 42. The pharmaceutical composition of claim 41, wherein the composition is a medicament for treating ...

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

44. 44. The pharmaceutical composition of claim 43, wherein the fibrosis is pulmonary fibrosis, liver fibrosis, kidney fibrosis, cardiac fibrosis, skin fibrosis, eye fibrosis or pancreatic fibrosis.

45. 44. The pharmaceutical composition 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, testis, or thyroid.

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

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