Compounds and compositions for treating conditions associated with LPA receptor activity

Abstract

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

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of International Patent Application No. PCT / CN2022 / 082072, filed March 21, 2022, and International Patent Application No. PCT / CN2021 / 125409, filed October 21, 2021, each of which is incorporated by reference in its entirety.

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

[0003] A variety of lipid mediators, including eicosanoids and platelet activating factors (PAFs), are generated from cell membranes by the activity of phospholipases. Lysophospholipids are a class of bioactive lipid mediators derived from these membranes and include lysophosphatidic acid (LPA). LPA is not a single molecular entity 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 affect many biological processes including neurogenesis, angiogenesis, wound healing, immunity and oncogenesis. LPA has a role as a biological effector molecule and has a diverse range of physiological actions including, but not limited to, effects on blood pressure, platelet activation and smooth muscle contraction, as well as versatile cellular effects including cell growth, cell rounding, neurite retraction, as well as actin stress fiber formation and cell migration. The effects of LPA are predominantly 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

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

[0005] In one embodiment, there is provided a compound of Table 1, or a pharma- ceutically acceptable salt or solvate thereof. In one embodiment, there is provided a compound of Table 2, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or mixture of stereoisomers thereof.

[0006] Also provided herein is a pharmaceutical composition comprising a compound of Table 1, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable excipient.

[0007] Also provided herein is a method for treating or preventing an LPA-related disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma-ceutically acceptable salt or solvate thereof), or a pharmaceutical composition thereof. In some embodiments, the LPA-related disease is an LPA1-related disease, such as, but not limited to, fibrosis, transplant rejection, cancer, osteoporosis, or inflammatory disorder.

[0008] In some embodiments, the LPA-related disease is fibrosis, transplant rejection, cancer, osteoporosis or inflammatory disorder.In some of these embodiments, fibrosis is lung, liver, kidney, heart, skin, eye or pancreatic fibrosis.In some embodiments, cancer is bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gallbladder, reproductive organs, urogenital organs, 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 some embodiments, the LPA-associated disease is idiopathic pulmonary fibrosis (IPF), nonalcoholic steatohepatitis (NASH), nonalcoholic 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 for treating or preventing fibrosis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharma- ceutical composition thereof.

[0011] In some embodiments, the fibrosis is idiopathic pulmonary fibrosis (IPF), nonalcoholic fatty liver disease (NASH), chronic kidney disease, diabetic kidney disease and systemic sclerosis.For example, the fibrosis can be IPF. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] definition The following description sets forth exemplary embodiments of the present technology, but it should be understood that such description is not intended as a limitation on the scope of the present disclosure, but is presented as a description of exemplary embodiments.

[0013] As used herein, the following words, phrases and symbols are generally intended to have the meanings set forth below, unless the context of their use dictates otherwise.

[0014] As used herein, the term "compound" is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as a particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0015] 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. It is understood by those skilled in the art that a compound includes both amide and imidic acid tautomers, regardless of whether the tautomer is shown and regardless of the nature of the equilibrium among the tautomers. Thus, an amide-containing compound is understood to include its imidic acid tautomer. Similarly, an imidic acid-containing compound is understood to include its amide tautomer.

[0016] Any compound or structure depicted herein is also intended to represent unlabeled forms of the compound as well as isotopically labeled forms. These forms of the compound are also referred to as "isotopically enriched analogs." Isotopically labeled compounds have the structures depicted herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 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 disclosure include, for example, radioactive isotopes, e.g. 3 H and 14 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 for radioactive treatment of patients.

[0017] The term "isotopically enriched analog" includes "deuterated analogs" of compounds described herein in which one or more hydrogens, e.g., hydrogens on carbon atoms, are replaced by deuterium. Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0018] Therapeutic compounds of the present disclosure that are labeled or substituted with deuterium may have improved DMPK (drug metabolism and pharmacokinetics) properties with respect to distribution, metabolism and transport (ADME). Substitution with heavier isotopes, such as deuterium, may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dosing requirements, and / or improved therapeutic index. 18 F, 3 H, 11C-labeled compounds may be useful for PET or SPECT or other imaging studies.The isotopically labeled compounds and prodrugs of the present disclosure can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents and carrying out the procedures disclosed in the schemes or examples and preparations described below.It is understood that deuterium in this context is intended as a substituent in the compounds described herein.

[0019] The concentration of such heavier isotopes, 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", it is understood that the position has hydrogen at its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0020] In many cases, the compounds of the 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.

[0021] 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 materials useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0022] The term "pharmaceutical acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutical acceptable salt" or "physiologically acceptable salt" includes, for example, salts with inorganic acids and salts with organic acids. Furthermore, when the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an addition salt, particularly a pharmaceutical acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will be aware of various synthetic methodologies that can be used to prepare non-toxic pharmaceutical 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, and phosphoric acid. 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. Similarly, pharma- ceutically 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 NH3, or primary, secondary, and tertiary amines, such as salts derived from N-containing heterocycles, N-containing heteroaryls, or salts of the formula N(R N )3 [For example, HN + (R N )3 or (alkyl)N + (R N )3] amines, each R Nare independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted, for example, with one or more (e.g., 1-5 or 1-3) 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(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine.

[0023] The term "substituted" means that any one or more hydrogen atoms on the specified atom or group are replaced with one or more substituents other than hydrogen, provided that the normal valence of the specified atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxylester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.

[0024] Polymers or similar undefined structures achieved by defining a substituent with infinitely more additional substituents (e.g., substituted aryl with substituted alkyl, which is itself substituted with substituted aryl group, which is further substituted with substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, 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 limited to [(substituted aryl)substituted aryl]substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluorines, or a heteroaryl group with two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" may describe other chemical groups as defined herein. Unless otherwise specified, when a group is described as being optionally substituted, any substituent of the group is itself unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, one or more of the substituents can be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents can be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0025] The term "optionally" or "may" means that the subsequently described event or circumstance may or may not occur, and that the description includes examples where said event or circumstance occurs and examples where said event or circumstance does not occur. Also, the term "optionally substituted" refers to the fact that any one or more hydrogen atoms on a specified atom or group may or may not be replaced with a non-hydrogen moiety.

[0026] A dash ("-") that is not between two letters or symbols is not used to indicate the point of attachment of a substituent. For example, -C(O)NH2 is attached through a carbon atom. Dashes before or after a chemical group are a matter of convenience, and a chemical group may be drawn with or without one or more dashes without losing its ordinary meaning. A wavy line drawn through a line in a structure indicates the point of attachment of the group. No directionality is indicated or implied by the order in which chemical groups are written or named, unless chemically or structurally required.

[0027] Prefix “C” u~v " indicates that the following group has u to v carbon atoms. For example, "C 1~6 "Alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0028] Reference herein to "about" a value or parameter includes (and describes) embodiments directed to the value or parameter itself. In certain embodiments, the term "about" includes ±10% of the amount referred to. In other embodiments, the term "about" includes ±5% of the amount referred to. In certain other embodiments, the term "about" includes ±1% of the amount referred to. Also, "about X" includes a reference to "X." Also, the singular forms "a" and "the" include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those of skill in the art.

[0029] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 1 to 20 carbon atoms (i.e., C 1~20 alkyl), 1 to 12 carbon atoms (i.e., C 1~12 alkyl), 1 to 8 carbon atoms (i.e., C 1~8 alkyl), 1 to 6 carbon atoms (i.e., C 1~6 alkyl) or 1 to 4 carbon atoms (i.e. C 1~4Examples 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 particular number of carbons is named by a chemical name or specified by a molecular formula, all positional isomers having that number of carbons can be included, thus, for example, "butyl" includes n-butyl [i.e., -(CH2)3CH3], sec-butyl [i.e., -CH(CH3)CH2CH3], isobutyl [i.e., -CH2CH(CH3)2], and tert-butyl [i.e., -C(CH3)3], and "propyl" includes n-propyl [i.e., -(CH2)2CH3] and isopropyl [i.e., -CH(CH3)2].

[0030] "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 Alkenyl refers to an alkyl group having an aryl group. Examples of alkenyl groups include, for example, ethenyl, propenyl, butadienyl (1,2-butadienyl and 1,3-butadienyl).

[0031] "Alkynyl" refers to an alkyl group containing at least one (e.g., 1 to 3, or 1) carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkynyl), 2 to 12 carbon atoms (i.e. C 2~12 alkynyl), 2 to 8 carbon atoms (i.e. C 2~8 alkynyl), 2 to 6 carbon atoms (i.e. C 2~6 alkynyl), or 2 to 4 carbon atoms (i.e. C 2-4The term "alkynyl" also includes groups having one triple bond and one double bond.

[0032] Certain alternative chemical names in common use can be used, for example, divalent radicals such as a divalent "alkyl" group, a divalent "aryl" group, etc., may also be referred to as an "alkylene" group, an "alkylenyl" group, an "arylene" group, or an "arylenyl" group, respectively.

[0033] "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.

[0034] "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 are replaced by halogen. For example, if a residue is substituted with more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to an alkyl substituted with two ("di") or three ("tri") halo groups, which may be, but are not necessarily, 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.

[0035] "Haloalkoxy" refers to an alkoxy group, as defined above, in which one or more (eg, 1 to 6, or 1 to 3) hydrogen atoms are replaced by halogen.

[0036] "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 by a hydroxy group.

[0037] "Alkylthio" refers to the group "alkyl-S--".

[0038] "Acyl" refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of acyls include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0039] "Amide" is -C(O)NR y R z -C-amide, which refers to the -NR group, y C(O)R z The "N-amide" group refers to both the y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein, or R y and R z taken together form a cycloalkyl or heterocyclyl, each of which may be optionally substituted as defined herein.

[0040] "Amino" is -NR y R z R refers to the group y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0041] "Amidino" is -C(NR y )(NRz 2) refers to R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0042] "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 ring system having from 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. When one or more aryl groups are fused to a heteroaryl, the resulting ring system is a heteroaryl, regardless of the point of attachment. When one or more aryl groups are fused to a heterocyclyl, the resulting ring system is a heterocyclyl, regardless of the point of attachment. When one or more aryl groups are fused to a cycloalkyl, the resulting ring system is a cycloalkyl, regardless of the point of attachment.

[0043] "Carbamoyl" is -OC(O)NR y R z The "O-carbamoyl" group, which refers to the -NR y C(O)OR z The "N-carbamoyl" group refers to both the y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0044] "Carboxyl ester" or "ester" is -OC(O)R xand -C(O)OR x Refers to both R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0045] "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 having 3 to 20 ring carbon atoms (i.e., at least one non-aromatic ring). 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. Furthermore, the term cycloalkyl is intended to encompass any non-aromatic ring that may be fused to an aryl ring, regardless of attachment to the rest of the molecule. Furthermore, cycloalkyl also includes "spirocycloalkyl", such as spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl, when there are two positions for substitution on the same carbon atom.

[0046] "Imino" is -C(NRy )R z R refers to the group y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0047] "Halogen" or "halo" refers to those atoms occupying Group VIIA of the periodic table, e.g., fluoro, chloro, bromo, or iodo.

[0048] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and some associated hydrogen atoms) are each independently replaced with the same or different heteroatom groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. By way of example, one, two or three carbon atoms may be independently replaced with the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted. Examples of heteroalkyl groups include -OCH3, -CHOCH3, -SCH3, -CH2SCH3, -NRCH3 and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl or heteroaryl, each of which may be optionally substituted. As used herein, heteroalkyl contains 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.

[0049] "Heteroaryl" refers to an aromatic group having a single ring or multiple condensed rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to an aromatic group having 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, each independently selected from nitrogen, oxygen, and sulfur. In some examples, heteroaryl includes a 5-10 membered ring system, a 5-7 membered ring system, or a 5-6 membered ring system having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, each independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindoline, and the like. Examples of aryl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl and triazinyl. Examples of fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, and heteroaryl may be bonded via the rings of the fused system. Any aromatic ring containing at least one heteroatom and having single or multiple fused rings is considered heteroaryl regardless of attachment to the rest of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0050] "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. Heterocyclyls can be monocyclic or polycyclic, which polycyclic rings can be fused, bridged, or spiro, and can contain one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O - ) moieties. Any non-aromatic ring containing at least one heteroatom is considered heterocyclyl regardless of attachment (i.e., it can be bonded through a carbon atom or a heteroatom). Additionally, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring, regardless of attachment to the remainder of the molecule, can be fused to a cycloalkyl, aryl, or heteroaryl ring. As used herein, heterocyclyl refers to a ring having from 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 3~6Heterocyclyl) 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 are, 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, octahydroisoquinol ... The term "heterocyclyl" includes "spiroheterocyclyl" when there are two positions for substitution on 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, where the heterocyclyl may be attached via a ring of the fused system.

[0051] "Sulfonyl" is -S(O)R y R refers to the groupy is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0052] "Alkylsulfonyl" refers to the group -S(O)R where R is alkyl.

[0053] "Alkylsulfinyl" refers to the group -S(O)R where R is alkyl.

[0054] As used herein, "pharmaceutical acceptable carrier" or "pharmaceutical acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients may also be incorporated into the compositions.

[0055] 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.

[0056] The term "LPA-related disease" as used herein is meant to include, but is not limited to, diseases, disorders, or conditions in which activation of at least one LPA receptor by LPA contributes to the symptomology or progression of the disease, disorder, or condition. These diseases, disorders, or conditions may result from one or more of genetic, iatrogenic, immunological, infectious, metabolic, neoplastic, toxic, surgical, and / or traumatic etiologies. Thus, inhibiting one or more lysophosphatidic acid (LPA) receptors (e.g., LPA1, LPA2, LPA3, LPA4, LPA5, or LPA6 receptors) 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, and modulating LPA1 receptor signaling can alter the pathology and / or symptoms and / or progression of the disease, disorder, or condition.

[0057] As used herein, the term "fibrosis" or "fibrotic disorder" refers to conditions associated with abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased fibroblast recruitment, including, but not limited to, fibrosis of individual organs or tissues, such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and gastrointestinal tract.

[0058] As used herein, the term "pharmaceutical acceptable" refers to a compound, or a salt or composition thereof, that is chemically and / or toxicologically compatible with other materials, including pharmaceutical agents, and / or with the subject being treated therewith.

[0059] The term "administration" or "administering" refers to the 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 a variety of factors, such as the components of the pharmaceutical composition, the site of the disease and the severity of the disease.

[0060] The term "effective amount" or "effective dosage" or "pharmaceutical effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of a chemical entity (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof) administered to relieve to some extent one or more symptoms of the disease or condition being treated, and may include a cure of the disease. "Cure" means that the symptoms of active disease are eliminated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is required to produce a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study. In some embodiments, a "therapeutically effective amount" of a compound provided herein refers to an amount of the compound that is effective as a monotherapy or combination therapy.

[0061] The term "excipient" or "pharmaceutical acceptable excipient" refers to a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In some embodiments, each component is "pharmaceutical acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation and suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. For example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical See Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0062] The term "pharmaceutical composition" refers to a mixture of a compound disclosed herein, or a pharma- ceutically acceptable salt or solvate thereof provided herein, and other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. A pharmaceutical composition facilitates administration of a compound to an organism. Several techniques of administering a compound exist in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0063] The terms "treat," "treating," and "treatment," in reference to the treatment of a disease, disorder, or condition, are meant to include alleviating or arresting the disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition, or slowing the development, spread, or worsening of the disease, disorder, or condition, or one or more symptoms thereof.

[0064] As used herein, the term "preventing" refers to the total or partial prevention of the onset, recurrence or spread of a disease or condition described herein, or a symptom thereof.

[0065] As used herein, the terms "subject", "patient" or "individual" are used interchangeably and refer to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates and humans. In some embodiments, the term refers to a subject, particularly a mammalian subject, for whom diagnosis, prognosis or treatment is desired or required. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease, disorder or condition to be treated and / or prevented.

[0066] The terms "treatment regimen" and "dosage" are used interchangeably to refer to the dosage and timing of administration of each therapeutic agent in a combination.

[0067] 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.

[0068] As used herein, the term "combination therapy" refers to the use of two different therapeutically active agents (i.e., components of a combination or combination partners), administered together or separately as prescribed by a medical care taker or in accordance with regulatory agencies as defined herein.

[0069] As used herein, the terms "modulate," "modulating," or "modulation" refer to regulation or modulation (e.g., increasing or decreasing) and can include, for example, agonism, partial agonism, or antagonism.

[0070] compound Provided herein are compounds that are LPA antagonists. In some embodiments, a compound selected from Table 1, or a pharma- ceutically acceptable salt or solvate thereof, is provided:

[0071] Table 1 [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0072] The compounds provided herein include the stereochemical forms of the compounds, such as optical isomers, e.g., enantiomers, diastereoisomers, and mixtures thereof, e.g., mixtures of enantiomers and / or diastereoisomers, including racemic mixtures, and equal or non-equal mixtures of individual enantiomers and / or diastereoisomers. Absolute and / or relative configurations can be determined using methods known in the art, including, but not limited to, chromatography, spectroscopy, X-ray crystallography, and the like. All stereochemical forms are contemplated in the present disclosure. Unless otherwise indicated, when a disclosed compound is named or depicted by structure without specifying stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound, e.g., those depicted in Table 2. In some embodiments, a compound selected from Table 2, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or mixture of stereoisomers thereof, is provided.

[0073] Table 2 [Table 2-1] [Table 2-2]

[0074] The compounds disclosed herein include their pharmaceutically acceptable salts.In addition, the compounds disclosed herein also include other salts of such compounds that are not necessarily pharmaceutically acceptable salts and may be useful as intermediates for preparing and / or purifying the compounds disclosed herein and / or for separating isomers or enantiomers of the compounds.Non-limiting examples of pharmaceutically acceptable salts of the compounds disclosed herein include trifluoroacetate salts.

[0075] It is further recognized that the compounds disclosed herein or their salts may be isolated in the form of solvates, and thus any such solvates are included within the scope of the present disclosure.For example, the compounds disclosed herein and their salts may exist in unsolvated as well as solvated forms with pharma- ceutically acceptable solvents, such as water, ethanol, and the like.

[0076] Treatment Methods and Uses The methods described herein may be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, such as within an animal or human. In this context, the methods described herein may be used as therapeutics in 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 are obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex vivo to determine optimal schedules and / or dosing intervals for administering the disclosed compounds for a given indication, cell type, individual, and other parameters. Information gathered from such use may be used for experimental purposes or in the clinic to set up 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 one of skill in the art. Selected compounds can be further characterized to test for safety or tolerated dosage in human or non-human animal subjects. Such properties can typically be tested using methods known to those of skill in the art.

[0077] The compounds provided herein, or their pharma- ceutical acceptable salts or solvates, 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 can be useful for preventing and / or treating various types of diseases, including diseases such as fibrosis (e.g., renal fibrosis, pulmonary fibrosis, liver fibrosis, arterial fibrosis, systemic sclerosis), urinary system diseases, carcinoma-related diseases, proliferative diseases, inflammation / immune system diseases, diseases caused by secretory dysfunction, brain-related diseases, and chronic diseases.

[0078] In some embodiments, the present disclosure provides a method for treating a subject (e.g., a human) with a disease, disorder, or condition (i.e., an LPA-associated disease), in which inhibition of one or more LPA receptors is beneficial for treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, the methods provided herein may include, or may further include, treating one or more associated conditions, comorbidities, or sequelae to any one or more of the conditions set forth herein.

[0079] Provided herein is a method for treating an LPA-associated disease, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutical acceptable salt or solvate thereof), or a pharmaceutical composition disclosed herein.

[0080] In some embodiments, the LPA-related disease is fibrosis of organs (e.g., liver, kidney, lung, heart and skin), liver disease (acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), impaired liver function, impaired liver blood flow, etc.), cell proliferative diseases (e.g., solid tumors, solid tumor metastases, angiofibromas, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia and chronic lymphocytic leukemia (CLL), and cancers including invasive metastasis of cancer cells, inflammatory diseases (e.g., psoriasis, nephropathy and pneumonia), gastrointestinal diseases (e.g., irritable bowel syndrome (TBS), inflammatory bowel disease (IBD) and abnormal pancreatic juice secretion), kidney disease, urinary tract-related disease (e.g., symptoms associated with benign prostatic hyperplasia or neurogenic bladder disease, spinal tumors, herniated discs, spinal canal stenosis, symptoms resulting from diabetes, lower urinary tract disease (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 obstruction), 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 scarring).

[0081] In some embodiments, provided herein is a method of 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 Table 1 or Table 2, or a pharma- ceutical acceptable salt or solvate thereof), or a pharmaceutical composition disclosed herein. For example, the method may include treating renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis, or systemic sclerosis. In some embodiments, provided herein is a method of 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 Table 1 or Table 2, or a pharma-ceutical acceptable salt or solvate thereof), or a pharmaceutical composition provided herein.

[0082] In some embodiments, a compound disclosed herein (e.g., a compound in Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, is used to treat or prevent fibrosis in a subject. For example, a compound disclosed herein (e.g., a compound in Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, can be used to treat organ or tissue fibrosis in a subject. In some embodiments, a method for preventing a fibrotic condition in a subject is provided herein, comprising administering to a subject at risk of developing one or more fibrotic conditions a therapeutically effective amount of a compound disclosed herein (e.g., a compound in Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein. For example, the subject may be exposed to one or more environmental conditions known to increase the risk of organ or tissue fibrosis. In some embodiments, the subject is exposed to one or more environmental conditions known to increase the risk of lung, liver, or kidney fibrosis. In some embodiments, the subject has a genetic predisposition to develop fibrosis of organ or tissue. In some embodiments, the compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), 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.

[0083] Exemplary diseases, disorders, or conditions involving fibrosis include fibrosis-associated lung diseases, such as idiopathic pulmonary fibrosis, iatrogenic drug induced, occupational / environmentally induced fibrosis (farmer's lung), granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen diseases (such as scleroderma), pulmonary alveolar proteinosis, Langerhans cell granulonmatosis, lymphangioleiomyomatosis, genetic diseases (e.g., Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage diseases, etc.), and pulmonary diseases (e.g., pulmonary fibrosis, pulmonary fibrosis, pulmonary fibrosis, etc.). pulmonary fibrosis secondary to lupus, idiopathic fibrosing alveolitis, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, bleomycin-induced pulmonary fibrosis, chronic asthma, silicosis, asbestos-induced pulmonary or pleural fibrosis, acute lung injury, acute respiratory distress syndrome (ARDS) and acute respiratory distress (including bacterial pneumonia-induced, trauma-induced, viral pneumonia-induced, ventilator-induced, non-pulmonary sepsis-induced and aspiration-induced).Chronic nephropathy can be classified as injury / fibrosis, renal fibrosis, glomerulonephritis secondary to systemic inflammatory diseases such as lupus and scleroderma, tubulointerstitial fibrosis, glomerulonephritis, glomerulosclerosis, focal segmental segmental), diabetes, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allografts 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 damage, primary biliary cirrhosis, infectious or viral-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 ablation keratomileusis), corneal transplantation and trabeculectomy; hypertrophic scarring, Duputren's disease disease), dermal fibrosis, cutaneous scleroderma, keloids, e.g. burn-induced or surgical; and other fibrotic diseases, e.g. sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, chronic lymphocytic leukemia, tumor metastasis, transplanted organ rejection (e.g. bronchiolitis obliterans), endometriosis, neonatal respiratory distress syndrome, and neuropathic pain, fibromyalgia, mixed connective tissue disease, and Peyronie's disease.

[0084] Provided herein is a method for improving pulmonary function in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, to a subject in need thereof. In some embodiments, the subject is diagnosed with pulmonary fibrosis. In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, is used to treat idiopathic pulmonary fibrosis in a subject. In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, is used to treat common interstitial pneumonia in a subject.

[0085] In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, is used to treat diffuse parenchymal interstitial lung diseases in a subject, such as iatrogenic drug-induced, occupational / environmentally induced fibrosis (farmer's lung), granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen 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 pneumonia).

[0086] In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, is useful for treating post-transplant fibrosis associated with chronic rejection in a subject, e.g., bronchiolitis obliterans after lung transplantation.

[0087] In some embodiments, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or the pharmaceutical compositions provided herein, are useful for treating skin fibrosis, such as cutaneous scleroderma, Dupuytren's disease, and keloids, in a subject.

[0088] In some embodiments, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or pharma- ceutical acceptable salts or solvates thereof) or pharmaceutical compositions provided herein are useful for treating liver fibrosis in subjects with or without cirrhosis, including 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.

[0089] In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, is useful for treating renal fibrosis (e.g., tubulointerstitial fibrosis and glomerulosclerosis) in a subject.

[0090] Further examples of diseases, disorders or conditions referred to 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, fibrosis of the nasal passages, sinusitis, neutrophil-mediated inflammation, and fibroblast-mediated fibrosis.

[0091] In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, is administered to a subject having organ or tissue fibrosis or predisposed to developing organ or tissue fibrosis with one or more other agents used to treat fibrosis. In some embodiments, the one or more agents include corticosteroids, immunosuppressants, B-cell antagonists, and uteroglobin.

[0092] In some embodiments, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or pharma- ceutically acceptable salts or solvates thereof) or pharmaceutical compositions provided herein are used to treat skin disorders in subjects. Such skin disorders include, but are not limited to, skin proliferative or inflammatory disorders, such as atopic dermatitis, blistering disorders, collagen diseases, psoriasis, scleroderma, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea, wound healing, scars, hypertrophic scars, keloids, Kawasaki disease, rosacea, Sjogren-Larsso Syndrome, or urticaria. In some embodiments, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or pharma-ceutically acceptable salts or solvates thereof) are used to treat systemic scleroderma.

[0093] In some embodiments, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or pharma- ceutically acceptable salts or solvates thereof) are useful for treating or preventing inflammation in a subject. For example, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or pharma-ceutically acceptable salts or solvates thereof) can be used to treat or prevent inflammation / immune disorders in a subject.

[0094] Examples of inflammatory / immune disorders include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, eczema, graft rejection of allogeneic or xenogeneic transplants (organs, bone marrow, stem cells, and other cells and tissues), graft versus host disease, lupus erythematosus, inflammatory diseases, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's thyroiditis and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, and atopic dermatitis.

[0095] In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, is used to treat pain in a subject. In some embodiments, the pain is acute pain or chronic pain. In some embodiments, the pain is neuropathic pain.

[0096] In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, is used to treat fibromyalgia. Fibromyalgia is believed to result from the formation of fibrous scar tissue in contractile (voluntary) muscles. Fibrosis binds to tissue, inhibiting blood flow and causing pain.

[0097] In some embodiments, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or pharma- ceutically acceptable salts or solvates thereof), or the pharmaceutical compositions provided herein, are used to treat cancer. In some embodiments, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or pharma- ceutically acceptable salts or solvates thereof), or the pharmaceutical compositions provided herein, are used to treat malignant and benign proliferative diseases. In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, is used to prevent or reduce tumor cell proliferation, carcinoma, pleural mesothelioma [Yamada, Cancer Sci., 2008, 99(8), 1603-1610] or peritoneal mesothelioma invasion and metastasis, 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 of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein. In some embodiments, the methods provided herein further comprise administration of a second therapeutic agent, wherein the second therapeutic agent is an anti-cancer agent.

[0098] The term "cancer" as used herein refers to an abnormal growth of cells that tend to grow uncontrollably and, in some cases, grow and metastasize (spread). Types of cancer include, but are not limited to, solid tumors at any stage of disease, with or without metastasis, such as tumors of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organs (thyroid), prostate, skin (melanoma or basal cell carcinoma), or blood tumors (e.g., leukemia).

[0099] Further non-limiting examples of cancers include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumor, brain and spinal cord tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumor, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing's sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, 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, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoma, Waldenstrom's macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer cancer, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing's sarcoma family tumors, sarcoma, Kaposi's sarcoma,kaposi), Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric (stomach) cancer, supratentorial 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.

[0100] In some embodiments, provided herein is a method of treating an allergic disorder in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof). In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma-ceutically acceptable salt or solvate thereof) is useful for treating a respiratory disease, disorder, or condition in a subject. For example, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma-ceutically acceptable salt or solvate thereof) can treat asthma (e.g., chronic asthma) in a subject.

[0101] The term "respiratory disease" as used herein refers to diseases that affect the organs involved in breathing, such as the nose, throat, larynx, Eustachian tube, trachea, bronchi, lungs, associated muscles (e.g., diaphragm and intercostal muscles) and nerves. Non-limiting examples of respiratory diseases include asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, severe acute asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperpnea, childhood-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic bronchitis or chronic obstructive pulmonary disease including emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or airway inflammation, and cystic fibrosis and hypoxia.

[0102] As used herein, the term "asthma" refers to any disorder of the lung characterized by variations in lung airflow associated with airway constriction of any cause (intrinsic, extrinsic, or both; allergic or non-allergic). The term asthma may be used with one or more adjectives indicating the cause.

[0103] Further provided herein is a method for treating or preventing chronic obstructive pulmonary disease in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof) provided herein. Examples of chronic obstructive pulmonary disease include, but are not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or airway inflammation, and cystic fibrosis.

[0104] In some embodiments, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or pharma- ceutically acceptable salts or solvates 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 found after blunt or surgical trauma (including postoperative cognitive dysfunction and spinal cord or brainstem injury), and neurological aspects of disorders, such as degenerative disc disease and sciatica.

[0105] In some embodiments, the present application provides a method for treating or preventing CNS disorder in a subject.Non-limiting examples of CNS disorder include multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, postoperative cognitive dysfunction, migraine headache, peripheral neuropathy / neuropathic pain, spinal cord injury, cerebral edema and head injury.

[0106] Also provided herein is a method for treating or preventing cardiovascular disease in a subject.The term "cardiovascular disease" as used herein refers to the disease that affects the heart or blood vessel, or both, including but not limited to arrhythmia (atrial or ventricular, or both); atherosclerosis and its sequelae; angina pectoris; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; heart or blood vessel aneurysm; vasculitis, stroke; peripheral occlusive arteriopathy of limbs, organ or tissue; reperfusion injury after ischemia of brain, heart or other organ or tissue; endotoxic, surgical or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including those related to migraine); vascular abnormality, inflammation, failure that is 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 Table 1 or Table 2, or a pharma- ceutical acceptable salt or solvate thereof).

[0107] In some embodiments, provided herein is a method 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 Table 1 or Table 2, or a pharma- ceutical acceptable salt or solvate thereof).

[0108] Further provided herein is a method for reducing vascular constriction in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof). For example, provided herein is a method for reducing or preventing elevated blood pressure in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma-ceutically acceptable salt or solvate thereof).

[0109] The ability of a test compound to act as an inhibitor of the LGA receptor 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 a cell line.

[0110] For example, Chinese hamster ovary cells overexpressing human LPA1 can be seeded overnight in DMEM / F12 medium in microplates (15,000 cells / well). After overnight incubation, cells are loaded with calcium indicator dye for 30 minutes at 37°C. Cells are then equilibrated to room temperature for 30 minutes before assay. Test compounds solubilized 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. Diluted compounds are added to cells at final concentrations ranging from 0.08 nM to 5 mM, followed by 20 min incubation at room temperature, at which time LPA is added to a final concentration of 10 nM to stimulate the cells. Compound IC 50 The IC value is defined as the concentration of test compound that inhibited 50% of the calcium influx induced by LPA alone. 50 Values ​​can be determined by fitting the data to a four-parameter logistic equation.

[0111] In another example, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof) provided herein is orally administered to CD-1 female mice po 2 hours prior to LPA challenge. The mice are then administered LPA in 0.15 mL of 0.1% BSA / PBS (2 pg / pL) via the tail vein (IV). Exactly 2 minutes after LPA challenge, the mice are euthanized by decapitation and trunk blood is collected. These samples are collectively centrifuged and individual 75 pL samples are frozen at -20°C until the histamine assay is performed. Plasma histamine analysis can be performed by standard EIA (enzyme immunoassay) methods. Plasma samples were thawed and diluted 1:30 with 0.1% BSA in PBS. The EIA protocol for histamine analysis previously described can be used in this assay.

[0112] LPA has a role as a biological effector molecule and has a diverse range of physiological actions including effects on blood pressure, platelet activation and smooth muscle contraction, as well as a variety of cellular effects including cell growth, cell rounding, neurite retraction, and actin stress fiber formation and cell migration.These effects are predominantly receptor mediated.

[0113] Activation of LPA receptors (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) with LPA mediates a range of downstream signaling cascades, non-limiting examples include mitogen-activated protein kinase (MAPK) activation, adenylyl cyclase (AC) inhibition / activation, phospholipase C (PLC) activation / Ca2+ mobilization, arachidonic acid release, Akt / PKB activation, and 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 the LPA receptors signal cooperatively. LPA1, LPA2 and LPA3 share high amino acid sequence similarity.

[0114] LPA1 (previously called VZG-1 / EDG-2 / mrec1.3) is a G protein that binds three types of G proteins, G i / o , G q and G 12 / 13 Through the activation of these G proteins, LPA mediates, for example, cell proliferation, serum-response element (SRE) activation, mitogen-activated protein kinase (MAPK) activation, adenylyl cyclase (AC) inhibition, phospholipase C (PLC) activation, and Ca2+ It induces a range of cellular responses through LPA1, including recruitment, Akt activation and Rho activation.

[0115] Expression of LPA1 is 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.

[0116] LPA2 (EDG-4) also binds three types of G proteins, G i / o , G q and G 12 / 13 It mediates LPA-induced cellular signaling by coupling to LPA2. Expression of LPA2 has been observed in the testis, kidney, lung, thymus, spleen, and stomach of adult mice, and in leukocytes of the human testis, pancreas, prostate, thymus, spleen, and peripheral blood. Expression of LPA2 is upregulated in various cancer cell lines, and several human LPA2 transcript variants with mutations in the 3'-untranslated region have been observed.

[0117] LPA3 activates PLC, Ca 2+ It can mediate pleiotropic LPA-induced signaling, including recruitment, AC inhibition / activation, and MAPK activation. Overexpression of LPA3 in neuroblastoma cells results in neurite outgrowth. Expression of LPA3 is observed in the testis, kidney, lung, small intestine, heart, thymus, and brain of adult mice. In humans, it is found in the heart, pancreas, prostate, testis, lung, ovary, and brain (frontal cortex, hippocampus, and amygdala).

[0118] LPA4 (p2y9 / GPR23) is a divergent sequence compared to LPA1, LPA2, and LPA3, and has close similarity to the platelet-activating factor (PAF) receptor. LPA4 mediates LPA-induced Ca 2+It mediates recruitment and cAMP accumulation, functional coupling to the G protein Gs for AC activation, as well as coupling to other G proteins. The LPA4 gene is expressed in the ovary, pancreas, thymus, kidney and skeletal muscle.

[0119] LPA5 (GPR92) is a member of the purinoter of GPCRs and is structurally most closely related to LPA4. LPA5 is expressed in human heart, placenta, spleen, brain, lung, and intestine. LPA is also highly expressed in the CD8+ lymphocyte compartment of the gastrointestinal tract.

[0120] LPA6 (p2y5) is a member of the purino-cluster of GPCRs and is structurally most closely related to LPA4. LPA6 is an LPA receptor that couples to the G12 / 13-Rho signaling pathway and is expressed in the inner root sheath of human hair follicles.

[0121] Improvements in any of the foregoing response criteria are specifically effected by the methods of the present disclosure.

[0122] Combination Therapy In one embodiment, the compounds disclosed herein may be used in combination with one or more additional therapeutic agents used and / or developed to treat 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 underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition.

[0123] The compounds provided herein, or their pharma- ceutical acceptable salts or solvates, 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 for preventing and / or treating various types of diseases, including diseases such as fibrosis (e.g., renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis, systemic sclerosis), urinary system diseases, carcinoma-related diseases, proliferative diseases, inflammation / immune system diseases, diseases caused by secretory dysfunction, brain-related diseases, and chronic diseases.

[0124] In some embodiments, the present disclosure provides a method for treating a subject (e.g., a human) with 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 underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, the methods provided herein may include, or may further include, treating one or more associated conditions, comorbidities, or sequelae to any one or more of the conditions presented herein.

[0125] Provided herein is a method for treating an LPA-associated disease, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutical acceptable salt or solvate thereof), or a pharmaceutical composition disclosed herein.

[0126] In some embodiments, the LPA-related disease is fibrosis of organs (e.g., liver, kidney, lung, heart and skin), liver disease (acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), impaired liver function, impaired liver blood flow, etc.), cell proliferative diseases (e.g., solid tumors, solid tumor metastases, angiofibromas, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia and chronic lymphocytic leukemia (CLL), and cancers including invasive metastasis of cancer cells, inflammatory diseases (e.g., psoriasis, nephropathy and pneumonia), gastrointestinal diseases (e.g., irritable bowel syndrome (TBS), inflammatory bowel disease (IBD) and abnormal pancreatic secretion). and / or urinary tract disorders, including, but not limited to, treating conditions such as age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, and glaucoma filtration surgery scarring.

[0127] In some embodiments, provided herein is a method of 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 Table 1 or Table 2, or a pharma- ceutical acceptable salt or solvate thereof), or a pharmaceutical composition disclosed herein. For example, the method may include treating renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis, or systemic sclerosis. In some embodiments, provided herein is a method of 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 Table 1 or Table 2, or a pharma-ceutical acceptable salt or solvate thereof), or a pharmaceutical composition provided herein.

[0128] In some embodiments, a compound disclosed herein (e.g., a compound in Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, is used to treat or prevent fibrosis in a subject. For example, a compound disclosed herein (e.g., a compound in Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, can be used to treat organ or tissue fibrosis in a subject. In some embodiments, a method for preventing a fibrotic condition in a subject is provided herein, comprising administering to a subject at risk of developing one or more fibrotic conditions a therapeutically effective amount of a compound disclosed herein (e.g., a compound in Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein. For example, the subject may be exposed to one or more environmental conditions known to increase the risk of organ or tissue fibrosis. In some embodiments, the subject is exposed to one or more environmental conditions known to increase the risk of lung, liver, or kidney fibrosis. In some embodiments, the subject has a genetic predisposition to develop fibrosis of organ or tissue. In some embodiments, the compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), 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.

[0129] Exemplary diseases, disorders or conditions involving fibrosis include fibrosis-associated lung diseases, such as idiopathic pulmonary fibrosis, iatrogenic drug-induced, occupational / environmentally induced fibrosis (farmer's lung), granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen 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 pneumonia), systemic inflammatory diseases, such as pulmonary fibrosis, ... Diseases, such as, but not limited to, rheumatoid arthritis, scleroderma, pulmonary fibrosis secondary to lupus, idiopathic fibrosing alveolitis, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, bleomycin-induced pulmonary fibrosis, chronic asthma, silicosis, asbestos-induced pulmonary or pleural fibrosis, acute lung injury, acute respiratory distress syndrome (ARDS) and acute respiratory distress (including bacterial pneumonia-induced, trauma-induced, viral pneumonia-induced, ventilator-induced, non-pulmonary sepsis-induced and aspiration-induced).Chronic nephropathy includes injury / fibrosis, kidney fibrosis (renal fibrosis), glomerulonephritis secondary to systemic inflammatory diseases, e.g. 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 viral-induced liver fibrosis (e.g. chronic HCV infection), inflammation / immune disorders and autoimmune hepatitis; head and neck fibrosis, e.g. corneal scarring, e.g. LASIK (laser ablation keratomileusis), corneal transplants and trabeculectomy; hypertrophic scars, Duputren's disease, dermal fibrosis, cutaneous scleroderma, keloids, e.g. burn-induced or surgical; and other fibrotic diseases, e.g. sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, chronic lymphocytic leukemia, tumor metastasis, transplanted organ rejection (e.g. bronchiolitis obliterans), endometriosis, neonatal respiratory distress syndrome, and neuropathic pain, fibromyalgia, mixed connective tissue disease, and Peyronie's disease.

[0130] Provided herein is a method for improving pulmonary function in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, to a subject in need thereof. In some embodiments, the subject is diagnosed with pulmonary fibrosis. In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, is used to treat idiopathic pulmonary fibrosis in a subject. In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, is used to treat common interstitial pneumonia in a subject.

[0131] In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, is used to treat a diffuse parenchymal interstitial lung disease in a subject, such as iatrogenic drug-induced, occupational / environmentally induced fibrosis (farmer's lung), granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen 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 pneumonia).

[0132] In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, is useful for treating post-transplant fibrosis associated with chronic rejection in a subject, e.g., bronchiolitis obliterans after lung transplantation.

[0133] In some embodiments, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or the pharmaceutical compositions provided herein, are useful for treating skin fibrosis, such as cutaneous scleroderma, Dupuytren's disease, and keloids, in a subject.

[0134] In some embodiments, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or pharma- ceutical acceptable salts or solvates thereof) or pharmaceutical compositions provided herein are useful for treating liver fibrosis in subjects with or without cirrhosis, 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.

[0135] In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, is useful for treating renal fibrosis (e.g., tubulointerstitial fibrosis and glomerulosclerosis) in a subject.

[0136] Further examples of diseases, disorders or conditions referred to 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, fibrosis of the nasal passages, sinusitis, neutrophil-mediated inflammation, and fibroblast-mediated fibrosis.

[0137] In some embodiments, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or the pharmaceutical compositions provided herein, are useful for treating one or more symptoms of COVID-19.

[0138] In some embodiments, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or the pharmaceutical compositions provided herein, are useful for treating chronic obstructive pulmonary disease (COPD).

[0139] In some embodiments, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or the pharmaceutical compositions provided herein, are useful for treating neuroinflammation.

[0140] In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, is useful for treating multiple sclerosis.

[0141] In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, is administered to a subject having organ or tissue fibrosis or predisposed to developing organ or tissue fibrosis with one or more other agents used to treat fibrosis. In some embodiments, the one or more agents include corticosteroids, immunosuppressants, B-cell antagonists, and uteroglobin.

[0142] In some embodiments, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or pharma- ceutically acceptable salts or solvates thereof) or pharmaceutical compositions disclosed herein are used to treat skin disorders in subjects. Such skin disorders include, but are not limited to, skin proliferative or inflammatory disorders, such as atopic dermatitis, blistering disorders, collagen diseases, psoriasis, scleroderma, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjogren-Larsson syndrome, or urticaria. In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof) is used to treat systemic scleroderma.

[0143] In some embodiments, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or pharma- ceutically acceptable salts or solvates thereof) are useful for treating or preventing inflammation in a subject. For example, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or pharma-ceutically acceptable salts or solvates thereof) can be used to treat or prevent inflammation / immune disorders in a subject.

[0144] Examples of inflammatory / immune disorders include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, eczema, graft rejection of allogeneic or xenogeneic transplants (organs, bone marrow, stem cells, and other cells and tissues), graft versus host disease, lupus erythematosus, inflammatory diseases, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's thyroiditis and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, and atopic dermatitis.

[0145] In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, is used to treat pain in a subject. In some embodiments, the pain is acute pain or chronic pain. In some embodiments, the pain is neuropathic pain.

[0146] In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, is used to treat fibromyalgia. Fibromyalgia is believed to result from the formation of fibrous scar tissue in contractile (voluntary) muscles. Fibrosis binds to tissue, inhibiting blood flow and causing pain.

[0147] In some embodiments, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or pharma- ceutically acceptable salts or solvates thereof), or the pharmaceutical compositions provided herein, are used to treat cancer. In some embodiments, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or pharma- ceutically acceptable salts or solvates thereof), or the pharmaceutical compositions provided herein, are used to treat malignant and benign proliferative diseases. In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, is used to prevent or reduce tumor cell proliferation, carcinoma, pleural mesothelioma [Yamada, Cancer Sci., 2008, 99(8), 1603-1610] or peritoneal mesothelioma invasion and metastasis, 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 of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein. In some embodiments, the methods provided herein further comprise administration of a second therapeutic agent, wherein the second therapeutic agent is an anti-cancer agent.

[0148] The term "cancer" as used herein refers to an abnormal growth of cells that tend to grow uncontrollably and, in some cases, grow and metastasize (spread). Types of cancer include, but are not limited to, solid tumors at any stage of disease, with or without metastasis, such as tumors of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organs (thyroid), prostate, skin (melanoma or basal cell carcinoma), or blood tumors (e.g., leukemia).

[0149] Further non-limiting examples of cancers include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumor, brain and spinal cord tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumor, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing's sarcoma family of tumors, eye cancer, omentum Membranoblastoma, Gallbladder cancer, Gastric (stomach) cancer, Gastrointestinal carcinoid tumor, Gastrointestinal stromal tumor (GIST), Gastrointestinal stromal cell tumor, Germ cell tumor, Glioma, Hairy cell leukemia, Head and neck cancer, Hepatocellular (liver) cancer, Hodgkin's lymphoma, Hypopharyngeal cancer, Intraocular melanoma, Islet cell tumor (endocrine pancreas), Kaposi's sarcoma, Kidney cancer, Langerhans cell histiocytosis, Laryngeal cancer, Leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Hairy cell leukemia, Liver cancer, Non-small cell lung cancer, Small cell lung cancer, Burkitt's lymphoma, Cutaneous T-cell lymphoma pulmonary tumor, 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 cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumor of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor , plasma 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 sarcoma tumors, sarcoma, Kaposi-Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric (stomach) cancer, supratentorial 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.

[0150] In some embodiments, provided herein is a method of treating an allergic disease in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof). In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma-ceutically acceptable salt or solvate thereof) is useful for treating a respiratory disease, disorder, or condition in a subject. For example, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma-ceutically acceptable salt or solvate thereof) can treat asthma (e.g., chronic asthma) in a subject.

[0151] The term "respiratory disease" as used herein refers to diseases that affect the organs involved in breathing, such as the nose, throat, larynx, Eustachian tube, trachea, bronchi, lungs, associated muscles (e.g., diaphragm and intercostal muscles) and nerves. Non-limiting examples of respiratory diseases include asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, severe acute 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.

[0152] As used herein, the term "asthma" refers to any disorder of the lung characterized by variations in lung airflow associated with airway constriction of any cause (intrinsic, extrinsic, or both; allergic or non-allergic). The term asthma may be used with one or more adjectives indicating the cause.

[0153] Further provided herein is a method for treating or preventing chronic obstructive pulmonary disease in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof) provided herein. Examples of chronic obstructive pulmonary disease include, but are not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or airway inflammation, and cystic fibrosis.

[0154] In some embodiments, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or pharma- ceutically acceptable salts or solvates 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 found after blunt or surgical trauma (including postoperative cognitive dysfunction and spinal cord or brainstem injury), and neurological aspects of disorders, such as degenerative disc disease and sciatica.

[0155] In some embodiments, the present application provides a method for treating or preventing CNS disorder in a subject.Non-limiting examples of CNS disorder include multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, postoperative cognitive dysfunction, migraine headache, peripheral neuropathy / neuropathic pain, spinal cord injury, cerebral edema and head injury.

[0156] Also provided herein is a method for treating or preventing cardiovascular disease in a subject.The term "cardiovascular disease" as used herein refers to the disease that affects the heart or blood vessel, or both, including but not limited to arrhythmia (atrial or ventricular, or both); atherosclerosis and its sequelae; angina pectoris; heart rhythm disorder; myocardial ischemia; myocardial infarction; heart or blood vessel aneurysm; vasculitis, stroke; peripheral occlusive arteriopathy of limbs, organ or tissue; reperfusion injury after ischemia of brain, heart or other organ or tissue; endotoxic, surgical or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including those related to migraine); vascular abnormality, inflammation, failure that is 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 Table 1 or Table 2, or a pharma- ceutical acceptable salt or solvate thereof).

[0157] In some embodiments, provided herein is a method 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 Table 1 or Table 2, or a pharma- ceutical acceptable salt or solvate thereof).

[0158] Further provided herein is a method for reducing vascular constriction in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof). For example, provided herein is a method for reducing or preventing elevated blood pressure in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma-ceutically acceptable salt or solvate thereof).

[0159] Pharmaceutical Compositions and Modes of Administration The compounds provided herein are typically administered in the form of a pharmaceutical composition.

[0160] When used as pharmaceuticals, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or pharma- ceutically acceptable salts or solvates thereof), including pharma- ceutically acceptable salts or solvates thereof, can be administered in the form of pharmaceutical compositions. These compositions can be prepared by techniques well known in the pharmaceutical arts and can be administered by a variety of routes and to the area to be treated, depending on whether local or systemic treatment is desired. Administration can be topical (including to mucous membranes, including transdermal, epidermal, ocular, and intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Oral administration can include dosage forms formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or infusion or injection; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose or, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oil bases, thickeners, etc. may be necessary or desirable.

[0161] Also provided herein are pharmaceutical compositions containing a compound disclosed herein as an active ingredient, or a pharma- ceutically acceptable salt or solvate thereof (e.g., a compound in Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), in combination with one or more pharma- ceutical acceptable excipients (carriers). For example, pharmaceutical compositions prepared using a compound disclosed herein, or a pharma- ceutical acceptable salt or solvate thereof (e.g., a compound in Table 1 or Table 2, or a pharma- ceutical acceptable salt or solvate thereof) are included. In some embodiments, the composition is suitable for topical administration. In making the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed within such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may 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, injectable sterile liquids, and packaged sterile 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.

[0162] Further provided herein is a pharmaceutical composition containing a compound disclosed herein, or a pharma- ceutically acceptable salt or solvate thereof, (e.g., a compound in Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof) with a pharma- ceutical acceptable excipient. A pharmaceutical composition containing a compound disclosed herein, or a pharma- ceutical acceptable salt or solvate thereof, (e.g., a compound in Table 1 or Table 2, or a pharma- ceutical acceptable salt or solvate thereof) as an active ingredient can be prepared by intimately mixing a compound disclosed herein, or a pharma- ceutical acceptable salt or solvate thereof, (e.g., a compound in Table 1 or Table 2, or a pharma- ceutical acceptable salt or solvate thereof) with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition.

[0163] Suitable pharma- ceutically acceptable carriers are well known in the art, and a description of some of these pharma- ceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0164] Methods for formulating pharmaceutical compositions are described in numerous publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al.; published by Marcel Dekker, Inc.

[0165] 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 Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances, such as phosphate, Tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, 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 solubilized derivatives, may also be used to enhance delivery of the compounds provided herein. Dosage forms or compositions may be prepared containing from 0.005% to 100% of the chemical entities provided herein, with the balance made up from non-toxic excipients. Contemplated compositions may contain from 0.001% to 100%, in one embodiment from 0.1 to 95%, in another embodiment from 75 to 85%, and in a further embodiment from 20 to 80% of the chemical entities provided herein. Actual methods of preparing such dosage forms are 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).

[0166] In some embodiments, a compound disclosed herein, or a pharma- ceutically acceptable salt or solvate thereof (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, may be administered to a subject in need thereof by any acceptable route of administration. Acceptable routes of administration include buccal, dermal, intracervical, endosinusial, intratracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intravesical, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, prostatic, intraperitoneal ... These include, but are not limited to, intraglandular, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, intranasal (e.g., intranasal), nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal. In some embodiments, the preferred route of administration is parenteral (e.g., intratumoral).

[0167] In some embodiments, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or pharma- ceutically acceptable salts or solvates thereof) provided herein, or pharmaceutical compositions thereof, can be formulated for parenteral administration, e.g., for injection via intra-arterial, intrasternal, intracranial, intravenous, intramuscular, subcutaneous, or intraperitoneal routes. For example, such compositions can be prepared as injections as liquid solutions or suspensions; solid forms suitable for use in preparing solutions or suspensions upon addition of liquid prior to injection can also be prepared; preparations can also be emulsified. The preparation of such formulations is known to those skilled in the art in light of the present disclosure. In some embodiments, a device is used for parenteral administration. For example, such devices can include needle injectors, microneedle injectors, needleless injectors, and injection techniques.

[0168] In some embodiments, pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the form must be sterile and must be fluid to the extent that it can be easily injected. In some embodiments, the form must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0169] In some embodiments, the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In some embodiments, proper fluidity may be maintained, for example, by the use of a coating, such as lecithin, to maintain the required particle size in the case of dispersions, and by the use of surfactants. In some embodiments, the prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal. In some embodiments, isotonic agents, for example, sugars or sodium chloride, are included. In some embodiments, prolonged absorption of the injectable composition may be achieved by the use in the composition of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0170] In some embodiments, sterile injectable solutions are prepared by incorporating a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof) in the required amount in an appropriate solvent with various other ingredients listed above, followed by filtered sterilization as necessary. In some embodiments, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and other required ingredients from those listed above. In some embodiments, sterile powders are used to prepare sterile injectable solutions. In some embodiments, the method of preparation is vacuum drying and freeze-drying techniques, which result in a powder of the active ingredient and any additional desired ingredients from its previously sterile-filtered solution.

[0171] In some embodiments, pharmacologically acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (such as PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, 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, anoxidized cellulose, sorbitol, sodium benzoate ... In some embodiments, the additives may be selected from the group consisting of SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomer, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0172] In some embodiments, suppositories can be prepared by mixing a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax, which is solid at ambient temperature but liquid at body temperature and thus melts in the rectum and releases the active compound. In some embodiments, the composition for rectal administration is in the form of an enema.

[0173] In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof) provided herein, or a pharmaceutical composition thereof, is formulated for local delivery to the digestive or GI tract (e.g., a solid or liquid dosage form) for oral administration.

[0174] In some embodiments, solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In some embodiments, the compounds disclosed herein, or pharma- ceutically acceptable salts or solvates thereof (e.g., compounds of Table 1 or Table 2, or pharma-ceutically acceptable salts or solvates thereof), may be combined with one or more pharma- ceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants, such as glycerol, d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents, such as glycerol, d) disintegrants ... agents), such as paraffin, f) absorption enhancers, 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 glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, for example, the dosage form may also include buffering agents. In some embodiments, solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules, using such excipients as lactose or milk sugar, and high molecular weight polyethylene glycols, and the like.

[0175] 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 Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof) provided herein, along with a diluent, such as lactose, sucrose, dicalcium phosphate, and the like; a lubricant, such as magnesium stearate, and the like; and a binder, such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, and the like. In some embodiments, another solid dosage form, a powder, a marume, a solution, or a suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) is encapsulated in a capsule (gelatin or cellulose-based capsule). In some embodiments, unit dosage forms in which one or more compounds and pharmaceutical compositions provided herein, or an additional active agent are physically separated, such as a capsule (or tablet in a capsule) with granules of each drug; a bilayer tablet; or a two-compartment gelcap, are also contemplated. In some embodiments, enteric coatings or delayed release oral dosage forms are also contemplated.

[0176] In some embodiments, other physiologically acceptable compounds may include wetting agents, emulsifying agents, dispersing agents or preservatives, which are particularly useful for preventing the growth or action of microorganisms. For example, various preservatives are well known and include, for example, phenol and ascorbic acid.

[0177] In some embodiments, the excipients are sterile and generally free of undesirable materials. For example, these compositions may be sterilized by conventional, well-known sterilization techniques. In some embodiments, sterility is not required for excipients of various oral dosage forms, such as tablets and capsules. For example, United States Pharmacopeia / National Formulary (USP / NF) standards may be sufficient.

[0178] In some embodiments, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or pharma- ceutically acceptable salts or solvates thereof) provided herein or pharmaceutical compositions thereof are formulated for intraocular administration. In some embodiments, the ophthalmic compositions may include, but are not limited to, one or more of the following: viscogene (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymers), cyclodextrin); preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.).

[0179] In some embodiments, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or pharma- ceutically acceptable salts or solvates thereof) provided herein, or pharmaceutical compositions thereof, are formulated for topical administration (e.g., dermal or transdermal) to the skin or mucosa. In some embodiments, topical compositions may include ointments and creams. In some embodiments, ointments are typically semi-solid preparations based on petrolatum or other petroleum derivatives. In some 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 typically composed of petrolatum and a fatty alcohol, such as cetyl or stearyl alcohol, and the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and typically contains a humectant. In some embodiments, the emulsifier in a cream formulation is typically a nonionic, anionic, cationic, or amphoteric surfactant. In some embodiments, ointment bases, like other carriers or vehicles, should be inert, stable, non-irritating and non-sensitizing.

[0180] In any of the foregoing embodiments, the pharmaceutical compositions provided herein may 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 particles supporting lipid bilayers.

[0181] In some embodiments, the dosage of a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof) is determined based on several factors, including, but not limited to, the type of subject, age, weight, sex, medical condition, severity of the subject's medical condition, route of administration and activity of the compound or a pharma-ceutically acceptable salt or solvate thereof. In some embodiments, the proper dosage for a particular situation can be determined by one of ordinary skill in the medical arts. In some embodiments, the total daily dosage can be divided and administered in portions throughout the day or by any means that provides for continuous delivery.

[0182] In some embodiments, the compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof) is administered at a dose of about 0.01 to about 1000 mg. For example, about 0.1 to about 30 mg, about 10 to about 80 mg, about 0.5 to about 15 mg, about 50 mg to about 200 mg, about 100 mg to about 300 mg, about 200 to about 400 mg, about 300 mg to about 500 mg, about 400 mg to about 600 mg, about 500 mg to about 800 mg, about 600 mg to about 900 mg, or about 700 mg to about 1000 mg. In some embodiments, the dose is a therapeutically effective amount.

[0183] In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutical acceptable salt or solvate thereof provided herein) is administered at a dose of from about 0.0002 mg / Kg to about 100 mg / Kg (e.g., from about 0.0002 mg / Kg to about 50 mg / Kg; from about 0.0002 mg / Kg to about 25 mg / Kg; from about 0.0002 mg / Kg to about 10 mg / Kg). Kg; about 0.0002mg / Kg to about 5mg / Kg; about 0.0002mg / Kg to about 1mg / Kg; about 0.0002mg / Kg to about 0.5mg / Kg; about 0.0002mg / Kg to about 0.1mg / Kg; about 0.001mg / Kg to about 50mg / Kg; about 0.001mg / Kg to about 25mg / Kg; about 0.001mg / Kg to about 10mg / Kg; about 0.001mg / Kg to about 5mg / Kg; about 0.001mg / Kg to about 1mg / Kg; about 0.001mg / Kg to about 0.5mg / Kg; about 0.001mg / Kg to about 0.1mg / Kg; about 0.01mg / Kg to about 50mg / Kg; about 0.01mg / Kg to about 25mg / Kg; about 0.01mg / Kg to about 10mg / Kg; about 0.01mg / Kg to about 5mg / Kg; about 0.01mg / Kg to about 1mg / Kg g; about 0.01 mg / Kg to about 0.5 mg / Kg; about 0.01 mg / Kg to about 0.1 mg / Kg; about 0.1 mg / Kg to about 50 mg / Kg; about 0.1 mg / Kg to about 25 mg / Kg; about 0.1 mg / Kg to about 10 mg / Kg; about 0.1 mg / Kg to about 5 mg / Kg; about 0.1 mg / Kg to about 1 mg / Kg; about 0.1 mg / Kg to about 0.5 mg / Kg). In some embodiments, the compounds disclosed herein (e.g., compounds of Table 1 or Table 2, or pharma- ceutically acceptable salts or solvates thereof provided herein) are administered at a dose of about 100 mg / Kg.

[0184] In some embodiments, the aforementioned dosages of a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof) can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily (e.g., every other day, every third day, every third day, once a week, twice a week, once every two weeks, once a month).

[0185] In some embodiments, the duration of administration of a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof) provided herein is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In some embodiments, the period during which administration is suspended is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof) is administered to a subject for a period of time, followed by another period during which administration of a compound disclosed herein, or a pharma- ceutically acceptable salt or solvate thereof (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof) is suspended. In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof) is administered for a first period of time, followed by a second period of time after the first period, administration is stopped during the second period of time, followed by a third period of time during which administration of a compound disclosed herein, or a pharma- ceutically acceptable salt or solvate thereof, (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof) is started, and then a fourth period of time during which administration is stopped after the third period of time. For example, the period of administration of a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof) followed by a period during which administration is stopped is repeated for a determined or undetermined period of time.In some embodiments, the duration 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 of time that administration is withheld 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.

[0186] In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof) is orally administered to a subject one or more times per day (e.g., once per day, twice per day, three times per day, four times per day, or in a single daily dose).

[0187] In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof) is administered to a subject by parenteral administration one or more times per day (e.g., 1 to 4 times one time per day, 2 times per day, 3 times per day, 4 times per day, or a single daily dose).

[0188] In some embodiments, a compound disclosed herein (e.g., a compound of Table 1 or Table 2, or a pharma- ceutically acceptable salt or solvate thereof) is administered to a subject weekly by parenteral administration.

[0189] Synthesis of compounds 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 given, it is recognized that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary depending on the reactants or solvents used, but such conditions can be determined by one skilled in the art through routine optimization procedures.

[0190] Moreover, as will be appreciated by those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting certain functional groups, are well known in the art. For example, numerous protecting groups are described in TW Greene and GM Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references therein.

[0191] In addition, the compounds of the present disclosure may contain one or more chiral centers. Therefore, if desired, such compounds may be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereoisomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds may be separated, for example, using chiral column chromatography, chiral resolving agents.

[0192] 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 suppliers 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 may be prepared by procedures described in standard reference texts, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0193] general synthesis Exemplary embodiments of the compounds described herein can be synthesized using the general reaction schemes described below. In light of the description herein, it is clear that the general schemes can be varied by replacing the starting materials with other materials having similar structures to obtain correspondingly different products. The description of the synthesis follows to show a number of examples of how the starting materials can be varied to obtain the corresponding products. Given the desired product with defined substituents, the required starting materials can generally be determined by inspection. Starting materials are typically obtained from commercial sources or can be synthesized using published methods. To synthesize the compounds that are embodiments described in this disclosure, the identification of each substituent is made by inspection of the structure of the compound to be synthesized. The identification of the final product generally reveals the identification of the required starting materials by a simple process of inspection in light of the examples herein. In general, the compounds described herein are typically stable and isolatable at room temperature and pressure. EXAMPLES

[0194] The following examples are included to demonstrate specific embodiments of the present disclosure. It should be recognized by those skilled in the art that the techniques disclosed in the following examples represent fully functional techniques in the practice of the present disclosure, and thus are considered to constitute specific modes for practicing the same. However, those skilled in the art should recognize in light of the present disclosure that many changes can be made in the specific embodiments disclosed and still obtain similar or similar results without departing from the spirit and scope of the present disclosure.

[0195] Abbreviations (used herein):

[0196] [Table 3-1] [Table 3-2]

[0197] General information: All evaporations or concentrations were performed in vacuum using a rotary evaporator. Analytical samples were dried in vacuum (1-5 mmHg) at rt. Thin layer chromatography (TLC) was performed on silica gel plates and spots were visualized by UV light (214 and 254 nm). Purifications by column and flash chromatography were performed using silica gel (100-200 mesh). Solvent systems were reported as mixtures by volume. NMR spectra were recorded on Bruker 400 or Varian (400 MHz) spectrometers. 1 H chemical shifts are reported in δ values ​​in ppm using deuterated solvents as internal standards. Data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, br=broad, m=multiplet), coupling constant (Hz), integration. LCMS spectra were obtained using electrospray ionization, or on a SHIMADZU LC20-MS2020, or an Agilent 1260 Series 6125B mass spectrometer or an Agilent 1200 Series 6110 or 6120 mass spectrometer, unless otherwise indicated. [Example A1]

[0198] 2-((2S,3R)-2-(cyclopentyloxy)-3-hydroxy-3-(3-methoxy-4-methylphenyl)propyl)-6-ethoxybenzo[d]thiazole-4-carboxylic acid (compound 101)

[0199] [ka]

[0200] [ka]

[0201] Step A: Methyl 2-amino-5-ethoxybenzoate

[0202] [ka] To a solution of methyl 2-amino-5-hydroxy-benzoate (10.0 g, 59.8 mmol), EtOH (5.51 g, 6.99 mL) and PPh3 (31.4 g, 120 mmol) in THF (150 mL) was added DIAD (24.2 g, 23.3 mL) dropwise at 25 °C. The resulting reaction mixture was stirred at 25 °C for 72 h. The solvent was removed under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography [ISCO®; 120 g SepaFlash® silica flash column, eluent of 0-15% EtOAc / PE gradient @ 100 mL / min] to give methyl 2-amino-5-ethoxy-benzoate (10.9 g, 93.0% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.17 (d, J = 2.8 Hz, 1H), 6.97 (dd, J = 8.8, 3.2 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.29 (s, 2H), 3.89 (q, J = 6.8 Hz, 2H), 3.78 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H).

[0203] Step B: Methyl 2-amino-3-bromo-5-ethoxybenzoate

[0204] [ka] To a solution of methyl 2-amino-5-ethoxy-benzoate (10.9 g, 55.6 mmol) in AcOH (80 mL) was added NBS (9.90 g, 55.6 mmol). The resulting mixture was stirred at 25 °C for 24 h. The reaction mixture was poured into water (60 mL) and stirred for 10 min. The aqueous phase was extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography [ISCO®; 120 g SepaFlash® silica flash column, eluent of 0-5% EtOAc / PE gradient @ 100 mL / min] to give methyl 2-amino-3-bromo-5-ethoxy-benzoate (6.65 g, 43.7% yield). 1 H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 2.8 Hz, 1H), 7.20 (d, J = 2.8 Hz, 1H), 5.59 (brs, 2H), 3.87 (q, J = 7.0 Hz, 2H), 3.80 (s, 3H), 1.29 (t, J =7.0 Hz, 3H).

[0205] Step C: Methyl 2-amino-5-ethoxy-3-((3-((2-ethylhexyl)oxy)-3-oxopropyl)thio)benzoate

[0206] [ka] To a solution of 2-ethylhexyl 3-sulfanylpropanoate (5.30 g, 24.3 mmol) and methyl 2-amino-3-bromo-5-ethoxy-benzoate (6.65 g, 24.3 mmol) in toluene (80 mL) was added Pd2(dba)3 (1.11 g, 1.21 mmol), Xantphos (1.40 g, 2.43 mmol) and DIEA (7.84 g, 60.7 mmol, 10.6 mL). The mixture was stirred at 110 °C for 36 h. The residue was poured into water (150 mL) and stirred for 10 min. The aqueous phase was extracted with EtOAc (80 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography [ISCO®; 120 g SepaFlash® silica flash column, eluent of 0-5% EtOAc / PE gradient @ 100 mL / min] to give methyl 2-amino-5-ethoxy-3-[3-(2-ethylhexoxy)-3-oxo-propyl]sulfanyl-benzoate (8.29 g, 83.0% yield).

[0207] Step D: Methyl 2-amino-5-ethoxy-3-[(3-ethoxy-5-methoxycarbonyl-phenyl)disulfanyl]benzoate

[0208] [ka] To a solution of methyl 2-amino-5-ethoxy-3-[2-(2-ethylhexoxy)-2-oxo-ethyl]sulfanyl-benzoate (8.29 g, 20.9 mmol) in EtOH (50 mL) was added EtONa (9.22 g, 27.1 mmol, 20% in EtOH). The reaction mixture was stirred at 25° C. for 12 h. The residue was diluted with water (100 mL), acidified to pH=6 with 37% HCl, and extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography [ISCO®; 120 g SepaFlash® silica flash column, elution with a 0-5% EtOAc / PE gradient @ 100 mL / min] to give methyl 2-amino-5-ethoxy-3-[(3-ethoxy-5-methoxycarbonyl-phenyl)disulfanyl]benzoate (1.09 g, 12.0% yield). 1 H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 3.2 Hz, 2H), 6.84 (d, J = 3.2 Hz, 2H), 6.37 (brs, 4H), 4.27 (q, J = 7.2 Hz, 4H), 3.75 (q, J = 6.8 Hz, 4H), 1.32 (t, J = 7.0 Hz, 6H), 1.24 (t, J = 7.0 Hz, 6H).

[0209] Step E: 2-(Cyclopentyloxy)acetic acid

[0210] [ka] To a solution of cyclopentanol (3 g, 34.83 mmol) in THF (50 mL) was added NaH (2.79 g, 69.66 mmol, 60% purity) at 0 °C. After stirring at 60 °C for 30 min, 2-chloroacetic acid (3.29 g, 34.83 mmol) was then slowly added to the reaction mixture at 25 °C. The resulting mixture was stirred at 60 °C for 16 h. After cooling, the reaction mixture was quenched with H2O (10 mL), diluted with H2O (50 mL), and the pH value was adjusted to 5 with 1N HCl. The mixture was extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE / EtOAc=1 / 0 to 1 / 1) to give 2-(cyclopentoxy)acetic acid (3.7 g, 73% yield). 1 H NMR (400 MHz, DMSO-d6) δ 4.21 - 4.19 (m, 1H), 3.94 (s, 2H), 1.71 - 1.28 (m, 8H).

[0211] Step F: 2-(Cyclopentyloxy)acetyl chloride

[0212] [ka] To a solution of 2-(cyclopentoxy)acetic acid (3.7 g, 25.66 mmol) in DCM (20 mL) was added oxalyl dichloride (4.89 g, 38.50 mmol) and DMF (0.1 mL). The mixture was then stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give 2-(cyclopentoxy)acetyl chloride (4.17 g, crude), which was used directly in the next step without further purification.

[0213] Step G: (R)-4-benzyl-3-(2-(cyclopentyloxy)acetyl)oxazolidin-2-one

[0214] [ka] To a solution of (4R)-4-benzyloxazolidin-2-one (6.82 g, 38.47 mmol) in THF (30 mL) was added n-BuLi (14.36 mL, 35.9 mmol, 2.5 M solution in hexane) dropwise at −78° C. under N2. After the addition, a solution of 2-(cyclopentoxy)acetyl chloride (4.17 g, 25.64 mmol) in THF (8 mL) was added to the mixture at −78° C. The resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was then quenched with sat. aq. NH4Cl solution (50 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with water (20 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE / EtOAc=1 / 0 to 1 / 1) to give (4R)-4-benzyl-3-[2-(cyclopentoxy)acetyl]oxazolidin-2-one (2.14 g, 23% yield). LC-MS: m / z 304.1 (M+H). + .

[0215] Step H: (R)-4-benzyl-3-((2R,3S)-2-(cyclopentyloxy)-3-hydroxy-3-(3-methoxy-4-methylphenyl)propanoyl)oxazolidin-2-one

[0216] [ka] To a solution of (R)-4-benzyl-3-(2-(cyclopentyloxy)acetyl)oxazolidin-2-one (1.8 g, 5.93 mmol) in DCM (45 mL) was added TiCl4 (683 μL, 6.23 mmol) at −78° C. under nitrogen. The mixture was stirred at −78° C. for 15 min. DIEA (2.58 mL, 14.8 mmol) was then added dropwise at −78° C. The resulting mixture was stirred at −78° C. for 40 min. NMP (577 μL, 5.93 mmol) was then added dropwise. The reaction mixture was stirred at −78° C. for 10 min under nitrogen. 3-Methoxy-4-methylbenzaldehyde (980 mg, 6.53 mmol) in dry DCM (10 mL) was then added dropwise. The resulting mixture was stirred at −78° C. for 2 h under nitrogen. The reaction mixture was then quenched with sat.aq.NH4Cl (50 mL) and extracted with DCM (60 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography [ISCO®; 40 g Sepa Flash® silica flash column, eluent of 0-45% EtOAc / PE gradient @ 40 mL / min] to give (R)-4-benzyl-3-((2R,3S)-2-(cyclopentyloxy)-3-hydroxy-3-(3-methoxy-4-methylphenyl)propanoyl)oxazolidin-2-one (2.27 g, 84.4% yield). LC-MS: m / z 476.2 (M+Na). + .

[0217] Step I: (R)-1-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(cyclopentyloxy)-3-(3-methoxy-4-methylphenyl)propane-1,3-dione

[0218] [ka] To a mixture of (R)-4-benzyl-3-((2R,3S)-2-(cyclopentyloxy)-3-hydroxy-3-(3-methoxy-4-methylphenyl)propanoyl)oxazolidin-2-one (2.27 g, 5.01 mmol) in DCM (30 mL) at 0° C., Dess-Martin periodinane (4.25 g, 10.0 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 2 h. The mixture was then quenched with H2O (50 mL) and DCM (50 mL). The mixture was filtered through Celite and extracted with DCM (50 mL×2). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography [ISCO®; 40 g Sepa Flash® silica flash column, elution with 0-35% EtOAc / PE gradient @ 40 mL / min] to give (R)-1-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(cyclopentyloxy)-3-(3-methoxy-4-methylphenyl)propane-1,3-dione (2.2 g, 97.4% yield). LC-MS: m / z 474.1 (M+Na). + .

[0219] Step J: (R)-4-benzyl-3-((2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3-methoxy-4-methylphenyl)propanoyl)oxazolidin-2-one

[0220] [ka] To a mixture of (R)-1-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(cyclopentyloxy)-3-(3-methoxy-4-methylphenyl)propane-1,3-dione (2.2 g, 4.87 mmol) in TFA (21.7 mL) and DCM (22 mL) at -10°C, dimethyl(phenyl)silane (2.27 mL, 14.6 mmol) was added dropwise. The reaction mixture was stirred at -10°C for 2 h. The solution was poured into sat. aq. NaHCO3 (200 mL) and extracted with DCM (30 mL x 3). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography [ISCO®; 40 g Sepa Flash® silica flash column, elution with 0-50% EtOAc / PE gradient @ 40 mL / min] to give (R)-4-benzyl-3-((2R,3R)-2-(cyclopentyloxy)-3-hydroxy-3-(3-methoxy-4-methylphenyl)propanoyl)oxazolidin-2-one (1.85 g, 83.7% yield). LC-MS: m / z 476.1 (M+Na). + .

[0221] Step K: (R)-4-benzyl-3-((2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3-methoxy-4-methylphenyl)propanoyl)oxazolidin-2-one

[0222] [ka] To a mixture of (R)-4-benzyl-3-((2R,3R)-2-(cyclopentyloxy)-3-hydroxy-3-(3-methoxy-4-methylphenyl)propanoyl)oxazolidin-2-one (1.85 g, 4.08 mmol) in DCM (15 mL) and 2,6-dimethylpyridine (950 μL, 8.16 mmol) was added [tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (1.88 mL, 8.16 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The mixture was then quenched with H2O (50 mL) and extracted with DCM (50 mL×3). The organic layer was washed with H2O (50 mL×2), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by flash silica gel chromatography [ISCO®; 20 g Sepa Flash® silica flash column, elution with a 0-10% EtOAc / PE gradient @ 35 mL / min] to give (4R)-4-benzyl-3-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3-methoxy-4-methyl-phenyl)propanoyl]oxazolidin-2-one (2.2 g, 95.0% yield).

[0223] Step L: (2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3-methoxy-4-methylphenyl)propan-1-ol

[0224] [ka] To a mixture of LiBH4 (9.69 mL, 38.76 mmol, 4 M solution in THF) in THF (10 mL) at 0 °C was added H2O (15.4 mg, 852 μmol) dropwise under N2. The mixture was stirred at 0 °C for 0.5 h. Then a solution of (R)-4-benzyl-3-((2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3-methoxy-4-methylphenyl)propanoyl)oxazolidin-2-one (2.2 g, 3.87 mmol) in THF (20 mL) was added dropwise. The reaction mixture was allowed to warm to 15 °C and stirred at 15 °C for 16 h. The reaction mixture was carefully neutralized with 1 M aq. HCl solution and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography [ISCO®; 40 g Sepa Flash® silica flash column, eluent of 0-10% EtOAc / PE gradient @ 40 mL / min] to give (2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3-methoxy-4-methylphenyl)propan-1-ol (1.26 g, 82.4% yield). 1 H NMR (400 MHz, CDCl3) δ 7.04 (d, J = 7.2 Hz, 1H), 6.85 (s, 1H), 6.79 (d, J = 7.6 Hz, 1H), 4.61 (d, J = 6.8 Hz, 1H), 3.82 (s, 3H), 3.81 - 3.70 (m, 3H), 3.36 - 3.35 (m, 1H), 2.20 (s, 3H), 1.58-1.26 (m, 8H), 0.89 (s, 9H), 0.05 (s, 3H), -0.16 (s, 3H).

[0225] Step M: (2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3-methoxy-4-methylphenyl)propyl methanesulfonate

[0226] [ka] To a mixture of (2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3-methoxy-4-methylphenyl)propan-1-ol (1.26 g, 3.19 mmol) in DCM (20 mL) and TEA (667 μL, 4.79 mmol) was added MsCl (439 mg, 3.83 mmol, 297 μL) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h. The mixture was quenched with sat. aq. NaHCO3 (50 mL) and extracted with DCM (20 mL×3). The organic layer was washed with 0.5 N HCl (20 mL×2), brine (20 mL×2), dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash silica gel chromatography [ISCO®; 20 g Sepa Flash® silica flash column, eluent of 0-15% EtOAc / PE gradient @ 35 mL / min] to give (2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3-methoxy-4-methylphenyl)propyl methanesulfonate (1.42 g, 94.1% yield). 1 H NMR (400 MHz, CDCl3) δ 7.05 (d, J = 7.6 Hz, 1H), 6.84 (s, 1H), 6.79 - 6.76 (m, 1H), 4.65 (d, J = 5.6 Hz, 1H), 4.41 - 4.27 (m, 2H), 3.82 (s, 4H), 3.57 - 3.56 (m, 1H), 2.99 (s, 3H), 2.20 (s, 3H), 1.61 -1.30 (m, 8H), 0.89 (s, 9H), 0.07 (s, 3H), -0.14 (s, 3H).

[0227] Step N: (3S,4R)-4-((tert-butyldimethylsilyl)oxy)-3-(cyclopentyloxy)-4-(3-methoxy-4-methylphenyl)butanenitrile

[0228] [ka] To a solution of [(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3-methoxy-4-methyl-phenyl)propyl]methanesulfonate (6.0 g, 12.69 mmol) in DMSO (60 mL) was added NaCN (3.11 g, 63.46 mmol). The mixture was stirred at 85 °C for 3 h. After cooling, the mixture was quenched with H2O (60 mL) and extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column (PE / EtOAc=10 / 1) to give (3S,4R)-4-((tert-butyldimethylsilyl)oxy)-3-(cyclopentyloxy)-4-(3-methoxy-4-methylphenyl)butanenitrile (4 g, 78.1% yield). LC-MS: m / z 426.2 (M+Na). + .

[0229] Step O: (3S,4R)-4-((tert-butyldimethylsilyl)oxy)-3-(cyclopentyloxy)-4-(3-methoxy-4-methylphenyl)butanal

[0230] [ka] To a solution of (3S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-3-(cyclopentoxy)-4-(3-methoxy-4-methyl-phenyl)butanenitrile (4.0 g, 9.91 mmol) in toluene (50 mL) was added DIBAL-H (19.82 mL, 19.82 mmol) at -78°C. The reaction mixture was stirred at 0°C for 1 h. The mixture was then quenched with potassium sodium tartaric solution (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to give crude (3S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-3-(cyclopentoxy)-4-(3-methoxy-4-methyl-phenyl)butanal (4.0 g, 99.2% yield), which was used in the next step without further purification.

[0231] Step P: (3S,4R)-4-((tert-butyldimethylsilyl)oxy)-3-(cyclopentyloxy)-4-(3-methoxy-4-methylphenyl)butanoic acid

[0232] [ka] To a solution of (3S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-3-(cyclopentoxy)-4-(3-methoxy-4-methyl-phenyl)butanal (4.0 g, 9.84 mmol) in t-BuOH (40 mL) and H2O (10 mL) was added NaH2PO4 (1.18 g, 9.84 mmol), sodium chlorite (3.20 g, 35.41 mmol) and 2-methylbut-2-ene (3.10 g, 44.27 mmol). The reaction mixture was stirred at 25 °C for 1 h. The mixture was then quenched with H2O (60 mL) and extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column (PE / EtOAc=10 / 1) to give (3S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-3-(cyclopentoxy)-4-(3-methoxy-4-methyl-phenyl)butanoic acid (1.6 g, 38.5% yield). LC-MS: m / z 445.1 (M+Na). + .

[0233] Step Q: Ethyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3-methoxy-4-methylphenyl)propyl)-6-ethoxybenzo[d]thiazole-4-carboxylate

[0234] [ka] To a solution of (3S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-3-(cyclopentoxy)-4-(3-methoxy-4-methyl-phenyl)butanoic acid (300 mg, 709.84 μmol) and ethyl 2-amino-3-[(2-amino-5-ethoxy-3-ethoxycarbonyl-phenyl)disulfanyl]-5-ethoxy-benzoate (341 mg, 709.84 μmol) in toluene (10 mL) was added tributylphosphane (430 mg, 2.13 mmol). The reaction mixture was stirred at 80 °C for 12 h. The mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column (PE / EtOAc=10 / 1) to obtain the compound ethyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3-methoxy-4-methyl-phenyl)propyl]-6-ethoxy-1,3-benzothiazole-4-carboxylate (110 mg, 24.7% yield). LC-MS: m / z 628.3 (M+H) + .

[0235] Step R: 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3-methoxy-4-methylphenyl)propyl)-6-ethoxybenzo[d]thiazole-4-carboxylic acid

[0236] [ka] To a solution of ethyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3-methoxy-4-methyl-phenyl)propyl]-6-ethoxy-1,3-benzothiazole-4-carboxylate (110 mg, 175.19 μmol) in THF (2 mL), EtOH (2 mL) and HO (2 mL) was added LiOH·HO (37 mg, 875.93 μmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was adjusted to pH = 4 with 1N HCl and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to give 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3-methoxy-4-methyl-phenyl)propyl]-6-ethoxy-1,3-benzothiazole-4-carboxylic acid (100 mg, 95.1% yield), which was used in the next step without further purification. LC-MS: m / z 600.3 (M+H). + .

[0237] Step S: 2-((2S,3R)-2-(cyclopentyloxy)-3-hydroxy-3-(3-methoxy-4-methylphenyl)propyl)-6-ethoxybenzo[d]thiazole-4-carboxylic acid (Compound 101)

[0238] [ka] To a solution of 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3-methoxy-4-methyl-phenyl)propyl]-6-ethoxy-1,3-benzothiazole-4-carboxylic acid (100 mg, 166.71 μmol) in THF (5 mL) was added TBAF (1.67 mL, 1.67 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by prep. HPLC [column: Welch Xtimate C18 150 x 30 mm x 5 μm; mobile phase A: [water (0.1% HCOOH)], mobile phase B: CH3CN; gradient: 55% B% to 85% B% in 7 min] to give 2-[(2S,3R)-2-(cyclopentoxy)-3-hydroxy-3-(3-methoxy-4-methyl-phenyl)propyl]-6-ethoxy-1,3-benzothiazole-4-carboxylic acid (30 mg, 36.5% yield). LC-MS: m / z 486.1 (M+Na). + . 1 H NMR (400MHz, CD3OD) δ 7.74 (d, J = 4.0, 1H), 7.71 (d, J = 4.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.98 (s, 1H), 6.88 (d, J = 8.0 Hz, 1H), 4.69 (d, J = 8.0 Hz, 1H), 4.15 (q, J = 8.0 Hz, 2H), 3.98 - 3.88 (m, 2H), 3.84 (s, 3H), 3.43 (d, J = 4.0 Hz, 2H), 2.15 (s, 3H), 1.54 - 1.40 (m, 8H), 1.38 - 1.28 (m, 3H). [Example A2]

[0239] 2-((2S,3R)-2-(cyclopentyloxy)-3-(4-(difluoromethyl)-3-methoxyphenyl)-3-hydroxypropyl)-6-methoxybenzo[d]thiazole-4-carboxylic acid (compound 102)

[0240] [ka] (3S,4R)-4-(4-Bromo-3-methoxyphenyl)-4-((tert-butyldimethylsilyl)oxy)-3-(cyclopentyloxy)butanoic acid (2-1) was synthesized according to the procedure described for the preparation of Example A1 (Steps H to P in Scheme 1) by using 4-bromo-3-methoxy-benzaldehyde in Step H.

[0241] [ka] Ethyl 2-amino-3-[(2-amino-3-ethoxycarbonyl-5-methoxy-phenyl)disulfanyl]-5-methoxy-benzoate (2-2) was synthesized by following the procedure described for the preparation of Example A1 (Steps C to D in Scheme 1) by using methyl 2-amino-3-bromo-5-methoxybenzoate in Step C. 1 H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 3.2 Hz, 2H), 6.88 (d, J = 3.2 Hz, 2H), 4.35 (q, J = 7.2 Hz, 4H), 3.63 (s, 6H), 1.40 (t, J = 7.2 Hz, 6H).

[0242] Step A: Ethyl 2-((2S,3R)-3-(4-bromo-3-methoxyphenyl)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)propyl)-6-methoxybenzo[d]thiazole-4-carboxylate

[0243] [ka] To a solution of (3S,4R)-4-(4-bromo-3-methoxyphenyl)-4-((tert-butyldimethylsilyl)oxy)-3-(cyclopentyloxy)butanoic acid (850 mg, 1.74 mmol) and ethyl 2-amino-3-[(2-amino-3-ethoxycarbonyl-phenyl)disulfanyl]benzoate (789 mg, 1.74 mmol) in toluene (10 mL) was added tributylphosphane (1.06 g, 5.23 mmol). The reaction mixture was stirred at 80 °C for 12 h. After cooling, the mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column (PE / EtOAc=10 / 1) to give ethyl 2-[(2S,3R)-3-(4-bromo-3-methoxy-phenyl)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)propyl]-6-methoxy-1,3-benzothiazole-4-carboxylate (500 mg, 42.2% yield) as a yellow oil. LC-MS: m / z 680.1 (M+H) + .

[0244] Step B: Ethyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3-methoxy-4-vinylphenyl)propyl)-6-methoxybenzo[d]thiazole-4-carboxylate

[0245] [ka] To a solution of ethyl 2-[(2S,3R)-3-(4-bromo-3-methoxy-phenyl)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)propyl]-6-methoxy-1,3-benzothiazole-4-carboxylate (330 mg, 486.19 μmol) in H2O (2 mL) and dioxane (8 mL) was added Pd(dppf)Cl2 (36 mg, 48.62 μmol), potassium ethenyl trifluoroborate (130 mg, 972.38 μmol) and Cs2CO3 (475 mg, 1.46 mmol). The mixture was stirred at 80 °C for 12 h. After cooling, the mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column (PE / EtOAc=10 / 1) to give ethyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3-methoxy-4-vinyl-phenyl)propyl]-6-methoxy-1,3-benzothiazole-4-carboxylate (240 mg, 78.8% yield). LC-MS: m / z 626.2 (M+H) + .

[0246] Step C: Ethyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(4-formyl-3-methoxyphenyl)propyl)-6-methoxybenzo[d]thiazole-4-carboxylate

[0247] [ka] To a solution of ethyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3-methoxy-4-vinyl-phenyl)propyl]-6-methoxy-1,3-benzothiazole-4-carboxylate (200 mg, 319.55 μmol) in THF (3 mL) and H2O (3 mL) was added NaIO4 (273 mg, 1.28 mmol) and K2OsO4.2H2O (1 mg, 1.92 μmol). The reaction mixture was stirred at 25 °C for 3 h. The mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column (PE / EtOAc=10 / 1) to give ethyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(4-formyl-3-methoxy-phenyl)propyl]-6-methoxy-1,3-benzothiazole-4-carboxylate (150 mg, 74.7% yield). LC-MS: m / z 628.3 (M+H) + .

[0248] Step D: Ethyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(4-(difluoromethyl)-3-methoxyphenyl)propyl)-6-methoxybenzo[d]thiazole-4-carboxylate

[0249] [ka] To a solution of ethyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(4-formyl-3-methoxy-phenyl)propyl]-6-methoxy-1,3-benzothiazole-4-carboxylate (150 mg, 238.91 μmol) in DCM (3 mL) was added DAST (192.55 mg, 1.19 mmol) at 0° C. The mixture was stirred at 25° C. for 12 h. The mixture was quenched with sat. aq. NaHCO3 (30 mL) and extracted with DCM (30 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column (PE / EtOAc=10 / 1) to give ethyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-[4-(difluoromethyl)-3-methoxy-phenyl]propyl]-6-methoxy-1,3-benzothiazole-4-carboxylate (70 mg, 45.1% yield). LC-MS: m / z 672.2 (M+Na). + .

[0250] [ka] 2-((2S,3R)-2-(cyclopentyloxy)-3-(4-(difluoromethyl)-3-methoxyphenyl)-3-hydroxypropyl)-6-methoxybenzo[d]thiazole-4-carboxylic acid (compound 102) was synthesized according to the procedure described for the preparation of Example A1 (steps R to S in scheme 1) by using ethyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(4-(difluoromethyl)-3-methoxyphenyl)propyl)-6-methoxybenzo[d]thiazole-4-carboxylate in step R. LC-MS: m / z 508.0 (M+H) + . 1H NMR (400MHz, CD3OD) δ 7.75 - 7.72 (m, 1H), 7.71 - 7.68 (m, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 7.09 (d, J = 7.8 Hz, 1H), 7.06 - 6.76 (m, 1H), 6.92 (t, J = 55.6 Hz, 1H), 4.74 (d, J = 4.0 Hz, 1H), 3.99 - 3.93 (m, 2H), 3.91 (s, 3H), 3.90 (s, 3H), 3.52 - 3.39 (m, 2H), 1.58 - 1.45 (m, 3H), 1.42 - 1.30 (m, 5H). [Example A3]

[0251] 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-6-(hydroxymethyl)benzo[d]thiazole-4-carboxylic acid (compound 103)

[0252] [ka]

[0253] [ka] Diethyl 3,3'-disulfanediylbis(2-amino-5-chlorobenzoate) (3-4) was synthesized by following the procedure described for the preparation of Example A1 (Steps B to D in Scheme 1) by using methyl 2-amino-5-chloro-benzoate in Step B. LC-MS: m / z 460.9 (M+H). + .

[0254] [ka] (3S,4R)-4-((tert-butyldimethylsilyl)oxy)-3-(cyclopentyloxy)-4-(3,5-dimethoxy-4-methylphenyl)butanoic acid (3-5) was synthesized according to the procedure described for the preparation of Example A1 (Steps H to P in Scheme 1) by using 3,5-dimethoxy-4-methylbenzene-1-carbaldehyde in Step H. 1 H NMR (400 MHz, CDCl3) δ 6.51 (s, 2H), 4.71 - 4.70 (m ,1H), 3.98 - 3.95 (m, 1H), 3.84 - 3.77 (m, 7H), 2.60 - 2.57 (m, 2H), 2.06 (s, 3H), 1.67 - 1.26 (m, 8H), 0.91 (s, 9H), 0.07 (s, 3H), -0.11 (s, 3H).

[0255] [ka] Ethyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-6-chlorobenzo[d]thiazole-4-carboxylate (3-6) was synthesized from diethyl 3,3′-disulfanediylbis(2-amino-5-chlorobenzoate) (3-4) and (3S,4R)-4-((tert-butyldimethylsilyl)oxy)-3-(cyclopentyloxy)-4-(3,5-dimethoxy-4-methylphenyl)butanoate (3-5) in step Q according to the procedure described for the preparation of Example A1 (step Q in Scheme 1). 1H NMR (400 MHz, CDCl3) δ 7.96-7.99 (m, 2H), 6.55 (s, 2H), 4.75 - 4.74 (m, 1H), 4.49 - 4.44 (m, 2H), 3.94 - 3.92 (m, 1H), 3.83 - 3.82 (m, 7H), 3.46 - 3.35 (m, 2H), 2.05 (s, 3H), 1.51 - 1.32 (m, 11H), 0.91 (s, 9H), 0.07 (s, 3H), -0.12 (s, 3H).

[0256] [ka] Ethyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-6-formylbenzo[d]thiazole-4-carboxylate (3-8) was synthesized by using ethyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-6-chlorobenzo[d]thiazole-4-carboxylate (3-6) according to the procedure described for the preparation of Example A2 (Steps B to C in Scheme 2). LC-MS: m / z 642.2 (M+H) + .

[0257] Step G: Ethyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-6-(hydroxymethyl)benzo[d]thiazole-4-carboxylate

[0258] [ka] To a solution of ethyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-6-formylbenzo[d]thiazole-4-carboxylate (30 mg, 46.78 μmol) in MeOH (1 mL) was added NaBH4 (5.30 mg, 140.21 μmol). The reaction mixture was stirred at 25 °C for 3 h. The mixture was then quenched with sat. aq. NH4Cl solution (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give ethyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-6-(hydroxymethyl)benzo[d]thiazole-4-carboxylate (20 mg, 66% yield). LC-MS: m / z 644.3 (M+H). + .

[0259] [ka] 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-6-(hydroxymethyl)benzo[d]thiazole-4-carboxylic acid (compound 103) was synthesized according to the procedure described for the preparation of Example A1 (steps S and R in scheme 1) by using ethyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-6-(hydroxymethyl)benzo[d]thiazole-4-carboxylate (3-9) in step S. LC-MS: m / z 502.3 (M+H). + . 1H NMR (400 MHz, CD3OD) δ 8.05 (s, 1H), 7.94 (s, 1H), 6.64 (s, 2H), 4.75 (s, 1H), 4.61 (s, 2H), 3.97 - 3.93 (m, 1H), 3.86 - 3.79 (m, 1H), 3.79 (s, 6H), 3.45 - 3.43 (m, 2H), 3.30-3.29 (m, 1H), 1.99 (s, 3H), 1.42 - 1.32 (m, 8H). [Example A4]

[0260] 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-6-(methoxymethyl)benzo[d]thiazole-4-carboxylic acid (compound 104)

[0261] [ka] Step A: Methyl 5-(bromomethyl)-2-nitrobenzoate

[0262] [ka] To a solution of methyl 5-methyl-2-nitro-benzoate (23.5 g, 120.41 mmol) in CCl4 (200 mL) was added AIBN (1.98 g, 12.04 mmol) and NBS (32.15 g, 180.61 mmol). The reaction mixture was stirred at 80 °C for 16 h. After cooling, the reaction was diluted with H2O (300 mL) and extracted with DCM (300 mL x 3). The combined organics were concentrated under reduced pressure to give a residue. The residue was purified by column (PE / EtOAc = 7 / 1) to give methyl 5-(bromomethyl)-2-nitrobenzoate (19.12 g, 38.6% yield).

[0263] Step B: Methyl 5-(methoxymethyl)-2-nitrobenzoate

[0264] [ka] To a solution of methyl 5-(bromomethyl)-2-nitrobenzoate (19.12 g, 69.77 mmol) in MeOH (180 mL) was added K2CO3 (9.64 g, 69.77 mmol). The mixture was stirred at 80 °C for 2 h. The reaction was diluted with H2O (300 mL) and extracted with EtOAc (300 mL x 3). The organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (PE / EtOAc = 5 / 1) to give methyl 5-(methoxymethyl)-2-nitrobenzoate (10.52 g, 66.9% yield). 1 H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 1.2 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 4.48 (s, 2H), 3.86 (s, 3H), 3.38 (s, 3H).

[0265] Step C: Methyl 2-amino-5-(methoxymethyl)benzoate

[0266] [ka] To a solution of methyl 5-(methoxymethyl)-2-nitro-benzoate (7.52 g, 33.39 mmol) in EtOAc (100 mL) was added 10% Pd / C (2.6 g) under N2, and the mixture was degassed and purged with N2 three times. The mixture was then degassed and purged with H2 three times. The mixture was stirred under H2 (45 psi) at 25 °C for 16 h. After filtration, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (PE / EtOAc = 6 / 1) to give methyl 2-amino-5-(methoxymethyl)benzoate (5.85 g, 79.6% yield). LC-MS: m / z 195.8 (M+H) + .

[0267] [ka] Dimethyl 3,3'-disulfanediylbis(2-amino-5-(methoxymethyl)benzoate) (4-7) was synthesized by following the procedure described for the preparation of Example A1 (Steps B to D in Scheme 1) by using methyl 2-amino-5-(methoxymethyl)benzoate in Step B. LC-MS: m / z 474.8 (M+Na). + .

[0268] [ka] 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-6-(methoxymethyl)benzo[d]thiazole-4-carboxylic acid (compound 104) was synthesized according to the procedure described for the preparation of Example A1 (Step Q to Step S in Scheme 1) by using dimethyl 3,3'-disulfanediylbis(2-amino-5-(methoxymethyl)benzoate) (4-7) and (3S,4R)-4-((tert-butyldimethylsilyl)oxy)-3-(cyclopentyloxy)-4-(3,5-dimethoxy-4-methylphenyl)butanoic acid (3-5) in Step Q. LC-MS: m / z 516.1 (M+H). + . 1 H NMR (400 MHz, CD3OD) δ 8.19 (d, J = 1.2 Hz, 1H), 8.12 (d, J = 1.6 Hz, 1H), 6.67 (s, 2H), 4.69 (d, J = 5.6 Hz, 1H), 4.65 (s, 2H), 4.04 - 3.99 (m, 1H), 3.97 - 3.90 (m, 1H), 3.83 (s, 6H), 3.53 - 3.48 (m, 2H), 3.46 (s, 3H), 1.99 (s, 3H), 1.55 - 1.34 (m, 8H). [Example A5]

[0269] 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-6-(methylamino)benzo[d]thiazole-4-carboxylic acid (compound 105)

[0270] [ka] Step A: Ethyl 6-((tert-butoxycarbonyl)amino)-2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)benzo[d]thiazole-4-carboxylate

[0271] [ka] To a solution of ethyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methyl-phenyl)propyl]-6-chloro-1,3-benzothiazole-4-carboxylate (500 mg, 771.22 μmol) and tert-butyl carbamate (271.04 mg, 2.31 mmol) in toluene (10 mL) was added Pd(dba)2 (44.35 mg, 77.12 μmol), K2CO3 (319.76 mg, 2.31 mmol) and S-Phos (63.32 mg, 154.24 μmol). The mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched by adding H2O (10 mL) at 0 °C and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (PE / EtOAc=100 / 1 to 10 / 1) to give ethyl 6-(tert-butoxycarbonylamino)-2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methyl-phenyl)propyl]-1,3-benzothiazole-4-carboxylate (500 mg, 88.9% yield). 1 H NMR (400MHz, CDCl3) δ 8.46 (br s, 1H), 7.66 (d, J = 2.1 Hz, 1H), 6.70 (s, 1H), 6.56 (s, 2H), 4.73 (d, J = 4.6 Hz, 1H), 4.48 - 4.42 (m, 3H), 3.95 - 3.90 (m, 1H), 3.82 (s, 6H), 3.45 - 3.40 (m, 1H), 3.31 - 3.25 (m, 1H), 2.06 (s, 3H), 1.53 (s, 9H), 1.43 - 1.25 (m, 10H), 1.43 - 1.24 (m, 1H), 0.91 (s, 9H), 0.07 (s, 3H), -0.12 (s, 3H).

[0272] Step B Ethyl 6-((tert-butoxycarbonyl)(methyl)amino)-2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)benzo[d]thiazole-4-carboxylate

[0273] [ka] To a solution of ethyl 6-(tert-butoxycarbonylamino)-2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methyl-phenyl)propyl]-1,3-benzothiazole-4-carboxylate (200 mg, 274.35 μmol) in DMF (2 mL) was added K2CO3 (189.58 mg, 1.37 mmol) and MeI (194.70 mg, 85.40 μL). The mixture was stirred at 80 °C for 12 h. After cooling, the reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (5 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep.TLC (SiO2, PE / EtOAc=10 / 1) to give ethyl 6-[tert-butoxycarbonyl(methyl)amino]-2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methyl-phenyl)propyl]-1,3-benzothiazole-4-carboxylate (40 mg, 19.6% yield). LC-MS: m / z 765.3 (M+Na). + .

[0274] Step C: Ethyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-6-(methylamino)benzo[d]thiazole-4-carboxylate

[0275] [ka] To a solution of ethyl 6-[tert-butoxycarbonyl(methyl)amino]-2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methyl-phenyl)propyl]-1,3-benzothiazole-4-carboxylate (30 mg, 40.37 μmol) in DCM (1 mL) was added TFA (29.89 μL, 400 μmol). The reaction mixture was stirred at 0° C. for 0.5 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give ethyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-6-(methylamino)benzo[d]thiazole-4-carboxylate (22.5 mg, 86.7% yield), which was used in the next step without further purification. LC-MS: m / z 643.1 (M+H). + .

[0276] Step D: Ethyl 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-6-(methylamino)benzo[d]thiazole-4-carboxylate

[0277] [ka] To a solution of ethyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methyl-phenyl)propyl]-6-(methylamino)-1,3-benzothiazole-4-carboxylate (30 mg, 46.66 μmol) in THF (0.5 mL) was added TBAF (466.62 μL, 466.62 μmol, 1 M solution in THF) at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give ethyl 2-[(2S,3R)-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methyl-phenyl)-3-hydroxy-propyl]-6-(methylamino)-1,3-benzothiazole-4-carboxylate (20 mg, 81.1% yield), which was used in the next step without further purification. LC-MS: m / z 528.7 (M+H). + .

[0278] Step E: 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-6-(methylamino)benzo[d]thiazole-4-carboxylic acid (Compound 105)

[0279] [ka] To a solution of ethyl 2-[(2S,3R)-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methyl-phenyl)-3-hydroxy-propyl]-6-(methylamino)-1,3-benzothiazole-4-carboxylate (20 mg, 37.83 μmol) in THF (0.8 mL), MeOH (0.2 mL) and H2O (0.2 mL) was added LiOH (4.53 mg, 189.16 μmol). The mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by prep. HPLC [column: Kromasil 100-5-C18; mobile phase A: water (0.1% HCOOH), mobile phase B: CH3CN; gradient: 50% B to 90% B in 10 min] to give 2-[(2S,3R)-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methyl-phenyl)-3-hydroxy-propyl]-6-(methylamino)-1,3-benzothiazole-4-carboxylic acid (7.92 mg, 41.8% yield). LC-MS: m / z 501.3 (M+H) + . 1 H NMR (400MHz, CDCl3) δ 7.57 (d, J = 2.3 Hz, 1H), 7.09 (d, J = 2.3 Hz, 1H), 6.57 (s, 2H), 4.93 (d, J = 4.3 Hz, 1H), 4.02 - 3.97 (m, 2H), 3.84 (s, 6H), 3.31 - 3.24 (m, 1H), 3.11 (dd, J = 3.5, 15.2 Hz, 1H), 2.92 (s, 3H), 2.06 (s, 3H), 1.61 - 1.40 (m, 8H). [Example A6]

[0280] 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-6-(dimethylamino)benzo[d]thiazole-4-carboxylic acid (compound 106)

[0281] [ka] Step A: Ethyl 6-amino-2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)benzo[d]thiazole-4-carboxylate

[0282] [ka] To a solution of ethyl 6-(tert-butoxycarbonylamino)-2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methyl-phenyl)propyl]-1,3-benzothiazole-4-carboxylate (100 mg, 137.17 μmol) in DCM (1 mL) was added TFA (101.56 μL, 1.37 mmol). The reaction mixture was stirred at 0° C. for 0.5 h. The reaction mixture was quenched by the addition of HO (10 mL) and extracted with DCM (10 mL×3). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give ethyl 6-amino-2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methyl-phenyl)propyl]-1,3-benzothiazole-4-carboxylate (80 mg, 92.74% yield), which was used in the next step without further purification. LC-MS: m / z 629.2 (M+H). + .

[0283] Step B: Ethyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-6-(dimethylamino)benzo[d]thiazole-4-carboxylate

[0284] [ka] To a solution of ethyl 6-amino-2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)benzo[d]thiazole-4-carboxylate (60 mg, 95.41 μmol) in DMF (1 mL) was added K2CO3 (39.56 mg, 286.22 μmol) and MeI (23.76 μL, 381.62 μmol). The reaction mixture was stirred at 80 °C for 12 h. After cooling, the reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered and concentrated to give ethyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-6-(dimethylamino)benzo[d]thiazole-4-carboxylate (55 mg, 87.75% yield), which was used in the next step without further purification. LC-MS: m / z 657.3 (M+H). + .

[0285] [ka] 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-6-(dimethylamino)benzo[d]thiazole-4-carboxylic acid, Example A6 (compound 106), was synthesized according to the procedure described for the preparation of Example A5 (Steps D to E in Scheme 5) by using ethyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-6-(dimethylamino)benzo[d]thiazole-4-carboxylate (6-2) in Step D. LC-MS: m / z 515.3 (M+H). + . 1H NMR (400MHz, CDCl3) δ 7.73 (d, J = 2.7 Hz, 1H), 7.19 (d, J = 2.6 Hz, 1H), 6.58 (s, 2H), 4.94 (d, J = 4.3 Hz, 1H), 4.03 - 3.97 (m, 2H), 3.85 (s, 6H), 3.31 - 3.24 (m, 1H), 3.14 - 3.09 (m, 1H), 3.08 (s, 6H), 2.07 (s, 3H), 1.56 - 1.32 (m, 8H). [Example A7]

[0286] 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-7-methoxybenzo[d]thiazole-4-carboxylic acid (compound 107)

[0287] [ka] Step A: Methyl 4-methoxy-2-pivalamidobenzoate

[0288] [ka] To a solution of methyl 2-amino-4-methoxybenzoate (25 g, 137.98 mmol) in DCM (200 mL) was added pyridine (22.27 mL, 275.96 mmol) and DMAP (168.57 mg, 1.38 mmol) at 25° C. Then 2,2-dimethylpropanoyl chloride (18.67 mL, 151.78 mmol) was added dropwise to the mixture at 0° C. The resulting mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched with 1N HCl solution (50 mL) and diluted with DCM (100 mL). The organic layer was separated and washed with 1N HCl solution (40 mL), sat. aq. NaHCO3 (50 mL) and brine (40 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give crude methyl 4-methoxy-2-pivalamidobenzoate (18 g, 60.9% yield), which was used directly in the next step without further purification. LC-MS: m / z 266.3 (M+H). + .

[0289] Step B: Methyl 3-bromo-4-methoxy-2-pivalamidobenzoate

[0290] [ka] To a solution of methyl 2-(2,2-dimethylpropanoylamino)-4-methoxy-benzoate (36 g, 135.69 mmol) in toluene (400 mL) was added Pd(OAc)2 (6.09 g, 27.14 mmol), NBS (53.13 g, 298.53 mmol) and 4-methylbenzenesulfonic acid (46.73 g, 271.39 mmol). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was then diluted with H2O (200 mL) and filtered. The filtrate was extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography [ISCO®; 80 g SepaFlash® silica flash column, eluent of 0-15% EtOAc / PE gradient @ 65 mL / min] to give methyl 3-bromo-2-(2,2-dimethylpropanoylamino)-4-methoxy-benzoate (4.8 g, 10.3% yield). LC-MS: m / z 344.2 (M+H). + .

[0291] Step C: Methyl 2-amino-3-bromo-4-methoxybenzoate

[0292] [ka] To a solution of methyl 3-bromo-4-methoxy-2-pivalamidobenzoate (4.8 g, 13.95 mmol) in MeOH (2 mL) was added conc. H2SO4 (44.66 g, 24.27 mL) dropwise at 0 °C. The reaction mixture was degassed and purged with N2 three times. The resulting mixture was stirred at 70 °C under N2 atmosphere for 4 h. After cooling, the reaction was diluted with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with PE (10 mL) and the suspension was isolated by filtration. The filter cake was washed with PE (20 mL) and then dried under reduced pressure to give methyl 2-amino-3-bromo-4-methoxybenzoate (2.4 g, 66.2% yield), which was used directly in the next step without further purification. LC-MS: m / z 262.1 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ 7.82 (d, J = 9.0 Hz, 1H), 6.45 (d, J = 9.0 Hz, 1H), 3.87 (s, 3H), 3.79 (s, 3H).

[0293] [ka] Diethyl 3,3'-disulfanediylbis(2-amino-4-methoxybenzoate) (7-6) was synthesized by using methyl 2-amino-3-bromo-4-methoxybenzoate (7-4) in step C according to the procedure described for the preparation of Example A1 (steps C to D in scheme 1). LC-MS: m / z 474.9 (M+Na). + .

[0294] [ka] 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-7-methoxybenzo[d]thiazole-4-carboxylic acid (compound 107) was synthesized according to the procedure described for the preparation of Example A1 (steps Q, S and R in scheme 1) by using diethyl 3,3'-disulfanediylbis(2-amino-4-methoxybenzoate) (7-6) in step D. LC-MS: m / z 502.3 (M+H). + . 1 H NMR (400MHz, CDCl3) δ 13.36 (br s, 1H), 8.32 (d, J = 8.6 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.58 (s, 2H), 4.95 (d, J = 4.3 Hz, 1H), 4.07 (s, 3H), 4.06 - 3.98 (m, 2H), 3.85 (s, 6H), 3.39 (dd, J = 8.3, 15.1 Hz, 1H), 3.21 (dd, J = 3.7, 15.1 Hz, 1H), 2.06 (s, 3H), 1.59 - 1.34 (m, 8H). [Example A8]

[0295] 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-4-(methylamino)pyrazolo[1,5-a]pyridine-7-carboxylic acid (compound 108)

[0296] [ka] (3S,4R)-4-((tert-butyldimethylsilyl)oxy)-3-(cyclopentyloxy)-4-(3,5-dimethoxy-4-methylphenyl)butanal (8-1) was synthesized according to the procedure described for the preparation of Example A1 (Steps H to O in Scheme 1) by using 3,5-dimethoxy-4-methylbenzene-1-carbaldehyde in Step H.

[0297] Step A: tert-butyl(((1R,2S)-2-(cyclopentyloxy)-1-(3,5-dimethoxy-4-methylphenyl)pent-4-yn-1-yl)oxy)dimethylsilane

[0298] [ka] 1-Diazo-1-dimethoxyphosphoryl-propan-2-one (3.8 g, 19.8 mmol) was added dropwise to a mixture of (3S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-3-(cyclopentoxy)-4-(3,5-dimethoxy-4-methyl-phenyl)butanal (7.2 g, 16.5 mmol) and K2CO3 (4.56 g, 33.0 mmol) in MeOH (70 mL) at 0° C. The reaction mixture was stirred under nitrogen at 15° C. for 16 h. The mixture was concentrated under vacuum. The residue was purified by flash silica gel chromatography [ISCO®; 220 g SepaFlash® silica flash column, eluent of 0-4% EtOAc / PE gradient @ 150 mL / min] to give tert-butyl-[(1R,2S)-2-(cyclopentoxy)-1-(3,5-dimethoxy-4-methyl-phenyl)pent-4-ynoxy]-dimethyl-silane (3.2 g, 44.9% yield). 1 H NMR (400 MHz, CDCl3) δ 6.54 (s, 2H), 4.59 - 4.58 (m, 1H), 3.85 -3.81 (m, 7H), 3.50 - 3.46 (m, 1H), 2.48 - 2.46 (m, 2H), 2.07 (s, 3H), 1.97 (s, 1H), 1.46 - 1.34 (m, 8H), 0.90 (s, 9H), 0.07 (s, 3H), -0.15 (s, 3H).

[0299] Step B: Methyl 5-amino-6-iodopicolinate

[0300] [ka] To a solution of methyl 5-aminopicolinate (10 g, 65.7 mmol) in DMF (80 mL) was added NaIO4 (5.61 g, 26.2 mmol) and I2 (13.4 g, 52.7 mmol). The reaction mixture was stirred at 60 °C for 48 h. After cooling, 10% aq. sodium sulfite solution (100 mL) was added to the reaction mixture. The resulting mixture was stirred for 10 min. The crystals were collected by filtration. The collected crystals were washed with water and dried under reduced pressure to give methyl 5-amino-6-iodo-pyridine-2-carboxylate (7.84 g, 42.9% yield). 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 4.68 (brs, 2H), 3.93 (s, 3H).

[0301] Step C: Methyl 5-amino-6-((4S,5R)-5-((tert-butyldimethylsilyl)oxy)-4-(cyclopentyloxy)-5-(3,5-dimethoxy-4-methylphenyl)pent-1-yn-1-yl)picolinate

[0302] [ka] To a solution of tert-butyl-[(1R,2S)-2-(cyclopentoxy)-1-(3,5-dimethoxy-4-methyl-phenyl)pent-4-ynoxy]-dimethyl-silane (1.71 g, 3.96 mmol) and methyl 5-amino-6-iodo-pyridine-2-carboxylate (1 g, 3.60 mmol) in MeCN (40 mL) was added Pd(PPh3)2Cl2 (252 mg, 360 μmol), CuI (68.5 mg, 360 μmol) and DIEA (3.13 mL, 17.95 mmol). The resulting mixture was stirred at 25 °C for 3 h. The mixture was diluted with water (200 mL) and extracted with EtOAc (150 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography [ISCO®; 40 g SepaFlash® silica flash column, elution with a 0-20% EtOAc / PE gradient @ 100 mL / min] to give methyl 5-amino-6-[(4S,5R)-5-[tert-butyl(dimethyl)silyl]oxy-4-(cyclopentoxy)-5-(3,5-dimethoxy-4-methyl-phenyl)pent-1-ynyl]pyridine-2-carboxylate (1.77 g, 84.2% yield). 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.6 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 6.55 (s, 2H), 4.75 (s, 2H), 4.65 (d, J = 6.0 Hz, 1H), 3.93 (s, 3H), 3.87 (d, J = 2.8 Hz, 1H), 3.83 (s, 6H), 3.66 - 3.57 (m, 1H), 2.91 - 2.81 (m, 1H), 2.80 - 2.70 (m, 1H), 2.08 (s, 3H), 1.73 - 1.63 (m, 2H), 1.52 - 1.30 (m, 6H), 0.91 (s, 9H), 0.08 (s, 3H), -0.13 (s, 3H).

[0303] Step D: Methyl 4-amino-2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)pyrazolo[1,5-a]pyridine-7-carboxylate

[0304] [ka] A mixture of tert-butyl ((mesitylsulfonyl)oxy)carbamate (946 mg, 3 mmol) and TFA (5 mL) was stirred at 0° C. for 1 h. The mixture was poured into ice-cold water (150 mL) and extracted with DCM (20 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the filtrate was added dropwise to a solution of methyl 5-amino-6-[(4S,5R)-5-[tert-butyl(dimethyl)silyl]oxy-4-(cyclopentoxy)-5-(3,5-dimethoxy-4-methyl-phenyl)pent-1-ynyl]pyridine-2-carboxylate (0.96 g, 1.65 mmol) in DCM (20 mL) at 25° C. The resulting mixture was stirred at 25° C. for 15 h. The reaction mixture was quenched with sat. aq. NaHCO3 (150 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography [ISCO®; 20 g SepaFlash® silica flash column, eluent of 0-20-40% EtOAc / PE gradient @ 80 mL / min] to give methyl 4-amino-2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methyl-phenyl)propyl]pyrazolo[1,5-a]pyridine-7-carboxylate (168 mg, 17.1% yield). LC-MS: m / z 598.8 (M+H). + .

[0305] Step E: Methyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-4-(methylamino)pyrazolo[1,5-a]pyridine-7-carboxylate

[0306] [ka] To a solution of methyl 4-amino-2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methyl-phenyl)propyl]pyrazolo[1,5-a]pyridine-7-carboxylate (84 mg, 141 μmol) in DMF (2 mL) was added K2CO3 (58.3 mg, 422 μmol) and MeI (70.0 μL, 1.12 mmol). The reaction mixture was stirred at 80 °C for 12 h. After cooling, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 4). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by flash silica gel chromatography [ISCO®; 4 g SepaFlash® silica flash column, elution with a 0-20% EtOAc / PE gradient @ 100 mL / min] to give methyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methyl-phenyl)propyl]-4-(methylamino)pyrazolo[1,5-a]pyridine-7-carboxylate (20 mg, 23.3% yield). LC-MS: m / z 634.0 (M+Na). + .

[0307] Step F: 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-4-(methylamino)pyrazolo[1,5-a]pyridine-7-carboxylic acid

[0308] [ka] To a solution of methyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methyl-phenyl)propyl]-4-(methylamino)pyrazolo[1,5-a]pyridine-7-carboxylate (20 mg, 32.7 μmol) in THF (2 mL), MeOH (5 mL) and H2O (2 mL) was added NaOH (261 mg, 6.54 mmol). The reaction mixture was stirred at 60 °C for 12 h. The solvent was removed under vacuum. The residue was diluted with water (5 mL) and acidified to pH = 4-5 with 6N HCl. The mixture was extracted with EtOAc (30 mL x 3). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by prep. HPLC [column: Kromasil 100-5-C18; mobile phase A: water (0.1% HCOOH), mobile phase B: CH3CN; gradient: 50% B to 80% B in 8 min] to give 2-[(2S,3R)-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methyl-phenyl)-3-hydroxy-propyl]-4-(methylamino)pyrazolo[1,5-a]pyridine-7-carboxylic acid (2.33 mg, 14.52% yield). LC-MS: m / z 484.3 (M+H) + . 1 H NMR (400 MHz, CD3OD) δ 7.76 (d, J = 8.2 Hz, 1H), 6.71 (s, 1H), 6.64 (s, 2H), 6.24 (d, J = 8.2 Hz, 1H), 4.61 - 4.58 (m, 2H), 3.87 - 3.74 (m, 8H), 3.22 - 3.14 (m, 1H), 3.07 - 3.01 (m, 1H), 3.00 (s, 3H), 1.99 (s, 3H), 1.46 -1.24 (m, 8H).

[0309] The compounds in Table 1 can be or were synthesized using similar procedures described in the Examples above using the appropriate starting materials. Data for certain compounds are shown in the table below. Purification conditions for certain compounds are as follows:

[0310] Prep. HPLC separation conditions for compound 102: Column: Welch Xtimate C18 150×30mm*5μm; Mobile phase A: Water (0.1% HCOOH), Mobile phase B: CH3CN; Gradient: 57% B to 87% B in 7min.

[0311] Prep. HPLC separation conditions for compound 103: Column: Kromasil 100-5-C18; Mobile phase A: water (0.1% HCOOH), Mobile phase B: CH3CN; Gradient: 50% B to 80% B in 10 min.

[0312] Prep. HPLC separation conditions for compound 104: Column: Welch Xtimate C18 150×30 mm×5 μm; Mobile phase A: water (0.01% NH3H2O+10 mM NH4HCO3), Mobile phase B: CH3CN; Gradient: 20% B to 50% B in 9 min.

[0313] Prep. HPLC separation conditions for compound 106: Column: Kromasil 100-5-C18; Mobile phase A: water (0.1% HCOOH), Mobile phase B: CH3CN; Gradient: 50% B to 90% B in 10 min.

[0314] Prep. HPLC separation conditions for compound 107: Column: Kromasil 100-5-C18; Mobile phase A: water (0.1% HCOOH), Mobile phase B: CH3CN; Gradient: 50% B to 85% B in 10 min.

[0315] Prep. HPLC separation conditions for compound 109: Column: Kromasil 100-5-C18; Mobile phase A: water (0.1% CF3COOH), Mobile phase B: CH3CN; Gradient: 50% B to 90% B in 10 min.

[0316] Prep. HPLC separation conditions for compound 110: Column: Kromasil 100-5-C18; Mobile phase A: water (0.1% HCOOH), Mobile phase B: CH3CN; Gradient: 55% B to 95% B in 9 min.

[0317] Prep. HPLC separation conditions for compound 111: Column: Boston Green ODS (150×30 mm×5 μm); Mobile phase A: water (0.225% HCOOH), Mobile phase B: CH3CN; Gradient: 60% B to 90% B in 8 min.

[0318] Prep. HPLC separation conditions for compound 112: Column: Phenomenex Gemini-NX C18 75×30 mm×3 μm; Mobile phase A: water (0.225% HCOOH), Mobile phase B: CH3CN; Gradient: 63% B to 93% B in 8 min.

[0319] Prep. HPLC separation conditions for compound 113: Column: Kromasil 100-5-C18; Mobile phase A: water (0.1% HCOOH), Mobile phase B: CH3CN; Gradient: 55% B to 100% B in 10 min.

[0320] Prep. HPLC separation conditions for compound 114: Column: DAICEL CHIRALPAK IF (250 mm x 30 mm x 10 μm); Mobile phase A: Water (0.1% NH3H2O), Mobile phase B: EtOH; Gradient: 20% B to 20% B in 8 min.

[0321] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0322] Biological assays In vitro LPA1 functional antagonist assay CHO-K1 cells overexpressing human LPA1 were seeded in a total volume of 20 μL in black-walled, clear-bottom poly-D-lysine coated 384-well microplates and incubated at 37°C for the appropriate time prior to testing. Assays were performed in 1× dye loading buffer consisting of 1× dye, 1× additive A and 2.5 mM probenecid in HBSS / 20 mM Hepes. Probenecid is freshly prepared. Cells are dye loaded prior to testing. Media is aspirated from cells and replaced with 20 μL dye loading buffer. Cells are incubated at 37°C for 30-60 minutes. After dye loading, cells are removed from the incubator and 10 μL 3× test compound is added. Cells are incubated in the dark at room temperature for 30 minutes to equilibrate plate temperature, followed by oleoyl LPA loading at 0.018 μM. Antagonist activity of compounds is measured on a FLIPR Tetra (MDS). Calcium mobilization is monitored for 2 min and 10 μL oleoyl LPA in HBSS / 20 mM Hepes is added to cells 5 seconds into the assay. Compound activity is analyzed using CBIS data analysis suite (ChemInnovation, CA). Percentage of inhibition is calculated using the following formula: % Inhibition=100%×(1−(mean RFU of test samples−mean RFU of medium control) / (mean RFU of LPA control−mean RFU of medium control)).

[0323] In vitro LPA1 calcium influx antagonist assay CHO-K1 cells overexpressing human LPA1 and G15a were seeded in Matrigel pre-coated 384-well plates (corning-3764) in a total volume of 20 μL (15000 cells / well) and incubated at 37°C. After overnight incubation, cells were serum starved for 4 h. Assays were performed in dye loading buffer containing 1× Fluo-8 AM (AAT Bioquest, 21080) and 2.5 mM probenecid (Thermo Fisher, 36400) in HBSS / 20 mM Hepes. After cell starvation, medium was replaced with 20 μL dye loading buffer and incubated at 37°C for 30 min. 5 μL of titrated 5× compound in dye loading buffer was then added to the cells and incubated for 30 min, followed by LPA loading at EC80. Calcium mobilization was measured on a FLIPR Tetra (MDS). For LPA EC80 determination, starved cells were incubated with 20 μL of dye-loading buffer for 1 h, and then 5 μL of titrated 5×LPA in dye-loading buffer was added to the cells. LPA-induced calcium signals were monitored by FLIPR.

[0324] The percentage of inhibition is calculated using the following formula: % Inhibition = 100% x (1 - (mean RFU of test samples - mean RFU of DMSO) / (mean RFU of LPA control - mean RFU of DMSO)).

[0325] Table B1 shows the biological activity of the compounds in the in vitro LPA1 calcium influx antagonist assay. The activity of the tested compounds is shown in Table B1 below as follows: +++=IC 50 <10nM;++=IC 50 10nM~100nM; +=IC 50 >100nM.

[0326] Table B1 [Table 5]

[0327] In vivo studies Pharmacokinetic measurements in mice The PK properties of selected compounds were determined in CD1 female mice after a single oral dose (5 mg / kg).

[0328] Compounds 103 and 104 were prepared in 1 mg / mL solutions in 10% Solutol HS15 and 90% saline for oral administration at 5 mL / kg, respectively, and administered to three groups of three mice. Blood samples were taken via dorsal metatarsal vein sampling at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after dosing, followed by centrifugation to obtain plasma. Samples were stored frozen at -80°C prior to compound extraction and LC-MS / MS analysis. Pharmacokinetic parameters of compounds 103 and 104 in mice were calculated from the systemic plasma concentration-time profiles by standard non-compartmental modeling.

[0329] Table B2 shows the mean pharmacokinetic parameters of compounds 103 and 104 in mice (CD1, female) as determined by a non-compartmental model.

[0330] Table B2 [Table 6]

[0331] Pharmacokinetic measurements in rats The PK properties of selected compounds were determined in SD male rats after single oral (5 mg / kg) and intravenous (1 mg / kg) doses.

[0332] Compounds 103 and 104 were prepared in 1 mg / mL solutions of 10% Solutol HS15 and 90% saline for oral administration at 5 mL / kg and in 0.2 mg / mL solutions of 10% Solutol HS15 and 90% saline for intravenous administration at 1 mL / kg, respectively, and administered to three rats per group. After administration, blood samples were taken (by cannula) via jugular vein sampling at 0.25, 0.5, 1, 2, 4, 6, 8, 24 h and 0.083, 0.25, 0.5, 1, 2, 4, 8, 24 h, respectively, followed by centrifugation to obtain plasma. Samples were stored frozen at -80°C prior to compound extraction and LC-MS / MS analysis. Pharmacokinetic parameters of compounds 103 and 104 in rats were calculated from the systemic plasma concentration-time profiles by standard non-compartmental modeling.

[0333] Table B3 shows the mean pharmacokinetic parameters of compounds 103 and 104 in rats (SD, male) determined by a non-compartmental model.

[0334] Table B3 [Table 7]

Claims

1. Table 1 below: Table 1 【Table 1】 【Table 2】 【Table 3】 【Table 4】 or a pharmaceutically acceptable salt or solvate thereof.

2. Table 2 below: Table 2 【Table 5】 【Table 6】 or a pharmaceutically acceptable salt or solvate thereof.

3. 10. A pharmaceutical composition comprising a compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

4. A pharmaceutical for treating an LPA-related disease, disorder or condition, comprising a compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 3.

5. The LPA-related disease, disorder or condition is １ The pharmaceutical composition according to claim 4, which is for a disease associated with rheumatoid arthritis.

6. The pharmaceutical composition according to claim 4 or 5, wherein the LPA-related disease, disorder or condition is fibrosis, transplant rejection, cancer, osteoporosis or an inflammatory disorder.

7. The pharmaceutical composition according to claim 6, wherein the fibrosis is pulmonary fibrosis, liver fibrosis, kidney fibrosis, cardiac fibrosis, skin fibrosis, eye fibrosis or pancreatic fibrosis.

8. The pharmaceutical composition of claim 6, wherein the cancer is cancer of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gallbladder, reproductive organs, urogenital organs, head, kidney, larynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testicle or thyroid gland.

9. The pharmaceutical composition according to claim 4 or 5, wherein the LPA-related disease, disorder or condition is idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, systemic sclerosis, COVID-19, chronic obstructive pulmonary disease (COPD), neuroinflammation or multiple sclerosis.

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