Compounds and compositions for treating symptoms associated with LPA receptor activity

Abstract

The present disclosure provides a compound of formula (I): The present invention relates to an LPA antagonist, which is a compound represented by the formula (TIFF2023546742000450.tif35119) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutical composition containing the same.

Description

[Technical Field]

[0001] This application describes LPA antagonists and pharmaceutical compositions comprising the compounds disclosed herein. Methods for treating LPA-related diseases, disorders, and symptoms are also provided. [Background technology]

[0002] Various lipid mediators, including eicosanoids and platelet-activating factor (PAF), are produced from the cell membrane by the activity of phospholipases. Lysophospholipids are a type of these membrane-derived physiologically active lipid mediators, and include lysophosphatidic acid (LPA). LPA is not a single molecule, but rather an aggregate of endogenous structural variants containing fatty acids with variable chain length and saturation (Fujiwara et al., J Biol. Chem., 2005, 280, 35038-35050). The structural backbone of LPA is derived from glycerol-based phospholipids such as phosphatidylcholine (PC) or phosphatidic acid (PA), and its general structural formula is: [ka] [In the formula, R is an acyl, alkyl, or alkenyl.] As shown, LPA includes, for example, lysophosphatidic acid (1-acylhydroxy-sn-glycero-3-phosphate; LPA), sphingosine 1-phosphate (SIP), lysophosphatidylcholine (LPC), and sphingosylphosphorylcholine (SPC).

[0003] LPA influences cellular functions, including cell proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. These functions affect numerous biological processes, including neurogenesis, angiogenesis, injury healing, immunity, and carcinogenesis. LPA has a role as a bioeffector molecule and exhibits a wide range of physiological effects, including, but is not limited to, effects on blood pressure, platelet activation, and smooth muscle contraction, as well as various cellular actions, including cell proliferation, cell rounding, neurite retraction, actin stress fiber formation, and cell migration. The effects of LPA are primarily receptor-mediated. Activation of LPA receptors (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) at LPA mediates a series of downstream signaling cascades.

[0004] Thus, antagonistic effects on LPA receptors (such as LPA1 receptors) may be useful in treating various disorders, including fibrosis such as pulmonary fibrosis, hepatic fibrosis, renal fibrosis, arterial fibrosis, and systemic sclerosis, and thus diseases resulting from fibrosis (for example, pulmonary fibrosis, e.g., idiopathic pulmonary fibrosis (IPF), hepatic fibrosis including non-alcoholic steatohepatitis (NASH), renal fibrosis such as diabetic nephropathy, and systemic sclerosis-scleroderma). [Overview of the project]

[0005] This application describes LPA antagonists and pharmaceutical compositions comprising the compounds disclosed herein. Methods for treating LPA-related diseases, disorders, and symptoms are also provided.

[0006] Therefore, equation (I): [ka] [In formula: L 1 teeth, · Joint; and ·C 1-6 Alkylene (1-6 R a (May be replaced as desired) Selected from the group consisting of; R 1 Rb ; C 2-6 Alkenyl (1 to 6 Rs a which may be optionally substituted); and C 2-6 Alkynyl (1 to 6 Rs a which may be optionally substituted) selected from the group consisting of; Ar 1 is · C 6-10 Aryl (1 to 4 of each being, R c1 and -(L b ) b -R b independently selected from the group consisting of, and may be optionally substituted with substituents); and · Heteroaryl (containing 5 to 10 ring atoms, 1 to 4 of which ring atoms are each independently selected from the group consisting of N, N(H), N(R d )), O, and S, where R c1 and -(L b ) b -R b and may be optionally substituted with 1 to 4 substituents independently selected from the group consisting of) selected from the group consisting of; Ar 2 is · C 6-10 Arylene (1 to 4 Rs c2 which may be optionally substituted); and · Heteroarylene (containing 5 to 10 ring atoms, 1 to 4 of which ring atoms are each independently selected from the group consisting of N, N(H), N(R d )), O, and S, and may be optionally substituted with 1 to 4 Rs c2 ) selected from the group consisting of; n is 0 or 1; R 3a and R 3b are independently H, -halo, C 1-6 alkyl, or C 1-4 haloalkyl; or ​​​3b Each of them, together with the carbon atom to which it is bonded, C 3-6 Forms a cycloalkyl group; R a Each time it appears, -OH;-HALO;-NR e R f ;C 1-4 Alkoxy; C 1-4 Haloalkoxy;-C(=O)O(C 1-4 Alkyl);-C(=O)(C 1-4 alkyl);-C(=O)OH;-CONR'R'';-S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 Independently selected from the group consisting of alkyl and cyano; R b Each time it appears, ·C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl (each of which contains 1 to 4 R g This may be replaced as desired); Heterocyclyl or heterocycloalkenyl (containing 3 to 10 ring atoms, of which 1 to 3 are heteroatoms, each being N, N(H), N(R) d ), O, and S(O) 0-2 Independently selected from the group consisting of, the heterocyclyl or heterocycloalkenyl has 1 to 4 R g This may be replaced as desired); • Heteroaryl (contains 5 to 10 ring atoms, of which 1 to 4 are heteroatoms, each being N, N(H), and N(R) d ), O, and S(O) 0-2 Independently selected from the group consisting of, its heteroaryl is 1 to 4 R g This may be replaced as desired); and ·C 6-10 Aryl (1 to 4 R g (May be replaced as desired) Selected independently from the group consisting of; b is 0, 1, 2, or 3; L b Each time it appears, C1-3 alkylene; -N(H)-; N(R d ); -O-; -S-; C(=O); and S(O) 1-2 selected from the group consisting of; R c1 and R c2 each time it appears, halo; cyano; C 1-10 alkyl (optionally substituted by independently selected R a in the range of 1 to 6); C 2-6 alkenyl; C 2-6 alkynyl; C 1-4 alkoxy; C 1-4 haloalkoxy; -S(O) 0-2 (C 1-4 alkyl); -NR e R f ; -OH; -S(O) 1-2 NR’R’’; -NO2; -C(=O)(C 1-10 alkyl); -C(=O)O(C 1-4 alkyl); -C(=O)OH; and -C(=O)NR’R’’ independently selected from the group consisting of; R d each time it appears, C 1-6 alkyl (optionally substituted by independently selected R a in the range of 1 to 3); -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CONR’R’’; -S(O) 1-2 NR’R’’; -S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 alkoxy independently selected from the group consisting of; R e and R f each time it appears, H; C 1-6 alkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CONR’R’’; -S(O) 1-2 NR’R’’; -S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4independently selected from the group consisting of alkoxy; R g each time it appears, halo; cyano; C 1-6 alkyl; C 1-6 haloalkyl; C 1-4 alkoxy; C 1-4 haloalkoxy; -OH; and independently selected from the group consisting of NR’R’’; and R’ and R’’ each time they appear, H; -OH; and C 1-4 independently selected from the group consisting of alkyl] A compound represented by, or a pharmaceutically acceptable salt thereof, is provided herein.

[0007] Also provided herein is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0008] Also provided herein is a method for treating or preventing in a subject that needs treatment or prevention of an LPA-related disease, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) (e.g., formula I-A, I-1, I-2, or I-3), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, the LPA-related disease is an LPA1-related disease.

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

[0010] In some embodiments, the LPA-related disease is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, and systemic sclerosis.

[0011] Furthermore, this specification provides a method for treating or preventing fibrosis in a subject requiring treatment or prevention, comprising administering a therapeutically effective amount of a compound of formula (I) (e.g., a compound of formula IA, I-1, I-2, or I-3), a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, to the subject.

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

[0013] All publications, patents, and patent applications referenced herein are incorporated herein by attribution to the same extent that each individual publication, patent, or patent application is specifically and individually indicated as being incorporated herein by attribution. To the extent that publications, patents, or patent applications incorporated herein by attribution conflict with any disclosures contained herein, this specification takes precedence over and / or takes precedence over such conflicting material.

[0014] Other features and advantages of the present invention will be apparent from the following detailed description and drawings, as well as from the claims. [Modes for carrying out the invention]

[0015] This specification provides LPA antagonists for use in the management of fibrosis and other conditions in which inactivation or reduction of LPA activity is useful.

[0016] definition Where numerical values ​​are given as a range, such disclosure will be understood to encompass disclosures of all possible subranges within that range, as well as disclosures of specific numerical values ​​within that range, regardless of whether specific numerical values ​​or subranges are explicitly stated.

[0017] As used herein, the terms "halo" or "halogen" refer to -F (sometimes referred to herein as "fluoro"), -Cl (sometimes referred to herein as "chloro"), -Br (sometimes referred to herein as "bromo"), and -I (sometimes referred to herein as "iodine").

[0018] As used herein, the term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon group containing a specified number of carbon atoms. For example, "C 1-6 "Alkyl" refers to a monovalent saturated hydrocarbon group having 1 to 6 carbon atoms, either linear or branched. Non-exclusive examples of alkyl groups include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, neopentyl, and hexyl.

[0019] As used herein, the term "alkylene" means a divalent alkyl group containing a specified number of carbon atoms. For example, "C 1-3 "Alkylene" refers to a divalent alkyl group having 1 to 3 carbon atoms (for example, -CH2-, -CH(CH3)-, -CH2CH2-, or -CH2CH2CH2-).

[0020] As used herein, the term "alkenyl" refers to a linear or branched monounsaturated hydrocarbon chain containing a specified number of carbon atoms. For example, "C 2-6 An "alkenyl" is a monounsaturated hydrocarbon chain consisting of 2 to 6 carbon atoms, either straight or branched. Non-exclusive examples of alkenyls include ethenyl, propenyl, butenyl, and pentenyl.

[0021] As used herein, the term "alkynyl" refers to a straight or branched diunsaturated hydrocarbon chain containing a specified number of carbon atoms. For example, "C 2-6 An "alkynyl" is a straight or branched diunsaturated hydrocarbon chain having 2 to 6 carbon atoms. Non-exclusive examples of alkynyls include ethynyl, propynyl, butynyl, or pentynyl.

[0022] As used herein, the term "haloalkyl" means an alkyl group as defined above, in which one or more hydrogen atoms are replaced by one or more halogen atoms. Non-limiting examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, chloromethyl, dichloromethyl, chloroethyl, trichloroethyl, bromomethyl, and iodomethyl.

[0023] As used herein, the term "alkoxy" means an -O-alkyl group in which the group is located on an oxygen atom. For example, "C 1-6 "alkoxy" is -O-(C 1-6 A haloalkoxy is an alkyl group in which the group is located on an oxygen atom. Examples of alkoxys include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. Therefore, as used herein, the term "haloalkoxy" refers to an O-haloalkyl group in which the group is located on an oxygen atom.

[0024] As used herein, the term "alkynyl" means an acyclic hydrocarbon chain, which may be linear or branched, having one or more carbon-carbon triple bonds. The alkynyl group contains a specified number of carbon atoms. For example, C 2-6 This indicates that the group may have 2 to 6 carbon atoms (including those at both ends). The alkynyl group can be unsubstituted or substituted with one or more substituents.

[0025] As used herein, the term "aryl" means a mono-, di-, tri-, or polycyclic group having 6 to 20 carbon atoms, wherein at least one ring in the system is aromatic (e.g., a monocyclic, bicyclic, or tricyclic aromatic ring system of 6-membered carbon atoms; and 0, 1, 2, 3, or 4 atoms of each ring may be substituted with substituents). Examples of aryl groups include phenyl, naphthyl, and tetrahydronaphthyl.

[0026] As used herein, the term "cycloalkyl" means a cyclic saturated hydrocarbon group having, for example, 3 to 20 ring carbons, preferably 3 to 16 ring carbons, more preferably 3 to 12 ring carbons, or 3 to 10 ring carbons, or 3 to 6 ring carbons, where the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A cycloalkyl group may include multiple condensed and / or crosslinked rings. Non-limiting examples of condensed / crosslinked cycloalkyls include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, etc. Cycloalkyls also encompass spirocyclic rings (e.g., spirocyclic bicycles in which two rings are positively connected by one atom). Non-exclusive examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, etc. In this context, the term "saturated" means that only single bonds exist between the constituent carbon atoms.

[0027] As used herein, the term "cycloalkenyl" means a partially unsaturated cyclic hydrocarbon group having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, more preferably 3 to 12 ring carbons, or 3 to 10 ring carbons, or 3 to 6 ring carbons, wherein the cycloalkenyl group may be optionally substituted. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. As a partially unsaturated cyclic hydrocarbon group, the degree of unsaturation of the cycloalkenyl group can be arbitrary, provided that one or more double bonds are present in the ring, none of the rings in the cyclic system are aromatic, and the cycloalkenyl group as a whole is not completely saturated. Cycloalkenyls may include multiple condensed and / or crosslinked and / or spirocyclic rings.

[0028] As used herein, the term "heteroaryl" means a ring group containing heteroatoms, having 5 to 20 ring atoms, or also 5, 6, 9, 10, or 14 ring atoms; a monocyclic, dicyclic, tricyclic, or polycyclic group sharing 6, 10, or 14 π electrons in a cyclic array, wherein at least one ring of the system is aromatic, and at least one ring of the system is independently selected from the group consisting of 1 or more N, O, and S atoms (however, it is not required that the ring contain a single heteroatom, such as tetrahydroisoquinolinyl or tetrahydroquinolinyl). The heteroaryl group may be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridadinyl, triazinyl, thiazolyl, benzothienyl, benzoxadiazolyl, benzofuranil, benzimidazolyl, benzotriazolyl, sinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthylidinyl, purinyl, thienopyridinyl, pyrido[2,3 -d]pyrimidinyl, pyrrolo[2,3-b]pyrimidinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyrimidinyl, pyrazolo[3,4-b]pyrimidinyl, pyrazolo[3,4-c]pyrimidinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyrimidinyl, tetrazolyl, chroman, 2,3-dihydrobenzo[b][1,4]dioxin, benzo[d][1,3]dioxol, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiine, isoindoline, etc. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.

[0029] As used herein, the term "heterocyclyl" means a saturated monocyclic, bicyclic, tricyclic, or polycyclic ring system having 3 to 16 ring atoms, with 1 to 3 heteroatoms if monocyclic, 1 to 6 heteroatoms if bicyclic, or 1 to 9 heteroatoms if tricyclic or polycyclic (e.g., a 5 to 8-membered monocyclic, an 8 to 12-membered bicyclic, or an 11 to 14-membered tricyclic ring system), where the heteroatoms are selected from O, N, or S (e.g., if monocyclic, bicyclic, or tricyclic, containing a carbon atom and 1 to 3, 1 to 6, or 1 to 9 N, O, or S heteroatoms, respectively), where 0, 1, 2, or 3 atoms in each ring may be substituted with substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl. Heterocyclyls may contain multiple condensed and bridged rings. Non-limiting examples of condensed / crosslinked heterocyclyls include 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo [3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, etc. Heterocyclines also include spirocyclic rings (e.g., spirocyclic dicyclic rings in which two rings are connected by only one atom).Non-restrictive examples of spirocyclic heterocyclines include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, and 2-oxaspiro[2 This includes pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane, etc. The term "saturated" as used in this context means that there are only single bonds between the constituent ring atoms, and other available valencies are occupied by hydrogen and / or other substituents as defined herein.

[0030] As used herein, the term "heterocycloalkenyl" means a partially unsaturated cyclic ring system having 3 to 16 ring atoms, having 1 to 3 heteroatoms if monocyclic, 1 to 6 heteroatoms if dicyclic, or 1 to 9 heteroatoms if tricyclic or polycyclic (e.g., a 5 to 8-membered monocyclic, an 8 to 12-membered dicyclic, or an 11 to 14-membered tricyclic), where the heteroatoms are selected from O, N, or S (e.g., if monocyclic, dicyclic, or tricyclic, including a carbon atom and 1 to 3, 1 to 6, or 1 to 9 N, O, or S heteroatoms, respectively), where 0, 1, 2, or 3 atoms in each ring may be substituted with substituents. Examples of heterocycloalkenyl groups include, but are not limited to, tetrahydropyridyl, dihydropyrazine, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, and dihydrothiophenyl. As a partially unsaturated cyclic group, the heterocycloalkenyl group can have any degree of unsaturation, provided that one or more double bonds are present in the ring, none of the rings in the cyclic system are aromatic, and the heterocycloalkenyl group as a whole is not completely saturated. The heterocycloalkenyl may include multiple condensed and / or bridged and / or spirocyclic rings.

[0031] Where used herein, [ka] This indicates a desirable single or double bond, as permissible by valency. When used herein, [ka] This indicates the bond point with the parent molecule.

[0032] As used herein, the term “compound” includes all stereoisomers, geometric isomers, tautomers, and isotopes having the structure shown. A compound identified by name or structure as a specific tautomer in this specification includes other tautomers unless otherwise specified. As used herein, the term "tautomer" refers to a compound whose structure differs significantly in the arrangement of atoms, but which readily and rapidly exists in equilibrium. The compounds provided herein may be described as different tautomers, and if a compound has tautomer forms, all tautomer forms are considered to be within the scope of this disclosure. The naming of the compounds should be understood not to exclude any of the tautomers.

[0033] As used herein, the term "carboxylic acid bioequivalent" means a group of compounds that have chemical and physical similarities to carboxylic acids, producing biological properties broadly similar to those of carboxylic acids (see Lipinski, Annual Reports in Medicinal Chemistry, 1986, 21, p283 "Bioisosterism In Drug Design"; Yun, Hwahak Sekye, 1993, pp. 33, 576-579 "Application Of Bioisosterism To New Drug Design"; Zhao, Huaxue Tongbao, 1995, pp. 34-38 25 "Bioisosteric Replacement And Development Of Lead Compounds In Drug Design"; Graham, Theochem, 1995, pp. 343, 105-109 "Theoretical Studies Applied To Drug Design: a initio Electronic Distributions In Bioisosteres"). Examples of suitable carboxylic acid bioequivalents include sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl, 3-hydroxyisoxazolyl and 3-hydroxy-1-methylpyrazolyl, heterocyclic phenyl, -CONH2, -CONHSO2Me, or [ka] Examples of amides include the following.

[0034] As used herein, the term “LPA-related disease” encompasses, unless limited, diseases, disorders, or symptoms in which activation of at least one LPA receptor by LPA contributes to the symptomatic or progression of the disease, disorder, or symptom. These diseases, disorders, or symptoms may arise from one or more genetic, ectopic, immunological, infectious, metabolic, oncological, toxic, surgical, and / or traumatic etiologies. Accordingly, the pathophysiology and / or signs and / or progression of the disease, disorder, or symptom may be altered by inhibiting the signaling of one or more lysophosphatidic acid (LPA) receptors (e.g., LPA1, LPA2, LPA3, LPA4, LPA5, or LPA6 receptors). In some embodiments, the LPA-related disease is an LPA1-related disease, where the pathophysiology and / or signs and / or progression of the disease, disorder, or symptom may be altered by modulating the signaling of the LPA1 receptor.

[0035] As used herein, the terms “fibrosis” or “fibrotic disorder” refer to conditions associated with the abnormal accumulation of cells and / or fibronectin and / or collagen, and / or increased recruitment of fibroblasts, and include, but are not limited to, fibrosis of individual organs or tissues such as the heart, kidneys, liver, joints, lungs, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal system, and gastrointestinal tract.

[0036] As used herein, the term “pharmaceutically acceptable” means that the compound, its salt, or composition is chemically and / or toxicologically compatible with the other components of the formulation and / or with the subject being treated therewith.

[0037] As used herein, the term “therapeutic compound” means, unless otherwise limited, all compounds of formula (I), or their pharmaceutically acceptable salts or solvates (e.g., any one of the compounds of formula IA, I-1, I-2, or I-3, or their pharmaceutically acceptable salts or solvates), and any composition (e.g., a pharmaceutical composition) (where the compound of formula (I), or its pharmaceutically acceptable salt or solvate (e.g., any one of the compounds of formula IA, I-1, I-2, or I-3, or its pharmaceutically acceptable salt or solvate) is an ingredient of the composition).

[0038] The terms "administer" or "to administer" refer to a method of giving a compound or pharmaceutical composition in dosage to vertebrates or invertebrates, including mammals, birds, fish, or amphibians. The method of administration may vary depending on various factors, such as the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

[0039] As used herein, “effective amount,” “effective dose,” or “pharmaceutically effective amount” means a sufficient amount of a chemical entity (e.g., a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof)) that would, to some extent, alleviate one or more signs of a disease or symptom being administered and treated, and may include curing the disease. “Cure” means the absence of active signs of the disease. Outcomes include a reduction and / or alleviation of the signs, symptoms or causes of the disease, or any other desired change in the biological system. For example, an “effective amount” for therapeutic use is the amount of a composition containing a compound as disclosed herein that is required to obtain a clinically significant reduction in the signs of the disease. The appropriate “effective” amount in any individual case is determined using any appropriate technique, such as a dose-escalation study. In some embodiments, the “therapeutably effective amount” of a compound provided herein means the amount of the compound that is effective as monotherapy or in combination therapy.

[0040] The terms “excipient” or “pharmaceutically acceptable excipient” mean a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, carrier, solvent or encapsulating material. In some embodiments, each component is “pharmaceutically acceptable” in the sense that it is compatible with other components of a pharmaceutical formulation, free from excessive toxicity, irritation, allergic reactions, immunogenicity or other problems or complications, and suitable for use in contact with human and animal tissues or organs, with an equal balance of reasonable benefits and risks. For example, see Remington: The Science and Practice of Pharmacy, 21st edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th edition; Rowe et al. (eds.); The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd edition; Ash and Ash (eds.); Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd edition; Gibson (ed.); CRC Press LLC: Boca Raton, FL, 2009.

[0041] The term "pharmaceutical composition" means a mixture of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof), as provided herein, with other chemical components such as carriers, stabilizers, diluents, dispersants, anti-precipitation agents, and / or thickeners (collectively referred to herein as "excipients"). Pharmaceutical compositions facilitate the administration of compounds to living organisms. There are several techniques in the art for administering compounds, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0042] In the context of treating a disease, disorder or symptom, the terms “treat,” “treating,” and “treatment” include alleviating or eliminating a disease, disorder or symptom, or one or more signs associated with such disease, disorder or symptom; or slowing the progression, spread, or worsening of a disease, disorder or symptom, or one or more signs thereof. As used herein, the term “prevent” means to prevent, in whole or in part, the onset, recurrence or spread of any disease, disorder or symptom, or sign thereof, as described herein.

[0043] As used herein, the terms “subject,” “patient,” or “individual” are interchangeable and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the terms refer to a subject, particularly a mammalian subject, for whom diagnosis, prognosis, or treatment is desirable or required. In some embodiments, the subject is human. In some embodiments, the subject is experiencing and / or exhibiting signs of at least one disease, disorder, or condition for which treatment and / or prevention is desired.

[0044] The terms "treatment regimen" and "administration regimen" are used interchangeably to refer to the dosage and timing of administration of various therapeutic agents in combination. As used herein, the term "pharmaceutical combination" means a pharmaceutical treatment obtained by mixing or combining two or more active ingredients, and includes both combinations in which the active ingredients are immobilized and those in which they are not.

[0045] As used herein, the term “combination therapy” means a regimen of administration of two different therapeutic activators (i.e., combination components or combination partners), which are administered together or separately by a healthcare professional or in accordance with a regulatory authority as provided herein.

[0046] As used herein, the terms “adjust,” “adjusting,” or “adjust” mean control or regulation (e.g., increase or decrease), and may include, for example, agonism, partial agonism, or antagonistism. The ability of test compounds to act as inhibitors of the LGA receptor can be demonstrated by assays known in the art. The activity of compounds and compositions provided herein as LGA receptor inhibitors can be assayed in vitro, in vivo, or in cell lines.

[0047] For example, Chinese hamster ovary cells overexpressing human LPA1 can be plated overnight in DMEM / F12 medium in a microplate (15,000 cells / well). After overnight culture, the cells are loaded with a calcium indicator dye at 37°C for 30 minutes. Next, 30 minutes before the assay, the cells are brought to equilibrium at room temperature. The test compound, solubilized in DMSO, is transferred to a multi-well unbound surface plate and diluted with assay buffer (e.g., IX HBSS with added calcium / magnesium, 20 mM HEPES, and 0.1% free acid-free BSA) to a final concentration of 0.5% DMSO. The diluted compound is added to the cells at a final concentration ranging from 0.08 nM to 5 mM, then incubated at room temperature for 20 minutes, at which point LPA is added at a final concentration of 10 nM to stimulate the cells. The IC50 value of the compound is defined as the concentration of the test compound that inhibits 50% of the calcium flux induced by LPA alone. The IC50 value can be determined by fitting the data to a 4-parameter logistic equation.

[0048] In another example, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., any one of the compounds of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof), as provided herein, is orally (po) administered to female CD-I mice two hours before LPA challenge. The mice are then administered LPA (2 pg / pL) (0.15 mL) in 0.1% BSA / PBS via the tail vein (IV). Exactly two minutes after LPA challenge, the mice are killed by decapitation and blood is collected from the trunk. These samples are comprehensively centrifuged, and individual 75 pL samples are frozen at -20°C until histamine assays are performed. Plasma histamine analysis can be performed by the standard EIA (Enzyme Immunoassay) method. The plasma samples are thawed and diluted 1:30 with 0.1% BSA in PBS. The EIA protocols for histamine analysis described above can be used for this assay.

[0049] LPA acts as a bioeffector molecule and possesses a wide variety of physiological effects, including those on blood pressure, platelet activation, and smooth muscle contraction, as well as various cellular actions such as cell proliferation, cell rounding, neurite retraction, actin stress filament formation, and cell migration. These effects are primarily mediated by receptors.

[0050] Activation of LPA receptors (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) at LPA mediates a series of downstream signaling cascades. In non-limited examples, these include activation of mitogen-activated protein kinase (MAPK), inhibition / activation of adenylyl cyclase (AC), and activation / Ca2 lipase C (PLC). 2+ This includes mobilization, arachidonic acid release, Akt / PKB activation, and activation of low molecular weight GTPases, Rho, ROCK, Rae, and Ras. Further pathways affected by LPA receptor activation include, for example, cyclic adenosine monophosphate (cAMP), cell division cycle 42 / GTP-binding protein (Cdc42), oncogenic serine / threonine protein kinase Raf (c-RAF), oncogenic tyrosine protein kinase Src (c-src), extracellular signal-regulated kinase (ERK), focal adhesion kinase (FAK), guanine nucleotide exchange factor (GEF), glycogen synthase kinase 3b (GSK3b), c-jun amino-terminal kinase (JNK), MEK, myosin light chain II (MLC II), nuclear factor kB (NF-kB), activation of N-methyl-D-aspartate (NMDA) receptor, phosphatidylinositol 3-kinase (PBK), protein kinase A (PKA), protein kinase C (PKC), and ms-related C3 botulinum toxin substrate 1 (RAC1). Almost all mammalian cells, tissues, and organs co-express several LPA receptor subtypes, indicating that LPA receptors perform coordinated signaling. LPA1, LPA2, and LPA3 share high similarity in their amino acid sequences.

[0051] LPA1 (formerly known as VZG-1 / EDG-2 / mrecl.3) binds to three types of proteins: Gi / o, Gq, and G12 / 13. Through the activation of these G proteins, LPA can, for example, stimulate cell proliferation, activation of serum response elements (SREs), activation of mitogen-activated protein kinases (MAPKs), inhibition of adenylyl cyclase (AC), activation of phospholipase C (PLC), and Ca 2+ LPA1 triggers a series of cellular responses, including the recruitment of Akt, activation of Rho, and activation of pharmacokinetics.

[0052] LPA1 expression is observed in mouse testes, brain, heart, lungs, small intestine, stomach, spleen, thymus, and skeletal muscle. Similarly, LPA1 is expressed in human tissues such as the brain, heart, lungs, placenta, colon, small intestine, prostate, testes, ovaries, pancreas, spleen, kidneys, skeletal muscle, and thymus.

[0053] LPA2(EDG-4) also binds to three types of G proteins, Gi / o, Gq, and G12 / 13, and mediates LPA-induced cellular signaling. LPA2 expression is observed in the testes, kidneys, lungs, thymus, spleen, and stomach of adult mice, and in human testes, pancreas, prostate, thymus, spleen, and peripheral blood leukocytes. LPA2 expression is upregulated in various cancer cell lines, and several human LPA2 transcription variants with mutations in the 3'-untranslated region have been observed.

[0054] LPA3 activates PLC and Ca 2+ LPA3 can mediate multifaceted LPA-induced signaling, including recruitment, AC inhibition / activation, and MAPK activation. Overexpression of LPA3 in neuroblastoma cells results in neurite outgrowth. LPA3 expression is observed in the testes, kidneys, lungs, small intestine, heart, thymus, and brain of adult mice. In humans, its expression has been found in the heart, pancreas, prostate, testes, lungs, ovaries, and brain (frontal cortex, hippocampus, and amygdala).

[0055] LPA4 (p2y9 / GPR23) has a different sequence from LPA1, LPA2, and LPA3 and is similar to the platelet-activating factor (PAF) receptor. LPA4 is involved in LPA-induced Ca 2+ It mediates the recruitment and accumulation of cAMP, as well as functional binding with G protein G for AC activation and binding with other G proteins. The LPA4 gene is expressed in the ovaries, pancreas, thymus, kidneys, and skeletal muscle.

[0056] LPA5 (GPR92) is a member of the purinocluster of GPCRs and is structurally most closely related to LPA4. LPA5 is expressed in the human heart, placenta, spleen, brain, lungs, and intestines. LPA is also expressed at extremely high levels in the CD8+ lymphocyte compartment of the gastrointestinal tract.

[0057] LPA6(p2y5) is a member of the GPCR prino cluster and is structurally most closely related to LPA4. LPA6 is an LPA receptor that binds to the Gl2 / 13-Rho signaling pathway and is expressed in the inner root sheath of human hair follicles.

[0058] compound In one embodiment, this disclosure relates to formula (I): [ka] [In formula: L 1 teeth: · Joint; and ·C 1-6 Alkylene (1-6 R a (May be replaced as desired) Selected from the group consisting of; R 1 R b ;C 2-6 Alkenyl (1-6 R a This may be replaced as desired; and C 2-6 Alkinyl (1-6 R a Selected from the group consisting of (which may be substituted as desired); Ar1 teeth: ·C 6-10 Aryl (1 to 4, each of which is R) c1 and -(L b ) b -R b A substituent, which may be optionally substituted, is independently selected from the group consisting of; and • Heteroaryl (containing 5-10 ring atoms, where each of the 1-4 ring atoms is N, N(H), N(R) d A ring heteroatom independently selected from the group consisting of ), O, and S, wherein the heteroaryl is R c1 and -(L b ) b -R b (Each of the substituents may be optionally substituted with 1 to 4 substituents independently selected from the group consisting of the above.) Selected from the group consisting of; Ar 2 teeth: ·C 6-10 Arrine (1 to 4 R c2 This may be replaced as desired); and Heteroarylenes (containing 5-10 ring atoms, where each of the 1-4 ring atoms is N, N(H), N(R) d A ring heteroatom independently selected from the group consisting of ), O, and S, comprising 1 to 4 R c2 (May be replaced as desired) Selected from the group consisting of; n is either 0 or 1; R 3a and R 3b These are independently H, -halo, and C. 1-6 Alkyl, or C 1-4 It is a haloalkyl; or R 3a and R 3b Each of them, together with the carbon atom to which it is bonded, C 3-6 Forms a cycloalkyl group; R a Each time it appears, -OH;-HALO;-NR e R f ;C 1-4 Alkoxy; C1-4 Haloalkoxy;-C(=O)O(C 1-4 Alkyl);-C(=O)(C 1-4 alkyl);-C(=O)OH;-CONR'R'';-S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 Independently selected from the group consisting of alkyl and cyano; R b Each time it appears, ·C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl (each of which contains 1 to 4 R g This may be replaced as desired); Heterocyclyl or heterocycloalkenyl (containing 3 to 10 ring atoms, where 1 to 3 ring atoms are N, N(H), and N(R) respectively) d ), O, and S(O) 0-2 Independently selected from the group consisting of 1 to 4 R g This may be replaced as desired); • Heteroaryl (contains 5 to 10 ring atoms, where 1 to 4 ring atoms are heteroatoms, each being N, N(H), and N(R) d ), O, and S(O) 0-2 Independently selected from the group consisting of 1 to 4 R g This may be replaced as desired); and ·C 6-10 Aryl (1 to 4 R g (May be replaced as desired) Selected independently from the group consisting of; b is 0, 1, 2, or 3; L b Each time it appears, C 1-3 Alkilen;-N(H)-;N(R) d )-;-O-;-S-;C(=O);and S(O) 1-2 Selected from the group consisting of; R c1 and R c2 Each time it appears, Halo;Cyan;C 1-10 Alkyl (1 to 6 independently selected R aThis may be replaced as desired); C 2-6 Alkenil; C 2-6 Alkinyl; C 1-4 Alkoxy; C 1-4 Haloalkoxy;-S(O) 0-2 (C 1-4 Alkyl);-NR e R f ;-OH;-S(O) 1-2 NR'R'';-NO2;-C(=O)(C 1-10 Alkyl);-C(=O)O(C 1-4 Independently selected from the group consisting of alkyl;-C(=O)OH; and-C(=O)NR'R''; R d Each time it appears, C 1-6 Alkyl (1 to 3 independently selected R a (This may be substituted as desired);-C(O)(C 1-4 Alkyl);-C(O)O(C 1-4 alkyl);-CONR'R'';-S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 alkyl);-OH;and C 1-4 Independently selected from the group consisting of alkoxys; R e and R f Each time it appears, H;C 1-6 Alkyl;-C(O)(C 1-4 Alkyl);-C(O)O(C 1-4 alkyl);-CONR'R'';-S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 alkyl);-OH;and C 1-4 Independently selected from the group consisting of alkoxys; and R g Each time it appears, Halo;Cyan;C 1-6 Alkyl; C 1-6 Haloalkyl; C 1-4 Alkoxy; C 1-4 Independently selected from the group consisting of haloalkoxys;-OH; and NR'R''; and R' and R'' each time they appear, H;-OH; and C 1-4 [Independently selected from the group consisting of alkyl groups] It is characterized by the compound shown or a pharmaceutically acceptable salt thereof.

[0059] In one embodiment, this disclosure relates to formula (Ia): [ka] [In formula: L 1 teeth: · Joint; and ·C 1-6 Alkylene (1-6 R a (May be replaced as desired) Selected from the group consisting of; R 1 R b ;C 1-6 Alkyl (1 to 6 R a This may be replaced as desired); C 2-6 Alkenyl (1-6 R a This may be replaced as desired; and C 2-6 Alkinyl (1-6 R a Selected from the group consisting of (which may be substituted as desired); Ar 1 teeth: ·C 6-10 Aryl (1 to 4, each of which is R) c1 and -(L b ) b -R b A substituent, which may be optionally substituted, is independently selected from the group consisting of; and • Heteroaryl (containing 5-10 ring atoms, where each of the 1-4 ring atoms is N, N(H), N(R) d A ring heteroatom independently selected from the group consisting of ), O, and S, wherein the heteroaryl is R c1 and -(L b ) b -R b (Each of the substituents may be optionally substituted with 1 to 4 substituents independently selected from the group consisting of the above.) Selected from the group consisting of; Ar 2 teeth: ·C 6-10 Arirene (R c2 and -(L b ) b -R b Each of 1 to 4 substituents independently selected from the group consisting of the above may be optionally substituted); and Heteroarylenes (containing 5-10 ring atoms, where each of the 1-4 ring atoms is N, N(H), N(R) d A ring heteroatom independently selected from the group consisting of ), O, and S, wherein the heteroarylene is R c2 and -(L b ) b -R b (Each of the substituents may be optionally substituted with 1 to 4 substituents independently selected from the group consisting of the above.) Selected from the group consisting of; R 2 is a -C(=O)OH or carboxylic acid biological equivalent; n is either 0 or 1; R 3a and R 3b These are independently H, -halo, and C. 1-6 Alkyl, or C 1-4 It is a haloalkyl; or R 3a and R 3b Each of them, together with the carbon atom to which it is bonded, C 3-6 Forms a cycloalkyl group; R a Each time it appears, -OH;-HALO;-NR e R f ;C 1-4 Alkoxy; C 1-4 Haloalkoxy;-C(=O)O(C 1-4 Alkyl);-C(=O)(C 1-4 alkyl);-C(=O)OH;-CONR'R'';-S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 Independently selected from the group consisting of alkyl and cyano; R b Each time it appears, ·C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl (each of which contains 1 to 4 R g This may be replaced as desired); Heterocyclyl or heterocycloalkenyl (containing 3 to 10 ring atoms, with 1 to 3 ring atoms each being N, N(H), and N(R) d ), O, and S(O) 0-2 Independently selected from the group consisting of 1 to 4 R g This may be replaced as desired); • Heteroaryl (contains 5 to 10 ring atoms, where 1 to 4 ring atoms are heteroatoms, each being N, N(H), and N(R) d ), O, and S(O) 0-2 Independently selected from the group consisting of 1 to 4 R g This may be replaced as desired); and ·C 6-10 Aryl (1 to 4 R g (May be replaced as desired) Selected independently from the group consisting of; b is 0, 1, 2, or 3; L b Each time it appears, C 1-3 Alkilen;-N(H)-;N(R) d )-;-O-;-S-;C(=O);and S(O) 1-2 Selected from the group consisting of; R c1 and R c2 Each time it appears, Halo;Cyan;C 1-10 Alkyl (1 to 6 independently selected R a This may be replaced as desired); C 2-6 Alkenil; C 2-6 Alkinyl; C 1-4 Alkoxy; C 1-4 Haloalkoxy;-S(O) 0-2 (C 1-4 Alkyl);-NR e R f ;-OH;-S(O)1-2 NR'R'';-NO2;-C(=O)(C 1-10 Alkyl);-C(=O)O(C 1-4 Independently selected from the group consisting of alkyl;-C(=O)OH; and-C(=O)NR'R''; R d Each time it appears, C 1-6 Alkyl (1 to 3 independently selected R a (This may be substituted as desired);-C(O)(C 1-4 Alkyl);-C(O)O(C 1-4 alkyl);-CONR'R'';-S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 alkyl);-OH;and C 1-4 Independently selected from the group consisting of alkoxys; R e and R f Each time it appears, H;C 1-6 Alkyl;-C(O)(C 1-4 Alkyl);-C(O)O(C 1-4 alkyl);-CONR'R'';-S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 alkyl);-OH;and C 1-4 Independently selected from the group consisting of alkoxys; R g Each time it appears, Halo;Cyan;C 1-6 Alkyl; C 1-6 Haloalkyl; C 1-4 Alkoxy; C 1-4 Independently selected from the group consisting of haloalkoxys;-OH; and NR'R''; and R' and R'' each time they appear, H;-OH; and C 1-4 [Independently selected from the group consisting of alkyl groups] It is characterized by the compound shown or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, the compound of formula (I) is of formula (IA): [ka] It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, the compound of formula (I) is formula (I-Aa): [ka] It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0062] Variable group Ar 1 In some embodiments of formula (I), (Ia), (IA), or (I-Aa), Ar 1 is C 6-10 The aryl group may be optionally substituted with 1 to 4 substituents, each of which is R c1 and -(L b ) b -R b (Selected independently from the group consisting of ).

[0063] In particular, these embodiments are Ar 1 phenyl (which may be optionally substituted with 1 to 4 substituents, each substituent being R c1 and -(L b ) b -R b (Selected independently from the group consisting of ). In a particular embodiment, Ar 1 phenyl (substituted with 1 to 4 substituents, each substituent being R) c1 and -(L b ) b -R b (Selected independently from the group consisting of ). In a particular embodiment, Ar 1 is phenyl (1 to 4 independently selected R c1 (It is replaced by...)

[0064] In a specific embodiment of the above, R c1 Each time it appears, Hello;C 1-6Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Independently selected from the group consisting of haloalkoxys and cyanos.

[0065] In a specific embodiment of the above, R c1 Each time it appears, Hello;C 1-6 Alkyl; C 1-6 Alkyl (substituted by 1 to 6 independently selected halos);-C(=O)(C 1-10 Alkyl); C 1-4 Alkoxy; C 1-4 Independently selected from the group consisting of haloalkoxys and cyanos.

[0066] In the above specific embodiments, -(L b ) b -R b Each time it appears, C is independently selected. 3-6 Cycloalkyl (1-2 R g (This may be substituted as desired.)

[0067] In certain embodiments, Ar 1 teeth [ka] And where m1 is 0, 1, 2, or 3; R Aa and R Ab Each of them operates independently, R c1 and -(L b ) b -R b Selected from the group consisting of

[0068] In certain embodiments of these, R Aa Each time it appears, Hello;C 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C3-6 Cycloalkyl (1-2 R g It is independently selected from the group consisting of (which may be substituted as desired).

[0069] In certain embodiments of these, R Aa Each time it appears, Hello;C 1-6 Alkyl; C 1-6 Alkyl (substituted by 1 to 6 independently selected halos);-C(=O)(C 1-10 Alkyl); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g Selected from the group consisting of (which may be substituted as desired).

[0070] In a particular example, R Aa is C 1-6 Alkyl, for example, C 1-3 It is alkyl. As a non-limiting example of the above-described embodiment, R Aa It can be methyl.

[0071] In a particular example, R Aa is C 1-6 It is an alkyl group (substituted with 1 to 6 independently selected halos). In certain embodiments of these, R Aa is C 1-3 It is alkyl (substituted with 1 to 6 F atoms). As a non-limiting example of the above embodiment, R Aa This could be CF3 or CHF2.

[0072] In a particular example, R Aa This is a halo, for example, -Cl. In a particular example, R Aa is C 3-6 It is a cycloalkyl. As a non-limiting example of the above embodiment, R Aa It may be cyclopropyl. In a particular embodiment, m1 is 2; in a particular embodiment, m1 is 1 or 3, for example, 1; in a particular embodiment, m1 is 0.

[0073] In a particular embodiment, if m1 is 1 or 2, then R that appears in one or both Ab R Aa It attaches to the ring atom in the ortho position relative to the ring atom bonded to it. In a particular example, R Ab Each time it appears, Hello;C 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g It is independently selected from the group consisting of (which may be substituted as desired).

[0074] In a particular example, R Ab Each of them is independent of C 1-4 Alkoxy or C 1-4 It is a haloalkoxy. For example, R Ab Each of them is C 1-4 It could be an alkoxy, such as methoxy. As a non-limiting example, Ar 1 teeth, [ka] It is possible.

[0075] As a further non-limiting example, Ar 1 teeth: [ka] A selection can be made from the group consisting of the following:

[0076] As a further non-limiting example, Ar 1 teeth: [ka] A selection can be made from the group consisting of the following:

[0077] In some embodiments, Ar 1 A heteroaryl compound contains 5 to 10 ring atoms, of which 1 to 4 ring atoms are N, N(H), and N(R). d ), which is a ring heteroatom independently selected from the group consisting of ), O, and S, where the heteroaryl may optionally be substituted with 1 to 4 substituents, each substituent being R c1 and -(L b ) b -R b It is independently selected from the group consisting of [the specified group].

[0078] In certain embodiments, Ar 1 A heteroaryl compound contains 5-6 ring atoms, of which 1-4 ring atoms are N, N(H), and N(R). d ), which is a ring heteroatom independently selected from the group consisting of ), O, and S, where the heteroaryl may optionally be substituted with 1 to 4 substituents, each substituent being R c1 and -(L b ) b -R b It is independently selected from the group consisting of [the specified group].

[0079] In certain embodiments, Ar 1 is a heteroaryl compound (containing 6 ring atoms, of which 1-2 are ring nitrogen atoms), where the heteroaryl compound may optionally be substituted with 1-4 substituents, each substituent being R c1 and -(L b ) b -R b It is independently selected from the group consisting of [the specified group].

[0080] In certain embodiments, Ar 1 Pyridyl (R c1 and -(L b ) b -R b(Optionally, it may be substituted with 1 to 3 substituents selected from the group consisting of ). As a non-limiting example of the above embodiment, Ar 1 is 3-pyridyl(R c1 and -(L b ) b -R b (Optionally, it may be substituted with 1 to 3 substituents selected from the group consisting of the above.)

[0081] Specific embodiment (Ar 1 (When R is a heteroaryl as described above), c1 Each time it appears, Hello;C 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Independently selected from the group consisting of haloalkoxys and cyanos. In a particular embodiment, -(L b ) b -R b Each time it appears, C is independently selected. 3-6 Cycloalkyl (1-2 R g (This may be substituted as desired.)

[0082] In certain embodiments, Ar 1 3-pyridyl (1-3 independently selected C 1-6 (It is substituted with alkyl.) In certain embodiments, Ar 1 3-pyridyl (1-3 independently selected C 1-6 (substituted with alkyl) or Ar 1 4-pyridyl (1-3 independently selected C 1-6 (It is substituted with alkoxy.)

[0083] As a non-limiting example, Ar 1 teeth [ka] It is possible.

[0084] As a further non-limiting example, Ar 1 teeth [ka] is or Ar 1 teeth [ka] That is the case.

[0085] Variable group L 1 In some embodiments of formula (I), (Ia), (IA), or (I-Aa), L 1 This is a joint. In some embodiments of formula (I), (Ia), (IA), or (I-Aa), L 1 is C 1-6 Alkylene (1-6 R a (This may be substituted as desired.) In certain or these embodiments, L 1 is C 1-3 Alkylene (1-6 R a (which may be substituted as desired). In a particular embodiment, L 1 is a non-substituted C 1-3 It is an alkylene. As a non-limiting example of the above-described embodiment, L 1 It can be CH2CH2. Another non-restrictive example is L 1 It could be CH2.

[0086] Variable group R 1 In some embodiments of formula (I), (Ia), (IA), or (I-Aa), R 1 is R b That is the case. In certain embodiments of these, R 1 teeth: ·C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl (each of which contains 1 to 4 R gThis may be replaced as desired); and ·C 6-10 Aryl (1 to 4 R g (May be replaced as desired) Selected from the group consisting of

[0087] In certain embodiments of these, R 1 is C 6-10 Aryl (1 to 4 R g (This may be substituted as desired.) In a particular embodiment, R 1 is 1-2 R g Phenyl (1-4 R) which may be substituted as desired g (which may be substituted as desired). As a non-limiting example of the above embodiments, R 1 It can be an unsubstituted phenyl.

[0088] In a particular example, R 1 is C 8-10 Double ring aryl (1 to 4 R) g (This may be replaced as desired.) Of these, a particular embodiment is R 1 is C 9-10 Biring aryl (1-2 R) g (This may be substituted as desired.) In a particular embodiment, R 1 is indanyl (1-2 R g (which may be substituted as desired). As a non-limiting example of the above embodiments, R 1 teeth [ka] It can be done with 1-2 R g It may be substituted as desired. For example, R 1 teeth [ka] It can be done this way.

[0089] A specific embodiment of formula (I), (Ia), (IA), or (I-Aa) is R 1 is C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl (each of which contains 1 to 4 R g (This may be replaced as desired.) Of these, a particular embodiment is R 1 is C 3-10 Cycloalkyl, with 1 to 4 R g It may be replaced as desired. In certain embodiments, R 1 This is 1-2 R g C may be substituted as desired. 3-6 It is a cycloalkyl group. In a particular embodiment, R 1 It is cyclobutyl or cyclopentyl, each of which contains 1-2 R g These may be substituted as desired, for example, 1-2 R g A cyclopentyl which may be substituted as desired. As a non-limiting example of the above embodiments, R 1 This can be unsubstituted cyclobutyl or cyclopentyl, for example, unsubstituted cyclopentyl.

[0090] In some embodiments of formula (I), (Ia), (IA), or (I-Aa), R 1 is C 2-6 Alkinyl (1-6 R a (This may be replaced as desired.) Of these, a particular embodiment is R 1 is C 2-4 Alkinyl (1-3 R a (which may be substituted as desired). As a non-limiting example of the above embodiments, R 1 teeth [ka] It is possible.

[0091] In some embodiments of formula (I), (Ia), (IA), or (I-Aa), R 1 is C 1-6Alkyl (1 to 6 R a (This may be substituted as desired.) In certain embodiments of these, R 1 is C 1-6 It is alkyl. In certain embodiments of these, R 1 is C 2-4 It is alkyl. In certain embodiments of these, R 1 These are C3 alkyl groups, such as n-propyl and i-propyl. As a non-restrictive example, R 1 It may be i-propyl.

[0092] In certain embodiments of these, R 1 is C 3-5 It is alkyl. In certain embodiments of these, R 1 These are C4 alkyl groups, such as n-butyl, i-butyl, sec-butyl, and tert-butyl. As another non-restrictive example, R 1 It may be i-butyl. In certain embodiments of these, L 1 This is a joint.

[0093] Variable group Ar 2 In some embodiments of formula (I), (Ia), (IA), or (I-Aa), Ar 2 Heteroarylenes contain 5 to 10 ring atoms, of which 1 to 4 ring atoms are N, N(H), and N(R). d The heteroarylene is a ring heteroatom independently selected from the group consisting of ), O, and S, and the heteroarylene has 1 to 4 R c2 It may be replaced as desired.

[0094] In some embodiments of formula (I), (Ia), (IA), or (I-Aa), Ar 2Heteroarylenes contain 5 to 10 ring atoms, of which 1 to 4 ring atoms are N, N(H), and N(R). d The heteroarylene is a ring heteroatom independently selected from the group consisting of ), O, and S, and the heteroarylene has 1 to 4 -(L b ) b -R b It may be replaced as desired.

[0095] In particular, these embodiments are Ar 2 Heteroarylenes contain 5-6 ring atoms, of which 1-4 ring atoms are N, N(H), and N(R) respectively. d A ring heteroatom independently selected from the group consisting of ), O, and S, where the heteroarylene has 1 to 4 R c2 It may be replaced as desired.

[0096] In particular, these embodiments are Ar 2 Heteroarylenes contain 5-6 ring atoms, of which 1-4 ring atoms are N, N(H), and N(R) respectively. d A ring heteroatom independently selected from the group consisting of ), O, and S, where the heteroarylene has 1 to 4, each of which is R c2 and -(L b ) b -R b The substituents may be optionally substituted with substituents independently selected from the group consisting of the above.

[0097] In certain embodiments, Ar 2 Heteroarylene (contains 5 ring atoms, of which 1 to 4 are N, N(H), and N(R) respectively) d A ring heteroatom independently selected from the group consisting of ), O, and S, where the heteroarylene has 1 to 4 R c2 It may be replaced as desired.

[0098] In certain embodiments, Ar 2Heteroarylene (contains 5 ring atoms, of which 1 to 4 are N, N(H), and N(R) respectively) d A ring heteroatom independently selected from the group consisting of ), O, and S, where the heteroarylene has 1 to 4, each of which is R c2 and -(L b ) b -R b The substituents may be optionally substituted with substituents independently selected from the group consisting of the above.

[0099] In certain embodiments, Ar 2 The group can be selected from pyrrolylene, pyrazolylene, thiazolylen, and 1,3,4-oxadiazolylen, each of which has 1 to 4 R c2 and -(L b ) b -R b The substituents may be optionally substituted with substituents independently selected from the group consisting of the above.

[0100] In certain embodiments, Ar 2 It is selected from the group consisting of pyrrolylene, pyrazolylene, and thiazolylen, each of which is R c2 It may be replaced as desired.

[0101] In certain embodiments, Ar 2 teeth [ka] And here: [ka] Each of these is independently either a single bond or a double bond: however, B 1 B 2 B 3 B 4 , and B 5 The ring containing the ring is a heteroaryl; aa is -(CR 3a R 3b ) nIt is a bonding site with -C(O)OH; B 2 and B 4 is C or N; B 1 B 3 , and B 5 These are independently O, S, N, N(H), N(R) d ), CH, or CR c2 This is the case where 1 to 4 B 1 B 2 B 3 B 4 , and B 5 These are independently selected heteroatoms.

[0102] A specific embodiment of formula (I), (Ia), (IA), or (I-Aa) (Ar 2 but [ka] In the case of B 2 is N. In a particular embodiment, B 4 is C. In a particular embodiment, B 1 B 3 , and B 5 Independently, CH or CR c2 As a non-limiting example of the above-described embodiment, B 5 CR c2 It can be done; B 1 and B 3 It can be CH.

[0103] Specific embodiment (Ar 2 but [ka] In the case of B 2 is N and B 4 C is; B 1 B 3 , and B 5 Independently, CH or CR c2 That is the case.

[0104] In certain embodiments, Ar 2 teeth [ka] And here aa is -(CR 3a R 3b ) n It is a bond point with -C(O)OH. In certain embodiments of these, R c2 is C(O)OC 1-4 Alkyl, for example, C(O)OMe.

[0105] Formulas (I), (Ia), (IA), or (I-Aa)(Ar 2 but [ka] In the case of B, a specific embodiment is B 2 is C. In a particular embodiment, B 4 is C. In a particular embodiment, B 5 is CH or CR c2 B 1 and B 3 One of them is N; B 1 and B 3 The other side is NH, N(R d ), O, or S, for example, S.

[0106] In particular, these embodiments are Ar 2 teeth [ka] And here aa is -(CR 3a R 3b ) n This is the bond point with -C(O)OH.

[0107] Formulas (I), (Ia), (IA), or (I-Aa)(Ar 2 but [ka] In the case of B, a specific embodiment is B 4 is N. In a particular embodiment, B 2 C is C. In a particular embodiment, B 3 is N and B 1 and B 5 Independently, CH or CR c2 That is the case.

[0108] In certain embodiments, Ar 2 teeth [ka] And here aa is -(CR 3a R 3b ) n This is the bond point with -C(O)OH.

[0109] In certain embodiments, Ar 2 teeth [ka] And here: [ka] Each of these is independently either a single bond or a double bond: however, B 1 B 2 B 3 B 4 , and B 5 The ring containing the ring is a heteroaryl; aa is -(CR 3a R 3b ) n -R 2 It is the junction point with; B 2 and B 4 is C or N; B 1 B 3 , and B 5 These are independently O, S, N, N(H), N(R) d ), CH, CR c2 , or C-(L b ) b -Rb is: However, 1 to 4 B 1 B 2 B 3 B 4 , and B 5 These are independently selected heteroatoms.

[0110] Formulas (I), (Ia), (IA), or (I-Aa)(Ar 2 but [ka] In the case of B, a specific embodiment is B 2 is N. In a particular embodiment, B 4 is C. In a particular embodiment, B 1 B 3 , and B 5 CH and CR are independent. c2 , or C-(L b ) b -R b As a non-limiting example of the above-described embodiment, B 5 CR c2 B 1 and B 3 It is CH.

[0111] Formulas (I), (Ia), (IA), or (I-Aa)(Ar 2 but [ka] In the case of B, a specific embodiment is B 2 is N and B 4 C is; B 1 B 3 , and B 5 CH and CR are independent. c2 , or C-(L b ) b -R b That is the case.

[0112] In certain embodiments, Ar 2 teeth [ka] And here aa is -(CR 3a R 3b ) n -R 2 This is the connection point with R. In a particular embodiment, R c2 is C(O)OC 1-4 Alkyl, for example, C(O)OMe.

[0113] Formulas (I), (Ia), (IA), or (I-Aa)(Ar 2 but [ka] In the case of B, a specific embodiment is B 2 is C. In a particular embodiment, B 4 is C. In a particular embodiment, B 5 CH, CR c2 , or C-(L b ) b -R b B 1 and B 3 One of them is N; B 1 and B 3 The other side is NH, N(R d ), O, or S, for example, S.

[0114] In a particular embodiment, Ar 2 teeth [ka] A group consisting of is selected, where aa is -(CR 3a R 3b ) n -R 2 It is the connection point with R. In a specific example, C2 is C(=O)C 1-4 Alkyl, for example, C(=O)Et or C(=O)Me. In certain examples, R C2 is C 1-6Alkyl compounds, such as methyl, ethyl, propyl, such as n-propyl. In certain examples, -(L b ) b -R b is C 3-10 Cycloalkyls, for example, cyclopropyls.

[0115] In a particular embodiment, Ar 2 teeth [ka] And here aa is -(CR 3a R 3b ) n -R 2 This is the point of connection.

[0116] Formulas (I), (Ia), (IA), or (I-Aa)(Ar 2 but [ka] In the case of B, a specific embodiment is B 2 C is; B 4 is N. In a particular embodiment, B 3 is N and; B 1 and B 5 CH and CR are independent. c2 , or C-(L b ) b -R b That is the case.

[0117] As a specific embodiment, Ar 2 teeth [ka] This can be done, where aa is -(CR 3a R 3b ) n -R 2 This is the point of connection.

[0118] A specific embodiment of formula (I), (Ia), (IA), or (I-Aa) is Ar 2This is a heteroarylene (containing 6 ring atoms, of which 1-2 are ring nitrogen atoms), where the heteroarylene has 1-4 R c2 It may be replaced as desired. A specific embodiment of formula (I), (Ia), (IA), or (I-Aa) is Ar 2 This is a heteroarylene (containing 6 ring atoms, of which 1-2 are ring nitrogen atoms), where the heteroarylene has 1-4 ring atoms, each of which is R c2 and -(L b ) b -R b The substituents may be optionally substituted with substituents independently selected from the group consisting of the above.

[0119] In particular, these embodiments are Ar 2 This is 1-2 R c2 It is pyridylene, which may be substituted as desired. In particular, these embodiments are Ar 2 There are 1 to 4 of them, each of which is R c2 and -(L b ) b -R b A pyridylene, which may be optionally substituted with a substituent, independently selected from the group consisting of the following.

[0120] In certain embodiments of the above, Ar 2 teeth [ka] And here aa is -(CR 3a R 3b ) n It is a bond point with -C(O)OH. In certain embodiments of these, R c2 is C 1-4 Alkoxy or C 1-4 Haloalkoxys, for example, -OMe.

[0121] In certain embodiments of the above, Ar 2 teeth [ka] And here aa is -(CR 3a R 3b ) n -R 2 This is the connection point with R. In certain embodiments of these, R c2 is C 1-4 Alkoxy or C 1-4 Haloalkoxys, for example, -OMe.

[0122] A specific embodiment of formula (I) or (IA) is Ar 2 This is a bicyclic heteroarylene (containing 9 to 10 ring atoms, of which 1 to 4 are N, N(H), and N(R)). d A ring heteroatom independently selected from the group consisting of ), O, and S, where the heteroarylene has 1 to 4 R c2 It may be replaced as desired.

[0123] A specific embodiment of formula (I) or (IA) is Ar 2 This is a bicyclic heteroarylene (containing 9 to 10 ring atoms, of which 1 to 4 are N, N(H), and N(R)). d A ring heteroatom independently selected from the group consisting of ), O, and S, where the heteroarylene has 1 to 4, each of which is R c2 and -(L b ) b -R b The substituents may be optionally substituted with substituents independently selected from the group consisting of the above.

[0124] A specific embodiment of formula (I) or (IA) is Ar 2 The group is selected from benzimidazolylene, indazolylene, benzothiazolylen, and imidazo[1,2-a]pyridylene (e.g., benzothiazolylen), each of which has 1 to 4 R c2 and -(L b ) b -R bThe substituents may be optionally substituted with substituents independently selected from the group consisting of the above.

[0125] In particular, these embodiments are Ar 2 These are benzimidazolylene or indazolylene, each containing 1 to 4 R c2 It may be replaced as desired.

[0126] A specific embodiment of formula (I), (Ia), (IA), or (I-Aa) is Ar 2 teeth [ka] And here [ka] Each of these is independently either a single bond or a double bond: however, B 6 B 7 B 8 B 9 , and B 10 The 5-membered ring containing B is a heteroaryl, 8 B 9 B 11 B 12 , and B 13 A six-membered ring containing this ring is either aryl or heteroaryl; aa is -(CR 3a R 3b ) n It is a bonding site with -C(O)OH; B 6 B 8 , and B 9 Independently, C or N; B 7 and B 10 O, S, N, N(H), N(R) d ), CH, and CR c2 Selected independently from the group consisting of; B 11 B 12 , and B 13 These are independently N, CH, or CR c2 B is: However,6 B 7 B 8 B 9 B 10 B 11 B 12 , and B 13 One to four of these are independently selected heteroatoms; B 7 B 10 B 11 B 12 , and B 13 Three or fewer of them are CR c2 That is the case.

[0127] Of these, a particular embodiment is B 8 and B 9 C is C. In a particular embodiment, B 11 B 12 , and B 13 Independently, CH or CR c2 As a non-limiting example of the above-described embodiment, B 11 B 12 , and B 13 Each of these can be CH. In a particular embodiment, B 6 It is N. In a particular embodiment, B 7 It is N. In a particular embodiment, B 10 is CH or CR c2 As a non-limiting example of the above-described embodiment, B 10 It can be CH.

[0128] As a non-limiting example of the above-described embodiment, Ar 2 teeth [ka] It could be, and it would be 1-2 R c2 It may be replaced as desired, where aa is -(CR 3a R 3b ) n This is the bond point with -C(O)OH.

[0129] A specific embodiment of formula (I), (Ia), (IA), or (I-Aa) is Ar 2 teeth [ka] And here [ka] Each of these is independently either a single bond or a double bond: however, B 6 B 7 B 8 B 9 , and B 10 The five-membered ring containing B is a heteroaryl, 8 B 9 B 11 B 12 , and B 13 A six-membered ring containing this ring is either aryl or heteroaryl; aa is -(CR 3a R 3b ) n -R 2 It is the junction point with; B 6 B 8 , and B 9 Independently, C or N; B 7 and B 10 O, S, N, N(H), N(R) d ), CH, CR c2 , and C-(L b ) b -R b Selected independently from the group consisting of; B 11 B 12 , and B 13 These are independently N, CH, CR c2 , or C-(L b ) b -R b B is: However, 6 B 7 B 8 B 9 B 10 B 11, B 12 , and B 13 One to four of which are heteroatoms independently selected; B 7 , B 10 , B 11 , B 12 , and B 13 Three or less of which are CR c2 , or C-(L b ) b -R b is.

[0130] In certain embodiments, B 8 and B 9 are C. In certain embodiments, B 11 , B 12 , and B 13 are, independently, CH, CR c2 , or C-(L b ) b -R b ) is. As a non-limiting example, B 11 , B 12 , and B 13 13 are CH.

[0131] In certain embodiments, B 6 is N. In certain embodiments, B 7 is N. In certain embodiments, B 10 is CH or CR c2 , or C-(L b ) b -R b is. As a non-limiting example, B 10 can be CH.

[0132] As a non-limiting example, Ar 2 is

Chemical formula

[0133] In certain embodiments, B 7 is N. In certain embodiments, B 10 is S. As a non-limiting example, Ar 2 is

Chemical formula

[0134] In certain embodiments, B 8 is C and B 9 is N. In certain embodiments, B 7 is N. In certain embodiments, B 10 , B 11 , B 12 , and B 13 is CH, CR c2 , or C-(L b ) b -R b is

[0135] As a non-limiting example, Ar 2 is

Chemical formula

[0136] As a further non-limiting example, Ar 2 teeth, [ka] A group consisting of can be selected, each of which has 1 to 2 elements, each of which is R c2 and -(L b ) b -R b A substituent selected from the group consisting of, which may optionally be substituted, where aa is -(CR 3a R 3b ) n -R 2 This is the point of connection.

[0137] As a further non-limiting example, Ar 2 teeth [ka] A group consisting of can be selected, each of which has 1 to 2 elements, each of which is R c2 and -(L b ) b -R b Selected from the group consisting of, which may optionally be substituted with substituents, independently selected from the group consisting of, where aa is -(CR 3a R 3b ) n -R 2 This is the point of connection.

[0138] As a further non-limiting example, Ar 2 teeth, [ka] A group consisting of can be selected, each of which has 1 to 2 elements, each of which is R c2 and -(Lb ) b -R b selected from the group consisting of, optionally substituted with substituents, where aa is -(CR 3a R 3b ) n -R 2 and is the point of attachment to.

[0139] In certain embodiments of formula (I), (Ia), (I-A) or (I-Aa), Ar 2 is:

Chemical formula

Chemical formula

[0140] A specific embodiment of formula (I), (Ia), (IA), or (I-Aa) is Ar 2 teeth [ka] And here [ka] Each of these is independently either a single bond or a double bond: however, B 14 B 15 B 16 B 17 , and B 18 The five-membered ring containing B is a heteroaryl, 16 B 17 B 19 B 20 , and B 21 A six-membered ring containing this ring is either aryl or heteroaryl; aa is -(CR 3a R 3b ) n -R 2 It is the junction point with; B 16 B 17 , and B 14 Independently, C or N; B 15 and B 18 O, S, N, N(H), N(R) d ), CH, and CR c2 Selected independently from the group consisting of; B 19 B 20, and B 21 These are independently N, CH, CR c2 , or C-(L b ) b -R b B is: However, 14 B 15 B 16 B 17 B 18 B 19 B 20 , and B 21 One to four of these are independently selected heteroatoms; B 15 B 18 B 19 B 20 , and B 21 Three or fewer of them are CR c2 or C-(L b ) b -R b That is the case.

[0141] Of these, a particular embodiment is B 16 and B 17 C is C. In a particular embodiment, B 19 B 20 , and B 21 These are independently N, CH, or CR c2 That is the case. In a particular embodiment, B 19 B 20 , and B 21 These are independently N, CH, CR c2 , or C-(L b ) b -R b That is the case.

[0142] In a particular embodiment, B 14 C is C. In a particular embodiment, B 15 and B 18 One of them is N; B 15 and B 18 The other is O, S, NH, or N(R d ), for example, NH or N(R d), for example, NH or N(C 1-3 It is alkyl.

[0143] As a non-limiting example of the above-described embodiment, Ar 2 teeth [ka] This can be done, and each of them has 1 to 2 R c2 It may be replaced as desired, where aa is -(CR 3a R 3b ) n This is the bond point with -C(O)OH.

[0144] As a further non-limiting example, Ar 2 teeth [ka] This can be done, and each of them has 1 to 2 R c2 It may be replaced as desired, where aa is -(CR 3a R 3b ) n -R 2 This is the point of connection.

[0145] A specific embodiment of formula (I), (Ia), (IA), or (I-Aa) is Ar 2 teeth [ka] It can be done that way, and it is 1 to 2 of them, each of which is R c2 and -(L b ) b -R b A substituent selected from the group consisting of, which may optionally be substituted, where aa is -(CR 3a R 3b ) n -R 2 This is the point of connection.

[0146] Variable group n, R 3a , and R 3b In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments (where n is 1), R 3a and R 3b H is H. In some embodiments (where n is 1), R 3a and R 3b One of them is H, and R 3a and R 3b The other is C 1-6 Alkyl compounds, such as ethyl or methyl. In some embodiments (where n is 1), R 3a and R 3b This means that each of them, together with the carbon atom to which it is bonded, C 3-6 It forms a cycloalkyl group, for example, a cyclopropyl group.

[0147] Variable group R 2 In some embodiments, R 2 It is -C(=O)OH. In some embodiments, R 2 It is a carboxylic acid biological equivalent. In a particular example, R 2 is -C(=O)NH2, -C(=O)NHSO2Me, or [ka] That is the case.

[0148] Non-limited combinations Equations (I-1), (I-1a) In a particular embodiment, the compound of formula (I) is formula (I-1): [ka] [In formula: [ka] Each of these is independently either a single bond or a double bond: however, B1 B 2 B 3 B 4 , and B 5 The ring containing the ring is a heteroaryl; B 2 and B 4 is C or N; B 1 B 3 , and B 5 These are independently O, S, N, N(H), N(R) d ), CH, or CR c2 This is the case where 1 to 4 B 1 B 2 B 3 B 4 , and B 5 are independently selected heteroatoms; and Ar 1 teeth: Phenyl (1-4, halo; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g Substituting with substituents independently selected from the group consisting of (which may be substituted as desired); and Heteroaryl (containing 6 ring atoms, of which 1-2 are ring nitrogen atoms, where the heteroaryl is composed of 1-4 halo atoms; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g From the group consisting of (which may be optionally substituted with), each is independently selected, which may be optionally substituted with a substituent. Selected from the group consisting of [ It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0149] In a particular embodiment, the compound of formula (I) is formula (I-1): [ka] [In formula: [ka] Each of these is independently either a single bond or a double bond: however B 1 B 2 B 3 B 4 , and B 5 The ring containing the ring is a heteroaryl; B 2 and B 4 is C or N; B 1 B 3 , and B 5 These are independently O, S, N, N(H), N(R) d ), CH, or CR c2 This is the case: however, 1 to 4 B 1 B 2 B 3 B 4 , and B 5 are independently selected heteroatoms; and Ar 1 teeth: Phenyl (1-4, halo; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g Substituting with substituents independently selected from the group consisting of (which may be substituted as desired); and Heteroaryl (containing 6 ring atoms, of which 1-2 are ring nitrogen atoms, and 1-4 halo atoms; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g Each of the group consisting of (which may be optionally substituted with) is independently selected, and which may be optionally substituted with a substituent. Selected from the group consisting of; and R 1 R b ;C 2-6 Alkenyl (1-6 R a This may be replaced as desired; and C 2-6 Alkinyl (1-6 R a (May be replaced as desired) Selected from the group consisting of [ It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0150] In a particular embodiment, the compound of formula (I) is formula (I-1): [ka] [In formula: [ka] Each of these is independently either a single bond or a double bond: however B 1 B 2 B 3 B 4 , and B 5 The ring containing the ring is a heteroaryl; B 2 and B 4 is C or N; B 1 B 3 , and B 5 These are independently O, S, N, N(H), N(R) d ), CH, or CR c2 This is the case where 1 to 4 B 1 B 2 B 3 B 4 , and B 5 These are independently selected heteroatoms; Ar 1 teeth: Phenyl (1-4, halo; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g Substituting with substituents independently selected from the group consisting of (which may be substituted as desired); and Heteroaryl (containing 6 ring atoms, of which 1-2 are ring nitrogen atoms, and 1-4 halo atoms; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g From the group consisting of (which may be optionally substituted with), each is independently selected, which may be optionally substituted with a substituent. Selected from the group consisting of; and R 1 is C 1-6 Alkyl (1 to 6 R a (This may be replaced as desired.) It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0151] In a particular embodiment, the compound of formula (I) is formula (I-1a): [ka] [In formula: [ka] Each of these is independently either a single bond or a double bond: however B 1 B 2 B 3 B 4 , and B 5 The ring containing the ring is a heteroaryl; B2 and B 4 is C or N; B 1 B 3 , and B 5 These are independently O, S, N, N(H), N(R) d ), CH, CR c2 , or C-(L b ) b -R b This is the case where 1 to 4 B 1 B 2 B 3 B 4 , and B 5 are independently selected heteroatoms; and Ar 1 teeth: Phenyl (1-4, halo; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g Substituting with substituents independently selected from the group consisting of (which may be substituted as desired); and Heteroaryl (containing 6 ring atoms, of which 1-2 are ring nitrogen atoms, and 1-4 halo atoms; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g From the group consisting of (which may be substituted as desired), each is independently selected and substituted with a substituent. Selected from the group consisting of [ It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0152] In a particular embodiment, the compound of formula (I) is formula (I-1a): [ka] [In formula: [ka] Each of these is independently either a single bond or a double bond: however B 1 B 2 B 3 B 4 , and B 5 The ring containing the ring is a heteroaryl; B 2 and B 4 is C or N; B 1 B 3 , and B 5 These are independently O, S, N, N(H), N(R) d ), CH, CR c2 , or C-(L b ) b -R b This is the case where 1 to 4 B 1 B 2 B 3 B 4 , and B 5 These are independently selected heteroatoms; Ar 1 teeth: Phenyl (1-4, halo; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g Substituting with substituents independently selected from the group consisting of (which may be substituted as desired); and Heteroaryl (containing 6 ring atoms, of which 1-2 are ring nitrogen atoms, and 1-4 halo atoms; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6Cycloalkyl (1-2 R g From the group consisting of (which may be optionally substituted with), each is independently selected, which may be optionally substituted with a substituent. Selected from the group consisting of; and R 1 R b ;C 2-6 Alkenyl (1-6 R a This may be replaced as desired; and C 2-6 Alkinyl (1-6 R a Selected from the group consisting of (which may be substituted as desired) It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0153] In a particular embodiment, the compound of formula (I) is formula (I-1a): [ka] [In formula: [ka] Each of these is independently either a single bond or a double bond: however B 1 B 2 B 3 B 4 , and B 5 The ring containing the ring is a heteroaryl; B 2 and B 4 is C or N; B 1 B 3 , and B 5 These are independently O, S, N, N(H), N(R) d ), CH, CR c2 , or C-(L b ) b -R b This is the case where 1 to 4 B 1 B 2 B 3 B 4 , and B 5 These are independently selected heteroatoms; Ar 1teeth: Phenyl (1-4, halo; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g Substituting with substituents independently selected from the group consisting of (which may be substituted as desired); and Heteroaryl (containing 6 ring atoms, of which 1-2 are ring nitrogen atoms, and 1-4 halo atoms; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g (which may be substituted as desired) Each of the following groups is independently selected and substituted with a substituent. Selected from the group consisting of; and R 1 is C 1-6 Alkyl (1 to 6 R a (This may be replaced as desired.) It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0154] In a particular embodiment of formula (I-1) or (I-1a), B 2 is N and; B 4 C is C. In a particular embodiment of formula (I-1) or (I-1a), B 1 B 3 , and B 5 Independently, CH or CR c2 That is the case. In a particular embodiment of formula (I-1) or (I-1a), B 1 B 3 , and B 5 CH and CR are independent. c2 or C-(Lb ) b -R b That is the case.

[0155] As a non-limiting example of the above-described embodiment, B 1 -B 5 The ring containing is [ka] This can be done, where aa is -(CR 3a R 3b ) n -This is the bonding site with C(O)OH, and R can be added if desired. c2 is C(O)OC 1-4 Alkyl is also acceptable.

[0156] As a non-limiting example of the above-described embodiment, B 1 -B 5 The ring containing is [ka] This can be done, where aa is -(CR 3a R 3b ) n -R 2 The connection point with, and R if desired c2 is C(O)OC 1-4 Alkyl is also acceptable.

[0157] In a particular embodiment of formula (I-1) or (I-1a), B 2 C is; B 4 It is N. In a particular embodiment of formula (I-1) or (I-1a), B 3 is N and; B 1 and B 5 Independently, CH or CR c2 That is the case. In a particular embodiment of formula (I-1) or (I-1a), B 3 is N and; B 1 and B 5 CH and CR are independent. c2 or C-(L b )b -R b That is the case.

[0158] As a non-limiting example of the above-described embodiment, B 1 -B 5 The ring containing is [ka] This can be done, where aa is -(CR 3a R 3b ) n This is the bond point with -C(O)OH.

[0159] As a non-limiting example of the above-described embodiment, B 1 -B 5 The ring containing is [ka] This can be done, where aa is -(CR 3a R 3b ) n -R 2 This is the point of connection.

[0160] In a particular embodiment of formula (I-1) or (I-1a), B 2 C is; B 4 C is C. In a particular embodiment of formula (I-1) or (I-1a), B 5 is CH or CR c2 B 1 and B 3 One of them is N; B 1 and B 3 The other side is NH, N(R d ), O, or S, for example, S.

[0161] As a non-limiting example of the above-described embodiment, B 1 -B 5 The ring containing is [ka] And here aa is -(CR 3aR 3b ) n This is the bond point with -C(O)OH.

[0162] As another non-limiting example of the above-described embodiment, B 1 -B 5 The ring containing is [ka] And here aa is -(CR 3a R 3b ) n -R 2 The connection point with, and R if desired c2 is C(O)OC 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy, or C 1-4 A haloalkoxy may also be used.

[0163] As another non-limiting example of the above-described embodiment, B 1 -B 5 The ring containing is [ka] And here aa is -(CR 3a R 3b ) n -R 2 The point of connection with, and optionally -(L b ) b -R b is C 3-10 It may also be a cycloalkyl, for example, cyclopropyl.

[0164] As another non-limiting example of the above-described embodiment, B 1 -B 5 The ring containing is [ka] And here aa is -(CR 3a R 3b ) n -R 2 This is the point of connection.

[0165] Equations (I-2), (I-2a) In a particular embodiment, the compound of formula (I) is formula (I-2): [ka] [In formula: [ka] Each of them is, Independently, they are single or double bonds: however B 6 B 7 B 8 B 9 , and B 10 The five-membered ring containing B is a heteroaryl, 8 B 9 B 11 B 12 , and B 13 A six-membered ring containing this ring is either aryl or heteroaryl; B 6 B 8 , and B 9 Independently, C or N; B 7 and B 10 O, S, N, N(H), N(R) d ), CH, or CR c2 Selected independently from the group consisting of; B 11 B 12 , and B 13 These are independently N, CH, or CR c2 B is: However, 6 B 7 B 8 B 9 B 10 B 11 B 12 , and B 13 One to four of them are independently selected heteroatoms; B 7 B 10 B 11 B 12 , and B 13 Three or fewer of them are CR c2and Ar 1 teeth: Phenyl (1-4, halo; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g Substituting with substituents independently selected from the group consisting of (which may be substituted as desired); and Heteroaryl (containing 6 ring atoms, of which 1-2 are ring nitrogen atoms, where the heteroaryl is composed of 1-4 halo atoms; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g From the group consisting of (which may be optionally substituted with), each is independently selected, which may be optionally substituted with a substituent. Selected from the group consisting of [ It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0166] In a particular embodiment, the compound of formula (I) is formula (I-2): [ka] [In formula: [ka] Each of these is independently either a single bond or a double bond: however B 6 B 7 B 8 B 9 , and B 10 The five-membered ring containing B is a heteroaryl, 8 B 9 B 11 B 12, and B 13 A six-membered ring containing this ring is either aryl or heteroaryl; B 6 B 8 , and B 9 Independently, C or N; B 7 and B 10 O, S, N, N(H), N(R) d ), CH, or CR c2 Selected independently from the group consisting of; B 11 B 12 , and B 13 These are independently N, CH, or CR c2 However, B 6 B 7 B 8 B 9 B 10 B 11 B 12 , and B 13 One to four of them are independently selected heteroatoms; B 7 B 10 B 11 B 12 , and B 13 Three or fewer of them are CR c2 and Ar 1 teeth: Phenyl (1-4, halo; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g Substituting with substituents independently selected from the group consisting of (which may be substituted as desired); and Heteroaryl (containing 6 ring atoms, of which 1-2 are ring nitrogen atoms, where the heteroaryl is composed of 1-4 halo atoms; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g From the group consisting of (which may be optionally substituted with), each is independently selected, which may be optionally substituted with a substituent. Selected from the group consisting of; and R 1 R b ;C 2-6 Alkenyl (1-6 R a This may be replaced as desired; and C 2-6 Alkinyl (1-6 R a Selected from the group consisting of (which may be substituted as desired) It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0167] In a particular embodiment, the compound of formula (I) is formula (I-2): [ka] [In formula: [ka] Each of these is independently either a single bond or a double bond: however B 6 B 7 B 8 B 9 , and B 10 The five-membered ring containing B is a heteroaryl, 8 B 9 B 11 B 12 , and B 13 A six-membered ring containing this ring is either aryl or heteroaryl; B 6 B 8 , and B 9 Independently, C or N; B 7 and B 10 O, S, N, N(H), N(R) d ), CH, or CR c2 Selected independently from the group consisting of; B 11 B 12 , and B 13 These are independently N, CH, or CR c2 However, B 6 B 7 B 8 B 9 B 10 B 11 B 12 , and B 13 One to four of them are independently selected heteroatoms; B 7 B 10 B 11 B 12 , and B 13 Three or fewer of them are CR c2 and Ar 1 teeth: Phenyl (1-4, halo; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g Substituting with substituents independently selected from the group consisting of (which may be substituted as desired); and Heteroaryl (containing 6 ring atoms, of which 1-2 are ring nitrogen atoms, where the heteroaryl is composed of 1-4 halo atoms; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g From the group consisting of (which may be optionally substituted with), each is independently selected, which may be optionally substituted with a substituent. The group consists of; and R 1 C 1-6 Alkyl (1 to 6 R a(This may be replaced as desired.) It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0168] A specific embodiment of formula (I-2) is B 8 and B 9 C is C. A specific embodiment of formula (I-2) is B 11 B 12 , and B 13 Independently, CH or CR c2 That is the case. A specific embodiment of formula (I-2) is B 6 is N and B 7 is N and; B 10 is CH or CR c2 That is the case.

[0169] As a non-limiting example of the above-described embodiment, B 6 ~B 13 The ring containing is [ka] It can be done with 1-2 R c2 It may be replaced as desired, where aa is -(CR 3a R 3b ) n This is the bond point with -C(O)OH.

[0170] In a particular embodiment, the compound of formula (I) is formula (I-2a): [ka] [In formula: [ka] Each of these is independently either a single bond or a double bond: however B 6 B 7 B 8 B 9 , and B 10 The five-membered ring containing B is a heteroaryl, 8 B9 B 11 B 12 , and B 13 A six-membered ring containing this ring is either aryl or heteroaryl; B 6 B 8 , and B 9 Independently, C or N; B 7 and B 10 O, S, N, N(H), N(R) d ), CH, CR c2 , or C-(L b ) b -R b Selected independently from the group consisting of; B 11 B 12 , and B 13 These are independently N, CH, CR c2 , or C-(L b ) b -R b However, B 6 B 7 B 8 B 9 B 10 B 11 B 12 , and B 13 One to four of them are independently selected heteroatoms; B 7 B 10 B 11 B 12 , and B 13 Three or fewer of them are CR c2 or C-(L b ) b -R b and; Ar 1 teeth: Phenyl (1-4, halo; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R gSubstituting with substituents independently selected from the group consisting of (which may be substituted as desired); and Heteroaryl (containing 6 ring atoms, of which 1-2 are ring nitrogen atoms, where the heteroaryl is composed of 1-4 halo atoms; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g From the group consisting of (which may be optionally substituted with), each is independently selected, which may be optionally substituted with a substituent. Selected from the group consisting of [ It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0171] In a particular embodiment, the compound of formula (I) is formula (I-2a): [ka] [In formula: [ka] Each of these is independently either a single bond or a double bond: however B 6 B 7 B 8 B 9 , and B 10 The five-membered ring containing B is a heteroaryl, 8 B 9 B 11 B 12 , and B 13 A six-membered ring containing this ring is either aryl or heteroaryl; B 6 B 8 , and B 9 Independently, C or N; B 7 and B 10 O, S, N, N(H), N(R) d ), CH, CR c2, or C-(L b ) b -R b Selected independently from the group consisting of; B 11 B 12 , and B 13 These are independently N, CH, CR c2 , or C-(L b ) b -R b However, B 6 B 7 B 8 B 9 B 10 B 11 B 12 , and B 13 One to four of them are independently selected heteroatoms; B 7 B 10 B 11 B 12 , and B 13 Three or fewer of them are CR c2 or C-(L b ) b -R b and; Ar 1 teeth: Phenyl (1-4, halo; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g Substituting with substituents independently selected from the group consisting of (which may be substituted as desired); and Heteroaryl (containing 6 ring atoms, of which 1-2 are ring nitrogen atoms, where the heteroaryl is composed of 1-4 halo atoms; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 Rg From the group consisting of (which may be optionally substituted with), each is independently selected, which may be optionally substituted with a substituent. Selected from the group consisting of; and R 1 R b ;C 2-6 Alkenyl (1-6 R a This may be replaced as desired; and C 2-6 Alkinyl (1-6 R a Selected from the group consisting of (which may be substituted as desired) It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0172] In a particular embodiment, the compound of formula (I) is formula (I-2a): [ka] [In formula: [ka] Each of these is independently either a single bond or a double bond: however B 6 B 7 B 8 B 9 , and B 10 The five-membered ring containing B is a heteroaryl, 8 B 9 B 11 B 12 , and B 13 A six-membered ring containing this ring is either aryl or heteroaryl; B 6 B 8 , and B 9 Independently, C or N; B 7 and B 10 O, S, N, N(H), N(R) d ), CH, CR c2 , or C-(L b ) b -R b Selected independently from the group consisting of; B 11 B12 , and B 13 These are independently N, CH, CR c2 , or C-(L b ) b -R b However, B 6 B 7 B 8 B 9 B 10 B 11 B 12 , and B 13 One to four of them are independently selected heteroatoms; B 7 B 10 B 11 B 12 , and B 13 Three or fewer of them are CR c2 or C-(L b ) b -R b and; Ar 1 teeth: Phenyl (1-4, halo; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g Substituting with substituents independently selected from the group consisting of (which may be substituted as desired); and Heteroaryl (containing 6 ring atoms, of which 1-2 are ring nitrogen atoms, where the heteroaryl is composed of 1-4 halo atoms; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g From the group consisting of (which may be optionally substituted with), each is independently selected, which may be optionally substituted with a substituent. Selected from the group consisting of; and R 1 is C 1-6 Alkyl (1 to 6 R a (This may be replaced as desired.) It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0173] In a particular embodiment of formula (I-2) or (I-2a), B 8 and B 9 C is C. In a particular embodiment of formula (I-2) or (I-2a), B 11 B 12 , and B 13 Independently, CH or CR c2 That is the case. In a particular embodiment of formula (I-2) or (I-2a), B 6 is N and B 7 is N and; B 10 is CH or CR c2 That is the case.

[0174] As a non-limiting example of the above-described embodiment of formula (I-2) or (I-2a), B 6 ~B 13 The ring containing is [ka] It can be done with 1-2 R c2 It may be replaced as desired, where aa is -(CR 3a R 3b ) n -R 2 This is the point of connection.

[0175] In a particular embodiment of formula (I-2) or (I-2a), B 7 is N. In a particular embodiment, B 10 S is. As a non-limiting example of an embodiment of formula (I-2) or (I-2a), B 6 ~B 13 The ring containing is [ka] It can be done that way, with 1 to 2, each of which is R c2 and -(L b ) b -R b A substituent selected from the group consisting of, which may optionally be substituted, where aa is -(CR 3a R 3b ) n -R 2 This is the point of connection.

[0176] In a particular embodiment of formula (I-2) or (I-2a), B 8 C is; B 9 is N. In a particular embodiment, B 7 It is N. In a particular embodiment of formula (I-2) or (I-2a), B 10 B 11 B 12 , and B 13 CH, CR c2 , or C-(L b ) b -R b That is the case.

[0177] As a non-limiting example of an embodiment of formula (I-2) or (I-2a), B 6 ~B 13 The ring containing is [ka] It can be done that way, with 1 to 2, each of which is R c2 and -(L b ) b -R b A substituent selected from the group consisting of, which may optionally be substituted, where aa is -(CR 3a R 3b ) n -R 2 This is the point of connection.

[0178] As a further non-limiting example of an embodiment of formula (I-2) or (I-2a), B 6 ~B13 The ring containing is [ka] Selected from the group consisting of; 1 to 2, each of which is R c2 and -(L b ) b -R b A substituent selected from the group consisting of, which may optionally be substituted, where aa is -(CR 3a R 3b ) n -R 2 This is the point of connection.

[0179] As a further non-limiting example of an embodiment of formula (I-2) or (I-2a), B 6 ~B 13 The ring containing is [ka] Selected from the group consisting of; 1 to 2, each of which is R c2 and -(L b ) b -R b A substituent selected from the group consisting of, which may optionally be substituted, where aa is -(CR 3a R 3b ) n -R 2 This is the point of connection.

[0180] As a further non-limiting example of an embodiment of formula (I-2) or (I-2a), B 6 ~B 13 The ring containing is [ka] Selected from the group consisting of; 1 to 2, each of which is R c2 and -(L b ) b -R b A substituent selected from the group consisting of, which may optionally be substituted, where aa is -(CR 3a R 3b ) n -R 2This is the point of connection.

[0181] Equations (I-3), (I-3a) In a particular embodiment, the compound of formula (I) is formula (I-3): [ka] [In formula: [ka] Each of these is independently either a single bond or a double bond: however B 14 B 15 B 16 B 17 , and B 18 The five-membered ring containing B is a heteroaryl, 16 B 17 B 19 B 20 , and B 21 A six-membered ring containing this ring is either aryl or heteroaryl; B 16 B 17 , and B 14 Independently, C or N; B 15 and B 18 O, S, N, N(H), N(R) d ), CH, and CR c2 Selected from the group consisting of; B 19 B 20 , and B 21 These are independently N, CH, or CR c2 However, B 14 B 15 B 16 B 17 B 18 B 19 B 20 , and B 21 One to four of them are independently selected heteroatoms; B 15 B 18 B 19 B 20 , and B 21Three or fewer of them are CR c2 and Ar 1 teeth: Phenyl (1-4, halo; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g Substituting with substituents independently selected from the group consisting of (which may be substituted as desired); and Heteroaryl (containing 6 ring atoms, of which 1-2 are ring nitrogen atoms, where the heteroaryl is composed of 1-4 halo atoms; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g From the group consisting of (which may be optionally substituted with), each is independently selected, which may be optionally substituted with a substituent. Selected from the group consisting of [ It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0182] In a particular embodiment, the compound of formula (I) is formula (I-3): [ka] [In formula: [ka] Each of these is independently either a single bond or a double bond: however B 14 B 15 B 16 B 17 , and B 18 The five-membered ring containing B is a heteroaryl, 16 B 17 B19 B 20 , and B 21 A six-membered ring containing this ring is either aryl or heteroaryl; B 16 B 17 , and B 14 Independently, C or N; B 15 and B 18 O, S, N, N(H), N(R) d ), CH, and CR c2 Selected independently from the group consisting of; B 19 B 20 , and B 21 These are independently N, CH, or CR c2 However, B 14 B 15 B 16 B 17 B 18 B 19 B 20 , and B 21 One to four of them are independently selected heteroatoms; B 15 B 18 B 19 B 20 , and B 21 Three or fewer of them are CR c2 and; Ar 1 teeth: Phenyl (1-4, halo; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g Substituting with substituents independently selected from the group consisting of (which may be substituted as desired); and Heteroaryl (containing 6 ring atoms, of which 1-2 are ring nitrogen atoms, where the heteroaryl is composed of 1-4 halo atoms; C) 1-6 Alkyl; C 1-6Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g From the group consisting of (which may be optionally substituted with), each is independently selected, which may be optionally substituted with a substituent. Selected from the group consisting of; and R 1 R b ;C 2-6 Alkenyl (1-6 R a This may be replaced as desired; and C 2-6 Alkinyl (1-6 R a Selected from the group consisting of (which may be substituted as desired) It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0183] In a particular embodiment, the compound of formula (I) is formula (I-3): [ka] [In formula: [ka] Each of these is independently either a single bond or a double bond: however B 14 B 15 B 16 B 17 , and B 18 The five-membered ring containing B is a heteroaryl, 16 B 17 B 19 B 20 , and B 21 A six-membered ring containing this ring is either aryl or heteroaryl; B 16 B 17 , and B 14 Independently, C or N; B 15 and B 18 O, S, N, N(H), N(R) d), CH, and CR c2 Selected independently from the group consisting of; B 19 B 20 , and B 21 These are independently N, CH, or CR c2 However, B 14 B 15 B 16 B 17 B 18 B 19 B 20 , and B 21 One to four of them are independently selected heteroatoms; B 15 B 18 B 19 B 20 , and B 21 Three or fewer of them are CR c2 and; Ar 1 teeth: Phenyl (1-4, halo; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g Substituting with substituents independently selected from the group consisting of (which may be substituted as desired); and Heteroaryl (containing 6 ring atoms, of which 1-2 are ring nitrogen atoms, where the heteroaryl is a halo; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g (The substituents may be optionally substituted with substituents independently selected from the group consisting of (which may be optionally substituted with) Selected from the group consisting of; and R 1 is C1-6 Alkyl (1 to 6 R a (This may be replaced as desired.) It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0184] In a particular embodiment, the compound of formula (I) is formula (I-3a): [ka] [In formula: [ka] Each of these is independently either a single bond or a double bond: however B 14 B 15 B 16 B 17 , and B 18 The five-membered ring containing B is a heteroaryl, 16 B 17 B 19 B 20 , and B 21 A six-membered ring containing this ring is either aryl or heteroaryl; B 16 B 17 , and B 14 Independently, C or N; B 15 and B 18 O, S, N, N(H), N(R) d ), CH, CR c2 , and C-(L b ) b -R b Independently selected from the group consisting of, B 19 B 20 , and B 21 These are independently N, CH, CR c2 , or C-(L b ) b -R b However, B 14 B 15 B 16 B 17 B 18 B19 B 20 , and B 21 One to four of them are independently selected heteroatoms; B 15 B 18 B 19 B 20 , and B 21 Three or fewer of them are CR c2 or C-(L b ) b -R b and Ar 1 teeth: Phenyl (1-4, halo; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g Substituting with substituents independently selected from the group consisting of (which may be substituted as desired); and Heteroaryl (containing 6 ring atoms, of which 1-2 are ring nitrogen atoms, where the heteroaryl is composed of 1-4 halo atoms; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g From the group consisting of (which may be optionally substituted with), each is independently selected, which may be optionally substituted with a substituent. Selected from the group consisting of [ It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0185] In a particular embodiment, the compound of formula (I) is formula (I-3a): [ka] [In formula: [ka] Each of these is independently either a single bond or a double bond: however B 14 B 15 B 16 B 17 , and B 18 The five-membered ring containing B is a heteroaryl, 16 B 17 B 19 B 20 , and B 21 A six-membered ring containing this ring is either aryl or heteroaryl; B 16 B 17 , and B 14 Independently, C or N; B 15 and B 18 O, S, N, N(H), N(R) d ), CH, CR c2 , and C-(L b ) b -R b Selected independently from the group consisting of; B 19 B 20 , and B 21 These are independently N, CH, CR c2 , or C-(L b ) b -R b However, B 14 B 15 B 16 B 17 B 18 B 19 B 20 , and B 21 One to four of them are independently selected heteroatoms; B 15 B 18 B 19 B 20 , and B 21 Three or fewer of them are CR c2 or C-(L b ) b -R b and; Ar 1 teeth: Phenyl (1-4, halo; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g Substituting with substituents independently selected from the group consisting of (which may be substituted as desired); and Heteroaryl (containing 6 ring atoms, of which 1-2 are ring nitrogen atoms, where the heteroaryl is composed of 1-4 halo atoms; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g From the group consisting of (which may be optionally substituted with), each is independently selected, which may be optionally substituted with a substituent. Selected from the group consisting of; and R 1 R b ;C 2-6 Alkenyl (1-6 R a This may be replaced as desired; and C 2-6 Alkinyl (1-6 R a Selected from the group consisting of (which may be substituted as desired) It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0186] In a particular embodiment, the compound of formula (I) is formula (I-3a): [ka] [In formula: [ka] Each of these is independently either a single bond or a double bond: however B 14 B15 B 16 B 17 , and B 18 The five-membered ring containing B is a heteroaryl, 16 B 17 B 19 B 20 , and B 21 A six-membered ring containing this ring is either aryl or heteroaryl; B 16 B 17 , and B 14 Independently, C or N; B 15 and B 18 O, S, N, N(H), N(R) d ), CH, CR c2 , and C-(L b ) b -R b Selected independently from the group consisting of; B 19 B 20 , and B 21 These are independently N, CH, CR c2 , or C-(L b ) b -R b However, B 14 B 15 B 16 B 17 B 18 B 19 B 20 , and B 21 One to four of them are independently selected heteroatoms; B 15 B 18 B 19 B 20 , and B 21 Three or fewer of them are CR c2 or C-(L b ) b -R b and; Ar 1 teeth: Phenyl (1-4, halo; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g Substituting with substituents independently selected from the group consisting of (which may be substituted as desired); and Heteroaryl (containing 6 ring atoms, of which 1-2 are ring nitrogen atoms, where the heteroaryl is composed of 1-4 halo atoms; C) 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g From the group consisting of (which may be optionally substituted with), each is independently selected, which may be optionally substituted with a substituent. Selected from the group consisting of; and R 1 is C 1-6 Alkyl (1 to 6 R a (This may be replaced as desired.) It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0187] In a particular embodiment of formula (I-3) or (I-3a), B 16 and B 17 C is C. In a particular embodiment of formula (I-3) or (I-3a), B 19 B 20 , and B 21 Independently, CH or CR c2 That is the case. In a particular embodiment of formula (I-3) or (I-3a), B 19 B 20 , and B 21 CH and CR are independent. c2 , or C-(L b ) b -R b That is the case. In a particular embodiment of formula (I-3) or (I-3a), B 14 C is B 15 and B 18 One of them is N; B 15 and B 18 The other is O, S, NH, or N(R d ) and for example, NH or N(R d ), for example, NH or N(C 1-3 It is alkyl.

[0188] As a non-limiting example of the above-described embodiment, B 14 ~B 21 The ring containing is [ka] This can be done, and each of them has 1 to 2 R c2 It may be replaced as desired, where aa is -(CR 3a R 3b ) n This is the bond point with -C(O)OH.

[0189] As a non-limiting example of the above-described embodiment, B 14 ~B 21 The ring containing is [ka] This can be done, and each of them has 1 to 2 R c2 It may be replaced as desired, where aa is -(CR 3a R 3b ) n -R 2 This is the point of connection.

[0190] In certain embodiments of formulas (I-1), (I-1a), (I-2), (I-2a), (I-3), or (I-3a), n is 1, and optionally R 3a and R 3b H may also be used. In certain embodiments of formulas (I-1), (I-1a), (I-2), (I-2a), (I-3), or (I-3a), n is 1, and R3a and R 3b One of them is H, and R 3a and R 3b The other is C 1-6 It is an alkyl group, for example, ethyl or methyl. In certain embodiments of formulas (I-1), (I-1a), (I-2), (I-2a), (I-3), or (I-3a), n is 1, and R 3a and R 3b This means that each of them, together with the carbon atom to which it is bonded, C 3-6 For example, a cycloalkyl group can be formed into a cyclopropyl group. In certain embodiments of equations (I-1), (I-1a), (I-2), (I-2a), (I-3), or (I-3a), n is 0.

[0191] In specific embodiments of formulas (I-1), (I-1a), (I-2), (I-2a), (I-3), or (I-3a), Ar 1 [ka] And; m1 is 0, 1, 2, or 3; R Aa and R Ab Each time it appears, Hello;C 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g It is independently selected from the group consisting of (which may be substituted as desired).

[0192] In specific embodiments of formulas (I-1), (I-1a), (I-2), (I-2a), (I-3), or (I-3a), Ar 1 teeth [ka] And; m1 is 0, 1, 2, or 3; R Aaand R Ab Each time it appears, halo;-C(=O)(C 1-10 Alkyl); C 1-6 Alkyl; C 1-6 Alkyl (substituted with 1 to 6 independently selected halos); C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and C 3-6 Cycloalkyl (1-2 R g It is independently selected from the group consisting of (which may be substituted as desired).

[0193] In one of these specific embodiments, m1 is 0. In certain embodiments, m1 is 1 or 2, and each R is optionally Ab is R Aa It may also be in the ortho position relative to it. In a particular embodiment, each R Ab If it exists, C 1-4 Alkoxy or C 1-4 It is a haloalkoxy, for example, C 1-4 Alkoxy, for example, methoxy. In a particular example, R Aa is C 1-3 Alkyl; C substituted with 1 to 6 F 1-3 alkyl; halo; or C 3-6 It is a cycloalkyl group.

[0194] As a non-limiting example of the above-described embodiment, Ar 1 teeth [ka] It can be done this way.

[0195] As a further non-limiting example, Ar 1 teeth [ka] A selection can be made from the group consisting of the following:

[0196] As a further non-limiting example, Ar 1 teeth [ka] A selection can be made from the group consisting of the following:

[0197] In certain embodiments of formulas (I-1), (I-1a), (I-2), (I-2a), (I-3), or (I-3a), L 1 This is a joint. In certain embodiments of formulas (I-1), (I-1a), (I-2), (I-2a), (I-3), or (I-3a), L 1 is C 1-3 Alkylene (1-6 R a (This may be substituted as desired.) For example, L 1 It could be CH2. Another non-restrictive example is L 1 It could be CH2CH2. In certain embodiments of formulas (I-1), (I-1a), (I-2), (I-2a), (I-3), or (I-3a), R 1 Phenyl (1-2 R g (This may be substituted as desired.)

[0198] In certain embodiments of formulas (I-1), (I-1a), (I-2), (I-2a), (I-3), or (I-3a), R 1 is C 9-10 Biring aryl (1-2 R) g (which may be substituted as desired). As a non-limiting example of the above embodiments, R 1 teeth [ka] It could be, and it would be 1-2 R g It may be replaced as desired.

[0199] In certain embodiments of formulas (I-1), (I-1a), (I-2), (I-2a), (I-3), or (I-3a), R 1 is 1-2 Rg C may be replaced as desired. 3-6 It is a cycloalkyl. As a non-limiting example of the above embodiment, R 1 This can be cyclobutyl or cyclopentyl, each of which contains 1-2 R g It may be replaced as desired. In certain embodiments of formulas (I-1), (I-1a), (I-2), (I-2a), (I-3), or (I-3a), R 1 is C 1-6 Alkyl (1 to 6 R a (which may be substituted as desired). In certain embodiments of formula (I-1), (I-1a), (I-2), (I-2a), (I-3), or (I-3a), R 1 is C 1-6 It is alkyl.

[0200] In certain embodiments of formulas (I-1), (I-1a), (I-2), (I-2a), (I-3), or (I-3a), R 1 is C 2-4 It is alkyl. As a non-limiting example of the above-described embodiment, R 1 It is a C3 alkyl group, for example, n-propyl and i-propyl. In certain embodiments of formulas (I-1), (I-1a), (I-2), (I-2a), (I-3), or (I-3a), R 1 is C 3-5 It is alkyl. In a particular embodiment of the above-described embodiment, R 1 is a C4 alkyl group, for example, n-butyl, i-butyl, sec-butyl, and tert-butyl. As a non-limiting example of the embodiments described above, R 1 It may be i-butyl. In certain embodiments of formulas (I-1), (I-1a), (I-2), (I-2a), (I-3), or (I-3a), L 1 This is a joint.

[0201] In a particular embodiment of formula (I-1), (I-1a), (I-2), (I-2a), (I-3), or (I-3a), [ka] teeth [ka] That is the case.

[0202] Compounds as a non-limiting example In certain embodiments, the compound is selected from the group consisting of compounds listed in Table C1 or pharmaceutically acceptable salts thereof.

[0203] Table C1 [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6]

[0204] In certain embodiments, the compound is selected from the group consisting of the compounds listed in Table C2 or pharmaceutically acceptable salts thereof.

[0205] Table C2 [Table 7] [Table 8] [Table 9] Table 10 Table 11 Table 12

[0206] Table 13 Table 14 Table 15

[0207] Table 16 Table 17 Table 18 Table 19 Table 20

[0208] Table 21 Table 22 Table 23 Table 24 Table 25

[0209] Table 26 Table 27 Table 28 Table 29 Table 30

[0210] Table 31 Table 32 Table 33 Table 34 Table 35

[0211] Table 36 Table 37 Table 38 Table 39 Table 40

[0212] Table 41 Table 42 Table 43

[0213] Table 44 Table 45 Table 46

[0214] Table 47 Table 48 Table 49 Table 50 Table 51

[0215] Table 52 Table 53 Table 54 Table 55 Table 56

[0216] Table 57 Table 58 Table 59 Table 60 Table 61

[0217] Table 62 Table 63 Table 64 Table 65 Table 66

[0218] Table 67 Table 68 Table 69 Table 70 [Table 71]

[0219] [Table 72] [Table 73] [Table 74] [Table 75] [Table 76] [Table 77] [Table 78]

[0220] The compounds of formula (I) provided herein include all stereochemical forms, e.g., enantiomers, diastereomers, and optical isomers such as mixtures thereof, e.g., racemic mixtures, and mixtures of enantiomers and / or diastereomers, including homogeneous or heterogeneous mixtures of individual enantiomers and / or diastereomers. All stereochemical forms are considered in this disclosure. Unless otherwise noted, if a compound of the disclosure is named or described by its structural formula without specifying its stereochemistry and has one or more chiral centers, it is understood that this represents all possible stereoisomers of the compound. Representative stereochemical forms are provided throughout the specification and include, but are not limited to, the compounds listed in Table C2.

[0221] The compounds of formula (I) include their pharmaceutically acceptable salts. In addition, the compounds of formula (I) also include other salts of such compounds that are not necessarily pharmaceutically acceptable but may be useful as intermediates for producing and / or purifying the compounds of formula (I) and / or separating enantiomers of the compounds of formula (I). Non-limiting examples of pharmaceutically acceptable salts of the compounds of formula (I) include trifluoroacetate.

[0222] It will be further understood that the compound of formula (I) or its salts can be isolated in the form of solvates, and therefore any such solvates are within the scope of this disclosure. For example, the compound of formula (I) and its salts may exist in non-solvated forms as well as in solvated forms with pharmaceutically acceptable solvents such as water and ethanol.

[0223] Pharmaceutical composition and administration When used as a pharmaceutical, compounds of formula (I) (e.g., compounds of formulas IA, I-1, I-2, or I-3) may be administered in the form of pharmaceutical compositions, including their pharmaceutically acceptable salts or solvates. These compositions can be manufactured by methods well known in the pharmaceutical field and may be administered by various routes depending on whether topical or systemic treatment is desired and the area to be treated. Administration may be topical (including transdermal, epidermal, ocular, and mucosal administration, including intranasal, intravaginal, and rectal delivery), pulmonary (e.g., administration by inhalation or aspiration of powder or aerosol, including administration via nebulizer), oral, or parenteral. Oral administration may include dosage forms prescribed for administration once daily or twice daily (BID). Parenteral administration may include intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose, or, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, etc., may be essential or desirable.

[0224] Pharmaceutical compositions are also provided herein that contain, as an active ingredient, a compound of formula (I) (e.g., a compound of formula IA, I-1, I-2, or I-3), or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more pharmaceutically acceptable excipients (carriers). For example, a pharmaceutical composition is prepared using a compound of formula (I) (e.g., a compound of formula IA, I-1, I-2, or I-3), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition is suitable for topical administration. To prepare the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted with an excipient, or encapsulated in such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When the excipient is used as a diluent, it may be a solid, semi-solid, or liquid material acting as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cashews, elixirs, suspensions, emulsions, solutions, syrups, aerosols (formed in a solid or liquid medium), ointments, soft and hard ceratin capsules, suppositories, sterile injections, and sterile packaged powders containing, for example, up to 10% by weight of the active ingredient. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is a solid oral formulation. In some embodiments, the composition is formulated as tablets or capsules.

[0225] Furthermore, pharmaceutical compositions containing a compound of formula (I) (e.g., compounds of formula IA, I-1, I-2, or I-3) or a pharmaceutically acceptable salt or solvate thereof together with a pharmaceutically acceptable excipient are also provided herein. Pharmaceutical compositions containing a compound of formula (I) (e.g., compounds of formula IA, I-1, I-2, or I-3) or a pharmaceutically acceptable salt or solvate thereof as an active ingredient can be prepared by mixing a compound of formula (I) (e.g., compounds of formula IA, I-1, I-2, or I-3) or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutical carrier according to conventional pharmaceutical formulation techniques. The carrier can be in a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral administration). In some embodiments, the composition is an oral solid composition.

[0226] Appropriate pharmaceutically acceptable carriers are well known in this field. Some of these pharmaceutically acceptable carriers can be found in "The Handbook of Pharmaceutical Excipients," published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0227] Methods for formulating pharmaceutical compositions are described in numerous publications, including "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. and published by Marcel Dekker, Inc.

[0228] Medicinally acceptable excipients include, but are not limited to, ion exchangers, self-emulsifying drug delivery systems (SEDDS) such as alumina, aluminum stearate, lecithin, d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymer delivery matrices, serum proteins such as human serum albumin, buffering substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of vegetable saturated fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and lanolin. The delivery of the compounds provided herein can also be enhanced using cyclodextrins, such as α-, β-, and γ-cyclodextrins, or chemically modified derivatives, such as hydroxyalkylcyclodextrins (including 2- and 3-hydroxypropyl-β-cyclodextrin), or other solubilizing derivatives. Dosage forms or compositions may be prepared containing the chemical entities provided herein in amounts ranging from 0.005% to 100%, with the remainder consisting of non-toxic excipients. The compositions to be considered may contain the chemical entities provided herein in amounts ranging from 0.001% to 100%, 0.1% to 95% in one embodiment, 75% to 85% in another embodiment, and 20% to 80% in yet another embodiment. Practical methods for preparing such dosage forms are known or obvious to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, UK. 2012).

[0229] In some embodiments, compounds of formula (I) (e.g., compounds of formula IA, I-1, I-2, or I-3), or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions provided herein, may be administered to subjects requiring them by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, the cheek, skin, intracervical, sinus, trachea, enteral, epidural, interstitial, abdominal, arterial, bronchial, sacral, cerebral, cisternal, coronary artery, intracutaneous, intraductal, duodenal, intradural, intraepidermal, esophageal, gastric, gingival, ileum, lymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, nasal cavity, intramedullary cavity, synovial bursa, testis, subarachnoid space, intraductal, tumor, uterine, intravascular, intravenous, nasal cavity (e.g., intranasal cavity), nasogastric, oral, parenteral, percutaneous, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, percutaneous, transmucosal, tracheal, ureteral, urethral, ​​and vaginal. In some embodiments, the preferred route of administration is parenteral (e.g., intratumor).

[0230] In some embodiments, compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof) or pharmaceutical compositions thereof provided herein may be formulated for parenteral administration, for example, for injection via intra-arterial, intrasternal, intracranial, intravenous, intramuscular, subcutaneous, or intraperitoneal routes. For example, such compositions may be prepared as either liquid solutions or suspensions for injection; a solid form suitable for preparing a solution or suspension may also be prepared by adding liquid before injection; the formulation may also be emulsified. The preparation of such formulations will be known to those skilled in the art in light of this disclosure. In some embodiments, devices for parenteral administration are used. For example, such devices may include needle syringes, microneedle syringes, needle-free syringes, and injection techniques.

[0231] In some embodiments, pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for in-situ preparation of sterile injection solutions or dispersions. In some embodiments, the forms must be sterile and fluid enough to be easily injected. In some embodiments, the forms must be stable under manufacturing and storage conditions and stored in a manner resistant to contamination by microorganisms such as bacteria and fungi.

[0232] In some embodiments, the carrier may also be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. In some embodiments, appropriate fluidity may be maintained by using a coating agent, for example, lecithin, to maintain the required particle size in the case of dispersion, and by using a surfactant. In some embodiments, prevention of microbial action may be achieved by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In some embodiments, isotonic agents, such as sugars or sodium chloride, may be included. In some embodiments, prolonged absorption of the injectable composition may be achieved by using absorption-delaying agents, such as aluminum monostearate and gelatin, in the composition.

[0233] In some embodiments, a sterile injection solution is prepared by compounding a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof) in a suitable solvent in the required amount, together with the various other components described above, and, if necessary, subsequently by sterile filtration. In some embodiments, a dispersion is prepared by compounding various sterile active ingredients into a sterile vehicle containing a basic dispersion medium and other components required from the above components. In some embodiments, a sterile powder is used for the preparation of a sterile injection solution. In some embodiments, the preparation method is a vacuum drying and freeze-drying technique, which yields the active ingredient powder, in addition to any further desired components, from the solution that has been previously sterile-filtered by this technique.

[0234] In some embodiments, pharmacokinetically acceptable excipients usable in rectal compositions as gels, creams, enemas, or rectal suppositories include, but are not limited to, one or more of any cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (similar to PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycol and fatty acid esters of polyethylene glycol of various molecular weights, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide SBN, vanilla essential oil, aerosols, etc. The sol contains parabens, sodium p-hydroxybenzoate propyl, diethylamine, carbomer, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylate, 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.

[0235] In some embodiments, suppositories may be prepared by mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition provided herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax that is solid at ambient temperature but liquid at body temperature, thereby dissolving in the rectum to release the active compound. In some embodiments, the composition for rectal administration is in the form of an enema.

[0236] In some embodiments, the compounds of formula (I) provided herein, or pharmaceutically acceptable salts or solvates thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof), or pharmaceutical compositions thereof, are formulated to be delivered topically to the gastrointestinal tract or GI tract by oral administration (e.g., in solid or liquid dosage forms).

[0237] In some embodiments, solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof) is one or more pharmaceutically acceptable excipients, e.g., sodium citrate or dicalcium phosphate, and / or a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and The solids are mixed with binders such as acacia, humectants such as glycerol, disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, solution retarders such as paraffin, absorption enhancers such as quaternary ammonium compounds, wetting agents such as cetyl alcohol and glycerol monostearate, adsorbents such as kaolin and bentonite clay, and lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. For example, in the case of capsules, tablets, and pills, the dosage form may also contain buffers. In some embodiments, similar types of solid compositions may also be used as fillers in soft or hard-filled gelatin capsules with excipients such as lactose and high molecular weight polyethylene glycol.

[0238] In some embodiments, the composition may take the form of a unit dosage form such as a pill or tablet, and thus the composition may contain, together with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof) provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, etc.; a lubricant such as magnesium stearate, etc.; and a binder such as starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc. In some embodiments, another solid dosage form, such as a powder, marume, solution, or 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, the one or more compounds and pharmaceutical compositions, or further activators provided herein, are intended to be physically separated unit dosage forms; for example, capsules (or tablets in capsules) containing granules of each drug; biphase tablets; two-compartment gel caps, etc. In some embodiments, enteric-coated or delayed-release oral dosage forms are also intended.

[0239] In some embodiments, other physiologically acceptable compounds may include wetting agents, emulsifiers, dispersants, or preservatives that are particularly useful for preventing the growth or action of microorganisms. For example, various preservatives are well known and include, for instance, phenol and ascorbic acid.

[0240] In some embodiments, the excipients are sterile and generally do not contain undesirable substances. For example, these compositions can 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, the United States Pharmacopeia / National Pharmacopoeia (USP / NF) standards may suffice.

[0241] In some embodiments, the compounds of formula (I) provided herein, or pharmaceutically acceptable salts or solvates thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof), or pharmaceutical compositions thereof, are formulated for ophthalmic administration. In some embodiments, the ophthalmic composition may include, but is not limited to, one or more of the following components: viscosities (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymer), cyclodextrin); and preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0242] In some embodiments, the compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof) or pharmaceutical compositions thereof provided herein are formulated for topical administration to the skin or mucous membranes (e.g., to be administered through the skin or transdermally). In some embodiments, topical compositions may include ointments and creams. In some embodiments, ointments are typically semi-solid formulations based on petrolatum or other petroleum derivatives. In some embodiments, creams containing the selected activator are typically viscous liquids or semi-solid emulsions, often either oil-in-water or water-in-oil. For example, cream bases are typically washable and contain an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase (sometimes also called the “internal phase”) generally contains petrolatum and fatty alcohols such as cetyl or stearyl alcohol; the aqueous phase usually, but not necessarily, exceeds the volume of the oil phase and generally contains a humectant. In some embodiments, the emulsifier in the cream formulation is generally a nonionic, anionic, cationic, or amphoteric surfactant. In some embodiments, the ointment base, as with other carriers or vehicles, should be inert, stable, non-irritating, and non-sensitizing.

[0243] In any of the embodiments described above, the pharmaceutical composition provided herein may comprise one or more components: lipids, interlayer crosslinked multilayer vesicles, biodegradable poly(D,L-lactic acid-coglycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and a lipid bilayer supporting nanoporous particles.

[0244] In some embodiments, the dosage of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof) is determined based on several factors, but are not limited, including the type of subject, age, weight, sex, medical condition, severity of the medical condition, route of administration, and the activity of the compound or its pharmaceutically acceptable salt or solvate. In some embodiments, the appropriate dosage for a particular situation may be determined by those skilled in the art in the medical field. In some embodiments, the total daily dose may be divided and administered in small amounts throughout the day or by means of providing continuous delivery.

[0245] In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof) is administered in doses of about 0.01 to about 1000 mg, for example, about 0.1 to about 30 mg, about 10 to about 80 mg, about 0.5 to about 15 mg, about 50 mg to about 200 mg, about 100 mg to about 300 mg, about 200 to about 400 mg, about 300 mg to about 500 mg, about 400 mg to about 600 mg, about 500 mg to about 800 mg, about 600 mg to about 900 mg, or about 700 mg to about 1000 mg. In some embodiments, the dose is a therapeutically effective amount.

[0246] In some embodiments, the compounds of formula (I) provided herein, or pharmaceutically acceptable salts or solvates thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof) are present in amounts of about 0.0002 mg / kg to about 100 mg / kg (e.g., about 0.0002 mg / kg to about 50 mg / kg; about 0.0002 mg / kg~about 25mg / kg;about 0.0002mg / kg~about 10mg / kg;about 0.0002mg / kg~about 5mg / kg;about 0.0002mg / kg~about 1mg / kg;about 0.0002mg / kg ~0.5mg / kg; approx. 0.0002mg / kg ~ approx. 0.1mg / kg; approx. 0.001mg / kg ~ approx. 50mg / kg; approx. 0.001mg / kg ~ approx. 25mg / kg; approx. 0.001mg / kg ~ approx. 10mg / kg; 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 0.01 mg / kg to about 50 mg / kg; about 0.01 mg / kg to about 25 mg / kg; about 0.01 mg / kg to about 10 mg / kg; about 0.01 mg / kg to about 5 mg / kg; about 0.01 mg The drugs are administered in doses of approximately 1 mg / kg, approximately 0.01 mg / kg to approximately 0.5 mg / kg, approximately 0.01 mg / kg to approximately 0.1 mg / kg, approximately 0.1 mg / kg to approximately 50 mg / kg, approximately 0.1 mg / kg to approximately 25 mg / kg, approximately 0.1 mg / kg to approximately 10 mg / kg, approximately 0.1 mg / kg to approximately 5 mg / kg, approximately 0.1 mg / kg to approximately 1 mg / kg, and approximately 0.1 mg / kg to approximately 0.5 mg / kg. In some embodiments, the compounds of formula (I) provided herein, or their pharmaceutically acceptable salts or solvates (e.g., any one of the compounds of formula IA, I-1, I-2, or I-3, or their pharmaceutically acceptable salts or solvates) are administered in doses of approximately 100 mg / kg.

[0247] In some embodiments, the above-mentioned dose of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof) may be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or on a non-daily basis (e.g., every other day, every two days, every three days, every week, every two weeks, once every two weeks, once a month).

[0248] In some embodiments, the duration of administration of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof) provided herein is between 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In some embodiments, the period during which administration is discontinued is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof) is administered to a subject for a certain period of time, followed by another certain period during which the administration of the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof) is discontinued. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof) is administered over a first period and a second period following the first period, during which administration is stopped, followed by a third period in which administration of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof) is started, and then a fourth period following the third period in which administration is stopped.For example, the period of administration of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof), followed by a period of discontinuation of administration, is repeated with a determined or undetermined duration. In some embodiments, the administration period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In some embodiments, the period of discontinuation of administration is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer.

[0249] In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof) is administered orally to a subject once or more times a day (e.g., once a day, twice a day, three times a day, four times a day, or a single daily dose).

[0250] In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof) is administered parenterally to a subject once or more times a day (e.g., 1 to 4 times, once a day, twice a day, three times a day, four times a day, or a single daily dose).

[0251] In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof) is administered to a subject weekly by parenteral administration.

[0252] Treatment method The compounds provided herein, their pharmaceutically 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 in the prevention and / or treatment of various diseases, including, for example, fibrosis (e.g., renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis, systemic sclerosis), urinary tract diseases, cancer-related diseases, proliferative disorders, inflammatory / immune system diseases, diseases due to secretory dysfunction, brain-related diseases, and chronic diseases.

[0253] In some embodiments, the Disclosure provides methods for treating subjects (e.g., humans) with a disease, disorder, or condition (i.e., an LPA-related disease) in which inhibition of one or more LPA receptors is beneficial for treating the underlying pathology and / or signs and / or progression of the disease, disorder, or condition. In some embodiments, the methods provided herein may include, or further encompass, treating one or more symptoms that are associated with, concurrent with, or sequelae of any one or more symptoms provided herein.

[0254] A method for treating LPA-related diseases is provided herein, comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition disclosed herein, to a subject in need of such treatment.

[0255] In some embodiments, LPA-related diseases include, but are not limited to, fibrosis of organs (e.g., liver, kidneys, lungs, heart, and skin), liver diseases (acute hepatitis, chronic hepatitis, hepatic fibrosis, cirrhosis, portal hypertension, recurrent failure, non-alcoholic steatohepatitis (NASH), hepatic dysfunction, hepatic blood flow disorders, etc.), cell proliferation disorders (e.g., cancer, including solid tumors, solid tumor metastases, angiofibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, and chronic lymphocytic leukemia (CLL), and invasive metastasis of cancer cells), inflammatory diseases (e.g., psoriasis, nephropathy, and pneumonia), and gastrointestinal diseases (e.g., irritable bowel syndrome (TBS), inflammatory bowel syndrome). This includes diseases (IBD and pancreatic secretory disorders), kidney disease, urinary tract disorders (e.g., signs associated with benign prostatic hyperplasia or neurogenic bladder disease, spinal cord tumors, herniated discs, spinal stenosis, signs of diabetes, lower urinary tract disorders (e.g., lower urinary tract obstruction), inflammatory diseases of the lower urinary tract, dysuria, and frequent urination), pancreatic diseases, abnormal angiogenesis-related disorders (e.g., arterial occlusion), scleroderma, brain-related disorders (e.g., stroke and cerebral hemorrhage), neuropathic pain, peripheral neuropathy, and eye diseases (e.g., age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), scarring pemphigus, and glaucoma filtration surgery scars).

[0256] In some embodiments, methods for treating or preventing fibrosis are provided herein, comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition disclosed herein. For example, the method may include the treatment of renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis, or systemic sclerosis. In some embodiments, methods for treating pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis (IPF)) are provided herein, comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein.

[0257] In some embodiments, the compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA, I-1, I-2, or I-3, or pharmaceutically acceptable salts or solvates thereof), or pharmaceutical compositions provided herein, are used to treat or prevent fibrosis in a subject. For example, the compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA, I-1, I-2, or I-3, or pharmaceutically acceptable salts or solvates thereof), or pharmaceutical compositions provided herein, may be used to treat fibrosis of organs or tissues in a subject. In some embodiments, the Specified Publicly Provided Methods for preventing fibrotic symptoms in a subject, comprising administering to a subject at risk of developing one or more fibrotic symptoms a therapeutically effective amount of a compound of formula (I) provided herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition. For example, the subject may be exposed to one or more environmental conditions known to increase the risk of organ or tissue fibrosis. In some embodiments, the subject is exposed to one or more environmental conditions known to increase the risk of lung, liver, or kidney fibrosis. In some embodiments, the subject has a genetic predisposition to develop organ or tissue fibrosis. In some embodiments, compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA, I-1, I-2, or I-3, or pharmaceutically acceptable salts or solvates thereof), or pharmaceutical compositions provided herein, are administered to a subject to prevent or minimize scarring after an injury. For example, such injury may include surgery.

[0258] Exemplary diseases, disorders, or conditions involving fibrosis include, but are not limited to, lung diseases associated with fibrosis, such as idiopathic pulmonary fibrosis, ectopic drug-induced, occupational / environment-induced fibrosis (farmer's lung), granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases (sclerosis, etc.), alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, genetic disorders (e.g., Hermanski-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, and familial interstitial lung disease), and systemic inflammation. Pulmonary fibrosis secondary to diseases such as rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrotic alveolitis, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, bleomycin-induced pulmonary fibrosis, chronic asthma, silicosis, asbestos-induced lung or pleural fibrosis, acute lung injury, acute respiratory distress syndrome (ARDS), and acute dyspnea (including bacterial pneumonia-induced, trauma-induced, viral pneumonia-induced, ventilator-induced, non-pulmonary sepsis-induced, and aspiration-induced dyspnea), injury / fibrosis Glomerulonephritis secondary to systemic inflammatory diseases such as associated chronic nephropathy, renal fibrosis, lupus and scleroderma, tubulointerstitial fibrosis, glomerulonephritis, glomerulosclerosis, focal segmental diabetes, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allogeneic transplantation and Alport syndrome; skin disorders, intestinal fibrosis, e.g., scleroderma and radiation-induced intestinal fibrosis; hepatic fibrosis, e.g., cirrhosis, alcohol-induced hepatic fibrosis, non-alcoholic steatohepatitis (NASH), non-alcoholic steatohepatitis Fatty liver disease (NAFLD), toxic / drug-induced hepatic fibrosis (e.g., hemacromatosis), biliary tract injury, primary biliary cirrhosis, infectious or virus-induced hepatic fibrosis (e.g., chronic HCV infection), inflammatory / immuno-disorders, and autoimmune hepatitis; head and neck fibrosis, e.g., corneal scarring, e.g., LASIK (laser-assisted myopia surgery), corneal transplantation, and trabeculectomy; hypertrophic scarring, Dupuytren's disease, cutaneous fibrosis, xerosis, keloids, e.g., burn-induced or surgical;and other fibrotic diseases, such as sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, restenosis, atherosclerosis, arteriosclerosis, Wegner granuloma, chronic lymphocytic leukemia, tumor metastasis, transplant organ rejection (e.g., bronchiolitis obliterans), endometriosis, neonatal respiratory distress syndrome, and neuropathic pain, fibromyalgia, mixed connective tissue disease, and Peyronie's disease.

[0259] A method for improving lung function in a subject is provided herein, comprising administering to the subject in need a therapeutically effective amount of a compound of formula (I) provided herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition thereof. In some embodiments, the subject has been diagnosed with pulmonary fibrosis. In some embodiments, a compound of formula (I) provided herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition thereof, is used to treat idiopathic pulmonary fibrosis in the subject. In some embodiments, compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA, I-1, I-2, or I-3, or pharmaceutically acceptable salts or solvates thereof), or pharmaceutical compositions provided herein are used to treat common interstitial pneumonia in a subject.

[0260] In some embodiments, compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA, I-1, I-2, or I-3, or pharmaceutically acceptable salts or solvates thereof), or pharmaceutical compositions provided herein, are used to treat ectopic drug-induced, occupational / environment-induced fibrosis (farmer's lung), granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases (sclerosis, etc.), alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, and genetic diseases (e.g., Hermanski-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, and familial interstitial lung disease) in subjects.

[0261] In some embodiments, compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA, I-1, I-2, or I-3, or pharmaceutically acceptable salts or solvates thereof), or pharmaceutical compositions provided herein are useful for treating post-transplant fibrosis associated with chronic rejection reactions such as obstructive bronchiolitis following lung transplantation in subjects.

[0262] In some embodiments, compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA, I-1, I-2, or I-3, or pharmaceutically acceptable salts or solvates thereof), or pharmaceutical compositions provided herein are useful for treating cutaneous fibrosis such as scleroderma, Dupuytren's disease, and keloids in subjects.

[0263] In some embodiments, compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA, I-1, I-2, or I-3, or pharmaceutically acceptable salts or solvates thereof), or pharmaceutical compositions provided herein are useful for treating, in subjects, hepatic fibrosis with or without cirrhosis, e.g., toxic / drug-induced fibrosis (hemochromatosis), alcoholic liver disease, viral hepatitis (hepatitis B virus, hepatitis C virus, HCV), non-alcoholic liver disease (NAFLD, NASH), and metabolic and autoimmune diseases.

[0264] In some embodiments, compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA, I-1, I-2, or I-3, or pharmaceutically acceptable salts or solvates thereof), or pharmaceutical compositions provided herein are useful for treating renal fibrosis (e.g., tubulointerstitial fibrosis and glomerulosclerosis) in subjects.

[0265] Further examples of diseases, disorders, or conditions provided herein include atherosclerosis, thrombosis, heart disease, vasculitis, scar tissue formation, restenosis, phlebitis, COPD (chronic obstructive pulmonary disease), pulmonary hypertension, pulmonary fibrosis, pneumonia, intestinal adhesions, bladder fibrosis and cystitis, nasal fibrosis, sinusitis, neutrophil-mediated inflammation, and fibroblast-mediated fibrosis.

[0266] In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein, is administered to a subject having organ or tissue fibrosis, or predisposed to developing organ or tissue fibrosis, together with one or more other agents used to treat fibrosis. In some embodiments, one or more agents include corticosteroids, immunosuppressants, B-cell antagonists, and uteroglobin.

[0267] In some embodiments, compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA, I-1, I-2, or I-3, or pharmaceutically acceptable salts or solvates thereof), or pharmaceutical compositions provided herein, are used to treat skin diseases in subjects. Such skin diseases include, but are not limited to, atopic dermatitis, vesicular diseases, collagen diseases, psoriasis, scleroderma, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren-Larso syndrome, or proliferative or inflammatory disorders of the skin. In some embodiments, compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA, I-1, I-2, or I-3, or pharmaceutically acceptable salts or solvates thereof) are used to treat systemic sclerosis.

[0268] In some embodiments, compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA, I-1, I-2, or I-3, or pharmaceutically acceptable salts or solvates thereof) are useful for treating or preventing inflammation in a subject. For example, compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA, I-1, I-2, or I-3, or pharmaceutically acceptable salts or solvates thereof) may be used to treat or prevent inflammation / immunodeficiency in a subject.

[0269] Examples of inflammation / immune disorders include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory myopathy, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, eczema, allograft rejection (of organs, bone marrow, stem cells, and other cells and tissues), graft-versus-host disease, lupus erythematosus, inflammatory diseases, type 1 diabetes, pulmonary fibrosis, dermatomyositis, Sjögren's syndrome, thyroiditis (e.g., Hashimoto's disease and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, and atopic dermatitis.

[0270] In some embodiments, compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA, I-1, I-2, or I-3, or pharmaceutically acceptable salts or solvates thereof), or pharmaceutical compositions provided herein are used for the treatment of pain in a subject. In some embodiments, the pain is acute or chronic. In some embodiments, the pain is neuropathic.

[0271] In some embodiments, compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA, I-1, I-2, or I-3, or pharmaceutically acceptable salts or solvates thereof), or pharmaceutical compositions provided herein are used in the treatment of fibromyalgia. Fibromyalgia is thought to originate from the formation of fibrous scar tissue in the contractile muscles (voluntary muscles). Fibrosis constricts the tissue, obstructs blood flow, and consequently causes pain.

[0272] In some embodiments, compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA, I-1, I-2, or I-3, or pharmaceutically acceptable salts or solvates thereof), or pharmaceutical compositions provided herein, are used in the treatment of cancer. In some embodiments, compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA, I-1, I-2, or I-3, or pharmaceutically acceptable salts or solvates thereof), or pharmaceutical compositions provided herein, are used in the treatment of malignant and benign proliferative cancers. In some embodiments, compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA, I-1, I-2, or I-3, or pharmaceutically acceptable salts or solvates thereof), or pharmaceutical compositions provided herein, are used to prevent or reduce tumor cell proliferation, carcinoma, pleural mesothelioma (Yamada, Cancer Sci., 2008, 99(8), 1603-1610), or invasion and metastasis of peritoneal mesothelioma, cancer pain, and bone metastasis (Boucharaba et al., J Clin. Invest., 2004, 114(12), 1714-1725; Boucharaba et al., Proc. Natl. acad Sci., 2006, 103(25)9643-9648). A method for treating cancer in a subject is provided herein, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition provided herein. In some embodiments, the method provided herein further comprises administering a second therapeutic agent, wherein the second therapeutic agent is an anticancer agent.

[0273] As used herein, the term "cancer" means a cellular growth that is prone to growing uncontrollably and, in some cases, prone to metastasis (spreading). Types of cancer include, but are not limited to, solid tumors (cancers of the bladder, intestines, brain, breast, endometrium, heart, kidneys, lungs, lymphoid tissue (lymphoma), ovaries, pancreas or other endocrine organs (thyroid), prostate, skin (melanoma or basal cell carcinoma)) or hematological malignancies (such as leukemia) that are at any stage of disease, with or without metastasis.

[0274] More atypical examples of cancer include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendiceal cancer, astrocytoma, atypical malformation / rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brainstem glioma, brain tumor, brain and spinal cord tumor, breast cancer, bronchial tumor, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonic tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing's sarcoma-type tumors, eye cancer, reticular cancer. Membryoblastoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, pilocytic cell leukemia, head and neck cancer, hepatocellular carcinoma (liver cancer), Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumor (pancreatic endocrine tumor), Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, pharyngeal cancer, leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, pilocytic cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstorm macroglobulinemia, medulloblastoma, medullary epithelioma, melanoma, mesothelioma, oral cancer, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial carcinoma, ovarian germ cell tumor, low-grade ovarian tumor, pancreatic cancer, papilloma, parathyroid cancer, penile cancer, pharyngeal cancer, moderately differentiated pineal parenchymal tumor, pineoblastoma and supratentorial primitive neuroectoderm tumor, pituitary tumor, phenotype Cellular neoplasms include multiple myeloma, pleuroblastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcomas, Ewing sarcoma-type tumors, Kaposi's sarcoma, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, supratentorial primitive neuroectodermal tumor, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstorm macroglobulinemia, and Welms tumor.

[0275] In some embodiments, a method is provided herein for treating an allergic disorder in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) provided herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof) is useful for treating respiratory diseases, disorders, or symptoms in a subject. For example, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof) may treat asthma (e.g., chronic asthma) in a subject.

[0276] As used herein, the term “respiratory disease” refers to any disease affecting the organs involved in respiration, such as the nose, throat, pharynx, Eustachian tube, trachea, bronchi, lungs, associated muscles (e.g., diaphragm and intercostal muscles), and nerves. Non-exclusive examples of respiratory diseases include asthma, adult respiratory distress syndrome and allergic (exogenous) asthma, non-allergic (endogenous) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, childhood-onset asthma, adult-onset asthma, cough variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease (including chronic bronchitis or emphysema), pulmonary hypertension, interstitial pulmonary fibrosis and / or airway inflammation and cystic fibrosis, and hypoxia.

[0277] As used herein, the term "asthma" refers to any lung disorder characterized by changes in airflow in the lungs associated with airway constriction, due to any cause (endogenous, exogenous, or both; allergic or non-allergic). The term "asthma" may be used with one or more adjectives to indicate the cause.

[0278] Further provided herein are methods for treating or preventing chronic obstructive pulmonary disease in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) provided herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof). Examples of chronic obstructive pulmonary disease include, but are not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or airway inflammation, and cystic fibrosis.

[0279] In some embodiments, compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA, I-1, I-2, or I-3, or pharmaceutically acceptable salts or solvates thereof) are useful in the treatment or prevention of neurological disorders in subjects. As used herein, the term “neurological disorder” means any condition that alters the structure or function of the brain, spinal cord, or peripheral nervous system, and includes, but is not limited to, Alzheimer’s disease, cerebral edema, cerebral ischemia, stroke, multiple sclerosis, neuropathy, Parkinson’s disease, conditions observed after blunt or surgical trauma (including postoperative cognitive impairment and spinal cord or brainstem injury), and neurological aspects of disorders such as degenerative disc disease and sciatica.

[0280] In some embodiments, methods for treating or preventing CNS disorders in subjects are provided herein. Non-limiting examples of CNS disorders include multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, postoperative cognitive impairment, migraine, peripheral neuropathy / neuropathic pain, spinal cord injury, cerebral edema, and head trauma.

[0281] Methods for treating or preventing cardiovascular disease in the subject area are also provided herein. As used herein, the term “cardiovascular disease” means, but is not limited to, diseases affecting the heart, or the blood vessels, or both; arrhythmias (atria, ventricles, or both); atherosclerosis and its sequelae; angina pectoris; cardiac rhythm disorders; myocardial ischemia; myocardial infarction; aneurysms of the heart or blood vessels; vasculitis, stroke; peripheral occlusive arteriosclerosis of the limbs, organs, or tissues; post-ischemia-reperfusion injury of the brain, heart, or other organs or tissues; toxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including those associated with migraines); vascular abnormalities, inflammation, or failure limited to a single organ or tissue. For example, the present invention provides a method 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 of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof).

[0282] In some embodiments, methods for alleviating cardiac reperfusion injury following myocardial ischemia and / or endotoxin shock are provided herein, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof) to a subject in need.

[0283] Further provided herein are methods for reducing vasoconstriction in a subject, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof). For example, provided herein are methods for lowering or preventing an increase in blood pressure in a subject, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof).

[0284] Combination therapy In some embodiments, this disclosure intends to cover both monotherapy regimens and combination therapy regimens. In some embodiments, the methods provided herein may further include administering one or more additional therapeutic agents (e.g., one or more additional therapeutic agents and / or one or more therapeutic regimens) in combination with the administration of the compounds provided herein.

[0285] In some embodiments, a compound of formula (I) provided herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt or solvate thereof) may be administered in combination with one or more further therapeutic agents.

[0286] Representative additional treatments include, but are not limited to, corticosteroids (e.g., dexamethasone or fluticasone), immunosuppressants (e.g., tacrolimus and pimecrolimus), analgesics, anticancer drugs, anti-inflammatory drugs, chemokine receptor antagonists, bronchodilators, leukotriene receptor antagonists (e.g., montelukast or zafirlukast), leukotriene formation inhibitors, and monoacylglycerol kinase inhibitors. Harmful agents, phospholipase A1 inhibitors, phospholipase A2 inhibitors, and lysophospholipase D (IysoPLD) inhibitors, autotaxin inhibitors, analgesics, antihistamines (e.g., loratidine), mucolytics, anticholinergics, antitussives, expectorants, antiinfectives (e.g., fudicic acid, especially for the treatment of atopic dermatitis), antifungal agents (e.g., clotriazole, especially for atopic dermatitis), anti-IgE antibody therapies (e.g., omalizumab), β2 adrenergic agonists (e.g., alpha-2 adrenergic agonists). Buterol or salmeterol), other PGD2 antagonists that act on other receptors such as DP antagonists, PDE4 inhibitors (e.g., siromilast), drugs that modulate cytokine production, e.g., TACE inhibitors, drugs that modulate the activity of Th2 cytokines IL-4 & IL-5 (e.g., monoclonal antibodies & drugs that block soluble receptors), PPARy agonists (e.g., rosiglitazone and pioglitazone), 5-lipoxygenase inhibitors (e.g., jiloyd). Ton), Pirfenidone, Nintedanib, Thalidomide, Carrumab, FG-3019, Fresolimmab, Interferon Alpha, Lecithinated Superoxide Dismutase, Simtuzumab, Tandicertive, Tralokinumab, hu3G9, AM-152, IFN-Gamma-lb, IW-001, PRM-151, PXS-25, Pentoxiferin / N-Acetyl-Cysteine, Pentoxiferin / Vitamin E, Salbutamol Sulfate, [Sar9,Met(02)11 J-Substance P, Pentoxifylline, Mercaptamine Ditartrate, Oveticolic Acid, Alamcol, GFT-505, Eicosapentyl Ethyl Ester, Metformin, Metreleptin, Muromonab-CD3, Ortiplasm, IMM-124-E, MK-4074, PX-102, RO-5093151,Angiotensin-converting enzyme (ACE) inhibitors, ramipril, angiotensin II receptor 1 subtype (AT1) antagonists, irbesartan, antiarrhythmic agents, doronedarone, peroxisome proliferator-activated receptor-alpha (PPAR-α) activators, peroxisome proliferator-activated receptor-gamma (PPAR-γ) activators, pioglitazone, rosiglitazone, prostanoids, endothelin receptor antagonists, bosentan, elastase inhibitors, calcium antagonists, beta-blockers, diuretics, aldosterone receptors Receptor antagonists, eplerenone, renin inhibitors, rho kinase inhibitors, soluble guanylate cyclase (sGC) activators, sGC sensitizers, phosphodiesterase (PDE) inhibitors, phosphodiesterase type 5 (PDE5) inhibitors, NO donors, digitalis drugs, angiotensin-converting enzyme / neutral endopeptidase (ACE / NEP) inhibitors, statins, bile acid reuptake inhibitors, platelet-derived growth factor (PDGF) receptor antagonists, vasopressin antagonists, aqueducts, sodium hydrogen exchange transporter subtype 1 (N HE1 inhibitors, factor II / Ma factor antagonists, factor IX / IXa factor antagonists, factor X / Xa factor antagonists, factor XIII / XIIIa factor antagonists, anticoagulants, antithrombotic agents, platelet inhibitors, fibrinolytic agents, thrombin-activated fibrinolytic inhibitors (TAFI), plasminogen-activating factor 1 (PAI1), coumarin, heparin, thromboxane antagonists, serotonin antagonists, cyclooxygenase inhibitors, acetylsalicylic acid, therapeutic antibodies, glycoprotein ILB / II This includes la(GPIIb / llla) antagonists (including absiximab), chymase inhibitors, cell division inhibitors, taxanes, paclitaxel, docetaxel, aromatase inhibitors, estrogen receptor antagonists, selective estrogen receptor modulators (SERMs), tyrosine kinase inhibitors, imatinib, receptor tyrosine kinase inhibitors, RAF kinase inhibitors, p38 mitogen-activated protein kinase (p38MAPK) inhibitors, pirfenidone, multi-kinase inhibitors, and sorafenib.

[0287] In any of the embodiments described above, a compound of formula (I) (e.g., a compound of formula IA, I-1, I-2, or I-3), or a pharmaceutically acceptable salt or solvate thereof, and further activators may be administered simultaneously or sequentially. For example, the activators may be incorporated into a single pharmaceutical composition or administered together as separate formulations.

[0288] Examples The present invention will be further illustrated by the following embodiments, but these embodiments will not limit the scope of the invention as described in the claims.

[0289] General Information: All evaporation was performed under vacuum using a rotary evaporator. Analytical samples were dried under vacuum (1-5 mmHg) at room temperature. Thin-layer chromatography (TLC) was performed on silica gel plates, and spots were visualized with UV light (214 and 254 nm). Purification by column and flash chromatography was performed using silica gel (100-200 mesh). Solvent systems were reported as mixtures by volume. NMR spectra were recorded using a Bruker 400 or Varian (400 MHz) spectrometer. The 1H chemical shift was reported as a ppm δ value using a deuterated solvent as the internal standard. Data were reported as follows: chemical shift, multiplicity (s=singular, d=doublet, t=triplet, q=quadruplet, br=broad, m=multilet), coupling constant (Hz), and integral value. LC-MS spectra were obtained using a Shimadzu LC20-MS2020 or Agilent 1260 series 6125B mass spectrometer, or an Agilent 1200 series, 6110 or 6120 mass spectrometer (ionization by electron jet is omitted unless otherwise specified).

[0290] Example 1 2-((2S,3R)-2-((2,3-dihydro-1H-inden-2-yl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-2H-indazole-7-carboxylic acid (compound 113a) [ka]

[0291] Step A: (3,5-dimethoxy-4-methylphenyl)methanol [ka]

[0292] A solution of 3,5-dimethoxy-4-methylbenzoic acid (10.0 g, 50.9 mmol) in THF (100 mL) was mixed with LiAlH4 (1.0 M, 56.1 mL in THF) at 0°C. The mixture was stirred at 50°C for 2 hours. The mixture was quenched with water (50 mL) and extracted with ELISA (30 mL x 3). The organic layers were combined, dried on anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to obtain (3,5-dimethoxy-4-methylphenyl)methanol (7.31 g, crude product) as a brown solid. 1 H NMR(400MHz, CDCl3)δ 6.56(s,2H), 4.68(d,J=4.0Hz,2H), 3.84(s,6H), 2.09(s,3H), 1.67(t,J=4.2Hz,1H)

[0293] Step B: 3,5-dimethoxy-4-methylbenzaldehyde [ka]

[0294] To a solution of (3,5-dimethoxy-4-methylphenyl)methanol (7.31 g, crude) in DCM (70 mL), DMP (20.4 g, 48.1 mmol) was added at 0°C. The mixture was stirred at 25°C for 1 hour. To the mixture, saturated aqueous solution of NaHCO3 (100 mL) and saturated aqueous solution of Na2S2O3 (100 mL) were added. The resulting mixture was stirred at 0°C for 30 minutes and then filtered. The filtrate was separated. The aqueous layer was extracted with DCM (30 mL x 3). The organic layers were combined and concentrated under vacuum to obtain 3,5-dimethoxy-4-methylbenzaldehyde (7.17 g, yield 99.2%) as a brown solid. 1 H NMR(400MHz, CDCl3)δ 9.91(s,1H), 7.06(s,2H), 3.90(s,6H), 2.16(s,3H)

[0295] Step C: 2-((2,3-dihydro-1H-inden-2-yl)oxy)acetic acid [ka]

[0296] NaH (17.9 g, 447 mmol) was added to a solution of indan-2-ol (30.0 g, 223 mmol) in THF (300 mL). The reaction mixture was stirred at 60°C for 0.5 hours. The mixture was cooled to 20°C, and 2-chloroacetic acid (24.5 g, 259 mmol) was added to the mixture. The reaction mixture was stirred at 65°C for 16 hours. After cooling, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The aqueous layer was acidified to pH=5 using 2N HCl and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, dried on anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to obtain 2-indan-2-yloxyacetic acid (36.5 g, crude) as a brown solid. 1 H NMR (400MHz, DMSO-d6)δ 7.25-7.18(m,2H), 7.16-7.09(m,2H), 4.44-4.33(m,1H), 4.04-4.03(s,2H), 3.10(dd,J=16.4, 4.0Hz,2H), 2.91(dd,J=16.8, 3.6Hz,2H)

[0297] Process D: 2-((2,3-dihydro-1H-inden-2-yl)oxy)acetyl chloride [ka]

[0298] To a solution of 2-indan-2-yloxyacetic acid (36.5 g, crude) in DCM (400 mL), DMF (693 mg, 9.49 mmol) was added, followed by oxalyl dichloride (72.3 g, 569 mmol). The reaction mixture was stirred at 20°C for 16 hours. The mixture was concentrated under vacuum to obtain 2-indan-2-yloxyacetyl chloride (41.6 g, crude) as a brown oil, which was used directly in the next step.

[0299] Step E (R)-4-benzyl-3-(2-((2,3-dihydro-1H-inden-2-yl)oxy)acetyl)oxazolidine-2-one [ka]

[0300] (4R)-4-benzyloxazolidine-2-one (42.0 g, 237 mmol) was dissolved in THF (400 mL) and n-BuLi (2.5 M, 237 mmol) was added under N2 conditions at -78 °C. 2-Indan-2-yloxyacetyl chloride (41.6 g, crude) / THF (100 mL) was added to the reaction mixture at -78 °C, and the mixture was stirred at 25 °C for 1.5 hours. The mixture was quenched with water (400 mL) and extracted with ELISA (80 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to obtain a crude product (73.5 g) as a brown oil. The residue was purified by flash chromatography (PE / siRNA=1 / 1) to obtain (R)-4-benzyl-3-(2-((2,3-dihydro-1H-inden-2-yl)oxy)acetyl)oxazolidine-2-one (48.6g, 62.1% yield over 3 steps) as a brown oil. 1H NMR (400MHz, CDCl3)δ 7.38-7.27(m,3H), 7.25-7.14(m,6H), 4.75(d,J=1.6Hz,2H), 4.74-4.66(m,1H), 4.52-4.49(m,1H ), 4.33-4.21(m,2H), 3.38-3.30(m,1H), 3.30-3.20(m,2H), 3.17-3.08(m,2H), 2.85-2.79(m,1H)

[0301] Process F (R)-4-benzyl-3-((2R,3S)-2-((2,3-dihydro-1H-inden-2-yl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropanoyl)oxazolidine-2-one [ka]

[0302] (R)-4-benzyl-3-(2-((2,3-dihydro-1H-inden-2-yl)oxy)acetyl)oxazolidine-2-one (12.1 g, 34.4 mmol) was added dropwise to a solution of (R)-4-benzyl-3-(2-((2,3-dihydro-1H-inden-2-yl)oxy)acetyl)oxazolidine-2-one (200 mL) in DCM (6.86 g, 36.2 mmol) under N2 conditions at -70°C. The solution was stirred at -70°C for 15 minutes. DIEA (11.1 g, 86.1 mmol) was added to the solution. The solution was stirred at -70°C for 1 hour. NMP (3.41 g, 34.4 mmol) was added to the solution at -70°C. The solution was stirred at -70°C for 10 minutes. 3,5-dimethoxy-4-methylbenzaldehyde (6.21 g, 34.4 mmol) was added to the solution. The mixture was stirred at -70°C for 1 hour, then at -40°C for 1 hour. The mixture was quenched with water (200 mL) and extracted with ethyl acetate (60 mL x 3). The organic layers were combined, dried on anhydrous sodium 2SO4, filtered, and the filtrate was concentrated under vacuum to obtain a crude product (23.0 g). The residue was purified by flash chromatography (PE / ethyl acetate = 1 / 1) to obtain (R)-4-benzyl-3-((2R,3S)-2-((2,3-dihydro-1H-inden-2-yl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropanoyl)oxazolidine-2-one (12.0 g, yield 61.8%) as a yellow oil. 1 H NMR (400MHz, CDCl3)δ 7.29-7.17(m,4H), 7.16-6.98(m,5H), 6.45(s,2H), 5.46(d,J=5.2Hz,1H), 4.76(t,J=4.8Hz,1H), 4.32-4.29(m,1H), 4.25-4.21(m,1H), 3.98(dd,J=8.8, 4.0Hz,1H), 3.65(s,6H), 3.25-3.17(m,1H), 3.17-3.08(m,1H), 3.07-2.96(m,2H), 2.95-2.94(m,1H), 2.79-2.68(m,2H)

[0303] Process G (2R)-1-[(4R)-4-benzyl-2-oxo-oxazolidine-3-yl]-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxy-propane-1,3-dione [ka]

[0304] (R)-4-benzyl-3-((2R,3S)-2-((2,3-dihydro-1H-inden-2-yl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropanoyl)oxazolidine-2-one (7.00 g, 13.2 mmol) was dissolved in DCM (70 mL), to which DMP (6.70 g, 15.8 mmol) was added. The mixture was stirred at 0°C for 2 hours. Saturated aqueous solutions of NaHCO3 and Na2S2O3 (1:1, 40 mL) were added to the mixture, and the mixture was stirred at 0°C for 30 minutes. The organic layers were then separated. The aqueous layers were extracted with DCM (20 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by flash chromatography (PE / siRNA = 1 / 1) to obtain (2R)-1-[(4R)-4-benzyl-2-oxo-oxazolidine-3-yl]-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxy-propane-1,3-dione (4.84 g, yield 69.4%) as a white solid. LC-MS: m / z 530.2 (M+H) +

[0305] Process H (4R)-4-benzyl-3-[(2R,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-indan-2-yloxy-propanoyl]oxazolidine-2-one [ka]

[0306] To a solution of (2R)-1-[(4R)-4-benzyl-2-oxo-oxazolidine-3-yl]-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxy-propane-1,3-dione (4.84 g, 9.14 mmol) in DCM (50 mL), TFA (77.0 g, 675 mmol) was added at 20 °C, and then dimethyl(phenyl)silane (3.74 g, 27.4 mmol) was added to the mixture at -10 °C. The resulting mixture was stirred at -10 °C for 2 hours. Next, the pH was adjusted to 7-8 using a saturated aqueous solution of NaHCO3, and the mixture was extracted with DCM (30 mL x 3). The organic layers were combined, dried on anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by flash chromatography (PE / siRNA=2 / 1) to obtain (4R)-4-benzyl-3-[(2R,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-indan-2-yloxy-propanoyl]oxazolidine-2-one (4.51 g, yield 92.9%) as a yellow oil. 1 1H NMR (400 MHz, CDCl3) δ 7.41-7.27(m,4H), 7.24-7.06(m,5H), 6.59(s,2H), 5.76(d,J=6.8Hz,1H) , 4.94-4.91(m,1H), 4.47-4.40(m,1H), 4.40-4.32(m,1H), 4.09(dd,J=6. 4, 2.4Hz,1H), 3.83-3.77(m,1H), 3.76(s,6H), 3.32-3.28(m,1H), 3.23-3 .13(m,1H), 3.08-2.98(m,2H), 2.86-2.72(m,3H), 2.06(s,3H);LC-MS:m / z 577.2(M+2Na) +

[0307] Step I (R)-4-benzyl-3-((2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((2,3-dihydro-1H-inden-2-yl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)propanoyl)oxazolidine-2-one [ka]

[0308] (4R)-4-benzyl-3-[(2R,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-indan-2-yloxy-propanoyl]oxazolidine-2-one (4.51 g, 8.48 mmol) was dissolved in 18 mL of DCM, to which TBDMSOTf (4.49 g, 16.9 mmol) and 2,6-lutidine (1.82 g, 16.7 mmol) were added at 0°C. The reaction mixture was heated to 20°C for 1 hour. The mixture was diluted with water (30 mL) and extracted with 3 x 20 mL of DCM. The organic layers were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by flash chromatography (PE / siRNA=3 / 1) to obtain (4R)-4-benzyl-3-[(2R,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxy-propanoyl]oxazolidine-2-one (5.11 g, yield 84.9%) as a bright yellow oil. 1 H NMR (400MHz, CDCl3)δ 7.49-7.28(m,4H), 7.22-7.05(m,3H), 6.99-6.87(m,1H), 6.62(s,2H), 5.64(d,J=8. 4Hz,1H), 4.86-4.75(m,1H), 4.71(d,J=8.8Hz,1H), 4.33-4.23(m,2H), 4.18-4.09(m ,1H), 3.73(s,6H), 3.42-3.38(m,1H), 3.16-3.06(m,1H), 3.01-2.90(m,2H), 2.93-2 .79(m,1H), 2.40-2.35(m,1H), 2.14(s,3H), 0.86(s,9H), 0.00(s,3H), -0.17(s,3H)

[0309] Process J (2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((2,3-dihydro-1H-inden-2-yl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)propan-1-ol [ka]

[0310] (4R)-4-benzyl-3-[(2R,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxy-propanoyl]oxazolidine-2-one (5.11 g, 7.91 mmol) was dissolved in THF (50 mL) and LiBH4 (258 mg, 11.9 mmol) was added at 0°C. The mixture was stirred at 20°C for 2 hours. The mixture was quenched with water (40 mL) and extracted with ELISA (30 mL x 3). The organic layers were combined, dried over anhydrous sodium 2SO4, filtered, and the filtrate was concentrated under vacuum to obtain (2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxy-propan-1-ol (4.23 g, crude product) as a bright yellow oil. LC-MS: m / z 495.2 (M+Na) +

[0311] Process K (2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((2,3-dihydro-1H-inden-2-yl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl methanesulfonate [ka]

[0312] (2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxy-propan-1-ol (4.23 g, crude) was dissolved in DCM (40 mL) and TEA (1.36 g, 13.4 mmol) and MsCl (1.70 g, 14.8 mmol) were added at 0°C. The mixture was stirred at 25°C for 1 hour. The mixture was quenched with saturated NaHCO3 (20 mL) and extracted with DCM (15 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by flash chromatography (PE / siRNA=3 / 1) to obtain [(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxypropyl]methanesulfonate (3.13 g, 5.61 mmol) as a colorless oil. 1 H NMR (400MHz, CDCl3)δ 7.23-7.17(m,1H), 7.16-7.08(m,2H), 7.05-6.98(m,1H), 6.48(s,2H), 4.59(d,J= 6.4Hz,1H), 4.44(dd,J=8.4, 2.4Hz,1H), 4.31-4.27(m,1H), 4.19-4.14(m,1H), 3. 74(s,6H), 3.70-3.63(m,1H), 3.07-2.94(m,2H), 2.85-2.80(m,1H), 2.75(s,3H), 2.50(d,J=2.8Hz,1H), 2.09(s,3H), 0.96-0.86(s,9H), 0.06(s,3H), -0.14(s,3H)

[0313] Process L: Methyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxypropyl]indazole-7-carboxylate [ka]

[0314] [(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxypropyl]methanesulfonate (400 mg, 0.726 mmol) in DMF (4 mL) Cs2CO3 (710 mg, 2.18 mmol) and methyl 2H-indazole-7-carboxylate (154 mg, 0.871 mmol) were added. The mixture was stirred at 70°C for 16 hours. The mixture was diluted with water (20 mL) and extracted with siRNA (15 mL x 3). The organic layers were combined, dried over anhydrous sodium 2SO4, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by flash chromatography (PE / siRNA = 1 / 1) to obtain methyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxypropyl]indazole-7-carboxylate (141 mg, yield 30.8%) as a colorless oil. 1 H NMR (400MHz, CDCl3)δ 8.09(d,J=6.4Hz,1H), 7.84(s,1H), 7.75(d,J=8.0Hz,1H), 7.15-7.09(m,1H), 7.08-7. 02(m,1H), 7.01-6.93(m,2H), 6.57(m,3H), 5.05-4.92(m,1H), 4.66(d,J=6.0Hz,1H), 4 .27-4.12(m,2H), 4.02(s,3H), 3.78(s,6H), 3.56-3.49(m,1H), 2.69-2.63(m,1H), 2.5 3-2.36(m,2H), 2.10(s,3H), 1.96-1.86(m,1H), 0.94(s,9H), 0.08(s,3H), -0.11(s,3H)

[0315] Process M: 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxypropyl]indazole-7-carboxylic acid [ka]

[0316] A solution of methyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxypropyl]indazole-7-carboxylate (120 mg, 0.190 mmol) in THF (1 mL), MeOH (1 mL), and H2O (1 mL) was mixed with LiOH·H2O (24 mg, 0.571 mmol). The mixture was stirred at 25°C for 2 hours. The mixture was concentrated under vacuum. The residue was diluted with water (10 mL) and extracted with ELISA (10 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to obtain 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxypropyl]indazole-7-carboxylic acid (91 mg, crude product) as a white solid. LC-MS: m / z 617.3 (M+H) +

[0317] Process N 2-[(2S,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-indan-2-yloxypropyl]indazole-7-carboxylic acid (compound 113a) [ka]

[0318] 91 mg, 0.147 mmol of 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxypropyl]indazole-7-carboxylic acid (91 mg, 0.147 mmol) was dissolved in 1 mL of THF, to which TBAF (1 M in THF, 0.295 mL) was added. The mixture was stirred at 40°C for 2 hours. The mixture was concentrated under vacuum to obtain a crude product, and the residue was diluted with water (10 mL) and extracted with siRNA (10 mL x 3). The organic layers were combined, dried on anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3μm; mobile phase: [water (0.225% FA)-ACN]; B%: 35%-75%, 9 minutes). The fraction was freeze-dried to obtain 2-[(2S,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-indan-2-yloxypropyl]indazole-7-carboxylic acid (32.71 mg, yield 34.2% over two steps) (compound 113a) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ 8.30(s,1H), 7.99-7.74(m,2H), 7.14(t,J=7.2Hz,1H), 7.04-6.96(m,1H), 6.95-6.88(m ,2H), 6.67(s,2H), 6.54(d,J=7.2Hz,1H), 5.80(brd,J=2.8Hz,1H), 4.77-4.74(m,1H), 4. 58-4.54(m,1H), 4.45-4.31(m,1H), 3.99-3.96(m,1H), 3.71(s,6H), 3.68-3.65(m,1H), 2.67-2.61(m,1H), 2.49-2.38(m,2H), 1.99(s,3H), 1.89(brd,J=14.8Hz,1H);LC-MS:m / z 503.2(M+H) +

[0319] Example 2 2-(1-((2S,3R)-2-((2,3-dihydro-1H-inden-2-yl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-4-(methoxycarbonyl)-1H-pyrrole-3-yl)acetic acid (compound 103a) [ka]

[0320] Step A: Methyl 1-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxypropyl]-4-(2-methoxy-2-oxoethyl)pyrrole-3-carboxylate [ka]

[0321] [(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxypropyl]methanesulfonate (122 mg, 0.221 mmol) was dissolved in DMF (2 mL), to which Cs2CO3 (216 mg, 0.665 mmol) and methyl 4-(2-methoxy-2-oxoethyl)-1H-pyrrole-3-carboxylate (52.4 mg, 0.266 mmol) were added. The mixture was stirred at 70°C for 16 hours. The mixture was diluted with water (15 mL) and extracted with siRNA (10 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by flash chromatography (PE / siRNA=3 / 1) to obtain methyl 1-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxypropyl]-4-(2-methoxy-2-oxo-ethyl)pyrrole-3-carboxylate (100 mg, yield 69.2%) as a colorless oil. 1H NMR (400MHz, CDCl3)δ 7.19(d,J=2.4Hz,1H), 7.10-7.05(m,2H), 7.03-6.94(m,2H), 6.54(d,J=2.4Hz,1H ), 6.49(s,2H), 4.78(brs,1H), 4.51(d,J=6.4Hz,1H), 4.21(d,J=14.0Hz,1H), 3.81 -3.71(m,10H), 3.67(s,3H), 3.59-3.50(m,2H), 2.73-2.61(m,2H), 2.40(d,J=2.8H) z,1H), 2.27(d,J=2.8Hz,1H), 2.10(s,3H), 0.93(s,9H), 0.05(s,3H), -0.14(s,3H)

[0322] Step B: 2-[1-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxypropyl]-4-methoxycarbonylpyrrole-3-yl]acetic acid [ka]

[0323] To a solution of methyl 1-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxypropyl]-4-(2-methoxy-2-oxo-ethyl)pyrrole-3-carboxylate (80 mg, 0.123 mmol) in THF (0.8 mL) and MeOH (0.8 mL), NaOH (1 M, 0.438 mL) was added. The mixture was stirred at 35°C for 2.5 hours. The pH was adjusted to 2-3 using 1 M aqueous HCl solution. The mixture was diluted with water (20 mL) and then extracted with ELISA (15 mL x 3). The organic layers were combined, dried over anhydrous sodium 2SO4, filtered, concentrated under reduced pressure, filtered again, and concentrated under reduced pressure to obtain 2-[1-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxypropyl]-4-methoxycarbonylpyrrole-3-yl]acetic acid (83 mg, crude) as a yellow oil. LCMS: m / z 660.2 (M+Na) +

[0324] Step C 2-[1-[(2S,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-indan-2-yloxypropyl]-4-methoxycarbonylpyrrole-3-yl]acetic acid (compound 103a) [ka]

[0325] 2-[1-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxypropyl]-4-methoxycarbonylpyrrole-3-yl]acetic acid (106 mg, crude) was dissolved in THF (2 mL) and TBAF (1 M, 0.332 mL) was added. The mixture was stirred at 40°C for 2 hours. The mixture was then diluted with water (15 mL) and extracted with siRNA (10 mL x 3). The organic layers were combined, dried on anhydrous sodium 2 SO4, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by preparative HPLC (column: Boston Prime C18 150x30mmx5μm; mobile phase: [water (0.05% ammonium hydroxide fluoride v / v)-ACN]; B%: 17%-57%, 9 minutes) to obtain 2-[1-[(2S,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-indan-2-yloxypropyl]-4-methoxycarbonylpyrrole-3-yl]acetic acid (compound 103a) (10.64 mg, yield 9.2% over two steps) as a white solid. 1 H NMR(400MHz, CD3OD)δ 7.25(s,1H), 7.06-6.98(m,3H), 6.90-6.82(m,1H), 6.66(s,1H), 6.56(s,2H), 4.35( d,J=8.0Hz,1H), 4.30(d,J=11.6Hz,1H), 3.96-3.91(m,1H), 3.82-3.75(m,1H), 3.72 (s,3H), 3.69(s,6H), 3.67-3.59(m,3H), 2.78(dd,J=16.0, 8.0Hz,1H), 2.62(dd,J=1 6.0, 4.0Hz,1H), 2.49-2.41(m,1H), 2.33(brd,J=16.0Hz,1H), 2.03(s,3H);LCMS:m / z 546.1(M+H) +

[0326] Example 3 2-(1-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-4-(methoxycarbonyl)-1H-pyrrole-3-yl)acetic acid (compound 102a) [ka]

[0327] Example 3 (compound 102a) was synthesized by following the procedure described for the production of Example 1 (procedures A to N of Scheme 1), by using cyclopentanol in step C and methyl 4-(2-methoxy-2-oxo-ethyl)-1H-pyrrole-3-carboxylate in step L. 1 H NMR (400MHz, DMSO-d6)δ 11.93(brs,1H), 7.30(d,J=2.4Hz,1H), 6.69(d,J=2.4Hz,1H), 6.60(s,2H), 5.59(brm,1H), 4.24(d,J=6.4Hz,1H), 4.15(dd,J=14.0, 2.4Hz ,1H), 3.92(dd,J=14.0, 6.8Hz,1H), 3.75(s,6H), 3.64(s,3H), 3.56(s,2H), 3.45-3.53(m,2H), 1.97(s,3H), 1.05-1.40(m,8H);LC-MS:m / z 476.2(M+H) +

[0328] Example 4 2-(1-((2S,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-(penta-3-in-1-yloxy)propyl)-4-(methoxycarbonyl)-1H-pyrrole-3-yl)acetic acid (compound 101a) [ka]

[0329] Example 4 (compound 101a) was synthesized by following the procedure described for the production of Example 1 (procedures from steps A to N of Scheme 1), by using penta-3-in-1-ol in step C and methyl 4-(2-methoxy-2-oxo-ethyl)-1H-pyrrole-3-carboxylate in step L. 1H NMR (400MHz, DMSO-d6)δ 11.94(s,1H), 7.35(d,J=2.0Hz,1H), 6.72(d,J=2.0Hz,1H), 6.62(s,2H), 5.62(d,J =4.0Hz,1H), 4.31(dd,J=6.4, 4.0Hz,1H), 4.13(dd,J=14.4, 2.4Hz,1H), 3.96(dd,J= 14.4, 6.8Hz, 1H), 3.76 (s, 6H), 3.64 (s, 3H), 3.58 (d, J=2.8Hz, 1H), 3.55 (s, 2H), 3.1 0(t,J=6.8Hz,2H), 1.98-2.02(m,2H), 1.97(s,3H), 1.67(t,J=2.4Hz,3H);LCMS:m / z 474.2(M+H) +

[0330] Example 5 2-(1-((2S,3R)-2-(cyclobutylmethoxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-4-(methoxycarbonyl)-1H-pyrrole-3-yl)acetic acid (compound 117a) [ka]

[0331] Example 5 (compound 117a) was synthesized by following the procedure described for the production of Example 1 (procedures from steps A to N of Scheme 1), using cyclobutylmethanol in step C and methyl 4-(2-methoxy-2-oxo-ethyl)-1H-pyrrole-3-carboxylate in step L. 1H NMR(400MHz, CD3OD)δ 7.35(d,J=2.4Hz,1H), 6.69(d,J=2.4Hz,1H), 6.65(s,2H), 4.42(d,J=7.2Hz,1H), 4.20(dd,J=14.0, 2.4Hz,1H), 3.97(dd,J=14.0, 7.2Hz,1H), 3.81(s,6H), 3.74(s,3 H), 3.66(s,2H), 3.57-3.48(m,1H), 3.02(dd,J=6.4, 2.4Hz,2H), 2.31-2.20(m,1H) ), 2.02(s,3H), 1.87-1.75(m,3H), 1.75-1.63(m,1H), 1.58-1.40(m,2H);LCMS:m / z 498.2(M+Na) +

[0332] Example 6 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-2H-indazole-7-carboxylic acid (compound 108a) [ka]

[0333] Example 6 (compound 108a) was synthesized by using cyclopentanol in step C and methyl 2H-indazole-7-carboxylate in step L, following the procedure described for the production of Example 1 (steps A to N of Scheme 1). 1 H NMR(400MHz, CD3OD)δ 8.33(s,1H), 8.03(d,J=7.2Hz,1H), 7.95(d,J=7.6Hz,1H), 7.18(d,J=8.0, 0.8Hz,1H), 6.71(s,2H), 4.91-4.77(m,1H), 4.64(d,J=6.4Hz, 1H), 4.56-4.50(m,1H), 4.09-3.99(m,1H), 3.84(s,6H), 3.53-3.32(m,1H), 2.03(s,3H), 1.40-1.09(m,7H), 0.94-0.80(m,1H);LC-MS:m / z 455.2 (M+H) +

[0334] Example 7 2-((2S,3R)-2-(cyclobutylmethoxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-2H-indazole-7-carboxylic acid (compound 118a) [ka]

[0335] Example 7 (compound 118a) was synthesized by following the procedure described for the production of Example 1 (procedures from steps A to N of Scheme 1), by using cyclobutylmethanol in step C and methyl 2H-indazole-7-carboxylate in step L. 1 H NMR (400MHz, DMSO-d6)δ 8.49(s,1H), 7.99(d,J=8.4Hz,1H), 7.90(d,J=6.8Hz,1H), 7.14-7.10(m,1H), 6.71(s,2H), 5.74(brd,J=2.8Hz,1H), 4.73-4.64(m,1H), 4.60(brd,J=3.2Hz,1H), 4.53-4.42(m,1H), 3. 89-3.82(m,1H), 3.77(s,6H)3.05(dd,J=9.2, 6.4Hz,1H), 2.76(dd,J=9.2, 6.8Hz,1H), 2.06 (brs,1H), 1.97(s,3H), 1.61-1.57(m,3H), 1.55-1.42(m,1H)1.29-1.23(m,2H);LC-MS:m / z 455.2(M+H) +

[0336] Example 8 2-((2S,3S)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-phenethoxypropyl)-2H-indazole-7-carboxylic acid (compound 105b) and 2-((2R,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-phenethoxypropyl)-2H-indazole-7-carboxylic acid (compound 105a) [ka]

[0337] (S)-4-benzyl-3-(2-phenethoxyacetyl)oxazolidine-2-one was synthesized by following the procedure described for the preparation in Example 1 (steps C to E of Scheme 1), using 2-phenylethanol in step C and (4S)-4-benzyloxazolidine-2-one in step E. LC-MS: m / z 339.9 (M+H) +

[0338] Process D (S)-4-benzyl-3-((2R,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-phenethoxypropanoyl)oxazolidine-2-one [ka]

[0339] (4S)-4-benzyl-3-[2-(2-phenylethoxy)acetyl]oxazolidine-2-one (6.41 g, 13.73 mmol) in SiO2 (5 mL) was mixed with 3,5-dimethoxy-4-methylbenzaldehyde (2.25 g, 12.48 mmol), TMSCl (2.03 g, 18.72 mmol), TEA (2.53 g, 24.96 mmol), and MgCl2 (237.68 mg, 2.50 mmol). The mixture was stirred under N2 at 40°C for 16 hours. The mixture was concentrated under reduced pressure. Then MeOH (20 mL) and TFA (2 mL) were added. After stirring for 1 hour, the solution was adjusted to pH 6 with saturated NaHCO3 and then concentrated under reduced pressure. The residue was purified by flash chromatography (PE / siRNA=2 / 1) to obtain (4S)-4-benzyl-3-[(2R,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-(2-phenylethoxy)propanoyl]oxazolidine-2-one (5.23 g, yield 65%) as a white solid. LC-MS: m / z 542.0 (M+Na) +

[0340] Step E (S)-4-benzyl-3-((2R,3R)-3-((tert-butyldimethylsilyl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-2-phenethoxypropanoyl)oxazolidine-2-one [ka]

[0341] (4S)-4-benzyl-3-[(2R,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-(2-phenylethoxy)propanoyl]oxazolidine-2-one (2 g, 3.85 mmol) was dissolved in DCM (10 mL), to which 2,6-lutidine (495 mg, 4.62 mmol) and TBDMSOTf (1.22 g, 4.62 mmol) were added. The mixture was stirred at 0°C for 2 hours. The mixture was washed with 1N HCl (20 mL) and extracted with DCM (20 mL x 2). The organic liquid was collected and concentrated. The residue was purified by flash chromatography (PE / siRNA=3 / 1) to obtain (4S)-4-benzyl-3-[(2R,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-(2-phenylethoxy)propanoyl]oxazolidine-2-one (yield 2.07 g, 84%) as a yellow oil. LC-MS: m / z 656.1 (M+Na) +

[0342] Process F (2S,3R)-3-((tert-butyldimethylsilyl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-2-phenethoxypropane-1-ol [ka]

[0343] To a solution of LiBH4 (1.50 g, 68.79 mmol) in THF (30 mL), H2O (0.28 mL, 15.20 mmol) was added at 0°C. The mixture was stirred at 0°C for 0.5 hours. (4S)-4-benzyl-3-[(2R,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-(2-phenylethoxy)propanoyl]oxazolidine-2-one (4.36 g, 6.88 mmol) was added to the mixture, and the mixture was stirred at 25°C for 16 hours. The mixture was slowly quenched with 1N HCl (30 mL) and extracted with ELISA (40 mL x 2). The organic liquid was collected and concentrated. The residue was purified by flash chromatography (PE / SiO=4 / 1) to obtain (2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-(2-phenylethoxy)propan-1-ol (2.46 g, yield 74%) as a yellow oil. LC-MS: m / z 483.1 (M+Na) +

[0344] Process G (2S,3R)-3-((tert-butyldimethylsilyl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-2-phenethoxypropyl methanesulfonate [ka]

[0345] (2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methyl-phenyl)-2-(2-phenylethoxy)propan-1-ol (800 mg, 1.74 mmol) was dissolved in THF (2 mL), to which MsCl (299 mg, 2.60 mmol) and TEA (316.30 mg, 3.13 mmol) were added at 0°C. The mixture was stirred at 0°C for 1 hour. The mixture was poured into ice-cold water and extracted with SiO (25 mL x 2). The organic liquid was collected and concentrated to obtain [(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methyl-phenyl)-2-(2--phenethoxy)propyl]methanesulfonate (829.3 mg, yield 88%) as a colorless oil. LC-MS: m / z 561.0 (M+Na) +

[0346] Process H: Methyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-2-phenethoxypropyl)-2H-indazole-7-carboxylate [ka]

[0347] [(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-(2-phenylethoxy)propyl]methanesulfonate (1.37 g, 2.54 mmol) was dissolved in DMF (10 mL) and Cs2CO3 (2.49 g, 7.63 mmol) and methyl-2H-indazole-7-carboxylate (538 mg, 3.05 mmol) were added. The mixture was stirred at 60°C for 16 hours. The mixture was washed with H2O (30 mL) and extracted with siRNA (20 mL x 2). The organic liquid was collected and concentrated. The residue was purified by flash chromatography (PE / SiO=2 / 1) to obtain methyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-(2-phenylethoxy)propyl]indazole-7-carboxylate (1.19 g, yield 70%) as a yellow oil. LC-MS: m / z 641.3 (M+Na) +

[0348] Step I: 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-2-phenethoxypropyl)-2H-indazole-7-carboxylic acid [ka]

[0349] Methyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methyl-phenyl)-2-(2-phenylethoxy)propyl]indazole-7-carboxylate (1.19 g, 1.92 mmol) was dissolved in THF (4 mL) and MeOH (4 mL), to which NaOH (2 M, 4.81 mL) was added. The mixture was stirred at 25 °C for 21 hours. The solution was adjusted to pH 7 with 1 N HCl and extracted with SiO (20 mL x 2). The organic liquid was collected and concentrated to obtain 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methyl-phenyl)-2-(2-phenylethoxy)propyl]indazole-7-carboxylic acid (817.9 mg, yield 48%) as a yellow oil. LC-MS: m / z 627.3 (M+Na) +

[0350] Step J 2-((2R,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-phenethoxypropyl)-2H-indazole-7-carboxylic acid (compound 105a) and 2-((2S,3S)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-phenethoxypropyl)-2H-indazole-7-carboxylic acid (compound 105b) [ka]

[0351] 817.9 mg, 1.35 mmol of 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-(2-phenylethoxy)propyl]indazole-7-carboxylic acid (817.9 mg, 1.35 mmol) was dissolved in 4 mL of THF, to which 1 M TBAF (13.52 mL) was added. The mixture was stirred at 40°C for 20 hours. The reaction product was diluted with 40 mL of ELISA and washed with 9 x 20 mL of H2O. The organic liquid was collected and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: DAISELCHIRALPAK IG (250mm x 30mm, 10μm); mobile phase: [Neu-MeOH]; B%: 50%-50%) to obtain 2-[(2R,3R)-3-(3,5-dimethoxy-4-methyl-phenyl)-3-hydroxy-2-(2-phenylethoxy)propyl]indazole-7-carboxylic acid (compound 105a) (29.76 mg, yield 74%) as a white solid, and 2-[(2S,3S)-3-(3,5-dimethoxy-4-methyl-phenyl)-3-hydroxy-2-(2-phenylethoxy)propyl]indazole-7-carboxylic acid (compound 105b) (14.94 mg, yield 37%) as a white solid.

[0352] 2-[(2R,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-(2-phenylethoxy)propyl]indazole-7-carboxylic acid (compound 105a): 1 H NMR(400MHz, CD3OD)δ 8.07(d,J=7.2Hz,1H), 7.97(s,1H), 7.90(d,J=8.4Hz,1 H), 7.19-7.16(m,1H), 7.15-7.09(m,3H), 6.91-6.88(m,2H), 6.67(s,2H), 4.82-4.71(m,1H), 4.68-4.62(m,1H), 4.54-4.4 8(m,1H), 4.01-3.98(m,1H), 3.80(s,6H), 3.38-3.34(m,1H), 3.15-3.08(m,1H), 2.52-2.48(m,2H), 2.01(s,3H);LC-MS:m / z 491.2(M+H) +

[0353] 2-[(2S,3S)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-(2-phenylethoxy)propyl]indazole-7-carboxylic acid (compound 105b): 1 H NMR(400MHz, CD3OD)δ 8.15-7.87(m,3H), 7.27-7.07(m,4H), 6.95-6.80(m,2H), 6.75-6.60(m,2H), 4.80-4.72(m,1H), 4.67-4.52(m,2H) , 4.45-4.31(m,1H), 4.20-4.05(m,1H), 3.79(s,6H), 3.05-2.92(m,1H), 2.60-2.45(m,2H), 2.01(s,3H);LC-MS:m / z 491.2(M+H) +

[0354] Example 9 1-(3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-phenethoxypropyl)-1H-indazole-7-carboxylic acid (compound 107) [ka]

[0355] Step A: Methyl 1-(3-((tert-butyldimethylsilyl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-2-phenethoxypropyl)-1H-indazole-7-carboxylate [ka]

[0356] Methyl 1-(3-((tert-butyldimethylsilyl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-2-phenethoxypropyl)-1H-indazole-7-carboxylate (561.5 mg, yield 34%) was isolated as an isomer according to the procedure described in step H of the manufacturing process in Example 8. LC-MS: m / z 619.2 (M+H) +

[0357] Step B: 1-(3-((tert-butyldimethylsilyl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-2-phenethoxypropyl)-1H-indazole-7-carboxylic acid [ka]

[0358] 1-(3-((tert-butyldimethylsilyl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-2-phenethoxypropyl)-1H-indazole-7-carboxylic acid was synthesized according to the procedure described in Step I of the preparation in Example 8. LC-MS: m / z 627.1 (M+Na) +

[0359] Step C 1-(3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-phenethoxypropyl)-1H-indazole-7-carboxylic acid (compound 107) [ka]

[0360] 1-(3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-phenethoxypropyl)-1H-indazole-7-carboxylic acid (compound 107) was synthesized according to the procedure described in step J of the manufacturing process in Example 8. 1 1H NMR (400 MHz, CD3OD) δ 8.11(s,1H), 7.93-7.88(m,2H), 7.23-7.18(m,1H), 7.07-7.01(m,3H), 6 .68-6.61(m,4H), 5.20-5.13(m,1H), 5.02-4.95(m,0.8H), 4.89-4.77(m ,0.2H), 4.52(d,J=6.4Hz,1H), 3.76(s,3H), 3.69-3.65(m,1H), 3.00-2. 77(m,1H), 2.60-2.42(m,1H), 2.30-2.05(m,2H), 1.99(s,3H);LC-MS:m / z 513.1(M+Na) +

[0361] Example 10 2-(1-((2S,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-phenethoxypropyl)-4-(methoxycarbonyl)-1H-pyrrole-3-yl)acetic acid (compound 104a) [ka]

[0362] Example 10 (compound 104a) was synthesized in step H using methyl 4-(2-methoxy-2-oxo-ethyl)-1H-pyrrole-3-carboxylate, following the procedure described for the preparation in Example 8 (steps H to J in Scheme 8). The crude mixture was isolated by SFC (DAICELCHIRALPAK IG (250 mm x 30 mm, 10 μm); mobile phase: [Neu-IPA]; B%: 35%-35%) to obtain 2-[1-[(2S,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-(2-phenylethoxy)propyl]-4-methoxycarbonylpyrrole-3-yl]acetic acid (37.38 mg, yield 19%) as a white solid. 1 H NMR(400MHz, CD3OD)δ 7.29(s,1H), 7.22-7.10(m,3H), 6.97-6.90(m,2H), 6.62(s,2H), 6.55-6.45(m,1H), 4.39(d,J=7.2Hz,1H), 4.20-4.12(m,1H), 4.00-3 .92(m,1H), 3.78(s,6H), 3.73(s,3H), 3.63(s,2H), 3.54-3.53(m,1H), 3.29-3.22(m,2H), 2.59-2.55(m,2H), 2.03(s,3H);LC-MS:m / z 534.1(M+Na) +

[0363] Example 11 2-(6-((2S,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-phenethoxypropyl)pyridine-3-yl)acetic acid (compound 106a) [ka]

[0364] Step A: tert-butyl((1R,2R)-1-(3,5-dimethoxy-4-methylphenyl)-3-iodo-2-phenylethoxypropoxy)dimethylsilane [ka]

[0365] [(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-(2-phenylethoxy)propyl]methanesulfonate (6.3 g, 11.32 mmol) was dissolved in acetone (40 mL) and NaI (16.97 g, 113.22 mmol) was added. The mixture was stirred at 60 °C for 16 hours. After cooling, the reaction mixture was diluted with H2O (60 mL) and extracted with SiO (50 mL x 2). The organic liquid was collected and concentrated under reduced pressure. The residue was purified by flash chromatography (PE / SiO = 10 / 1) to obtain tert-butyl-[(1R,2R)-1-(3,5-dimethoxy-4-methylphenyl)-3-iodo-2-(2-phenylethoxy)propoxy]dimethylsilane (4.69 g, yield 72%) as a pale yellow oil. LC-MS: m / z 439.1 (M-OTBS) +

[0366] Process B: Methyl 2-(6-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-2-phenethoxypropyl)pyridine-3-yl)acetate [ka]

[0367] Dichloronickel; 1,2-dimethoxyethane (19 mg, 87.63 micromoles) and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (24 mg, 87.63 micromoles) in dried DME (5 mL) were stirred at 25°C for 25 minutes. Next, tert-butyl-[(1R,2R)-1-(3,5-dimethoxy-4-methylphenyl)-3-iodo-2-(2-phenylethoxy)propoxy]dimethylsilane (500 mg, 876.31 micromoles), methyl 2-(6-chloro-3-pyridyl)acetate (243.97 mg, 1.31 mmol), bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+); 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine; hexafluorophosphate (98 mg, 87.63 micromoles), and Na2CO3 (279 mg, 2.63 mmol) were added. N2 was passed through the solution for 5 minutes. Next, bis(trimethylsilyl)silyl-trimethylsilane (0.4 mL, 1.31 mmol) was added. The solution was irradiated with a blue LED at 25°C for 12 hours. The reaction mixture was filtered. The filtrate was collected and concentrated. The residue was purified by flash chromatography (PE / Â=3 / 1) to obtain methyl 2-[6-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-(2-phenylethoxy)propyl]-3-pyridyl]acetate (170 mg, yield 6%) as a yellow oil. LC-MS: m / z 594.3 (M+H) +

[0368] Step C 2-(6-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-2-phenethoxypropyl)pyridine-3-yl)acetic acid [ka]

[0369] 2-(6-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-2-phenethoxypropyl)pyridine-3-yl)acetic acid was synthesized according to the procedure described in step M of the preparation for Example 1. LC-MS: m / z 580.2(M+H) +

[0370] Step D: 1-(3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-phenethoxypropyl)-1H-indazole-7-carboxylic acid (compound 106a) [ka]

[0371] 1-(3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-phenethoxypropyl)-1H-indazole-7-carboxylic acid (compound 106a) was synthesized according to the procedure described in step N of the manufacturing process in Example 1. 1 H NMR(400MHz, CD3OD)δ 8.28(s,1H), 7. 58(d,J=8.0Hz,1H), 7.21-7.04(m,4H), 6.99-6.87(m,2H), 6.64(s,2H), 4.66(d,J=5.2Hz,1H), 3.78(s,6H), 3.60(s,2H) , 3.46-3.37(m,1H), 3.23-3.14(m,1H), 3.03-2.96(m,1H), 2.90-2.82(m,1H), 2.56-2.46(m,2H), 2.00(s,3H);LC-MS:m / z 466.2(M+H) +

[0372] Example 12 2-(6-((2S,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-phenethoxypropyl)-2-methoxypyridine-3-yl)acetic acid (compound 130a) [ka] [ka]

[0373] Step A: Methyl 2,6-dichloronicotinate [ka]

[0374] To a solution of 2,6-dichloropyridine-3-carboxylic acid (25 g, 130.21 mmol) in MeOH (130 mL), SOCl2 (18.59 g, 156.25 mmol) was added at 0°C, and the mixture was stirred at 20°C for 0.5 hours. The reaction mixture was then stirred at 70°C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent and obtain a residue. The residue was then dissolved in  (350 mL), washed with saturated aqueous solution of NaHCO3 (200 mL x 4), dried on anhydrous Na2SO4, and concentrated to obtain methyl 2,6-dichloronicotinate (25.40 g, yield 94%) as a white solid. LC-MS: m / z 205.8 (M+H) +

[0375] Step B: Methyl 6-chloro-2-methoxynicotinate [ka]

[0376] To a solution of methyl 2,6-dichloronicotinate (5 g, 24.27 mmol) in DCM (70 mL), CH3ONa (1.97 g, 36.40 mmol) was added at 0°C, and the mixture was stirred at 25°C for 16 hours. The pH was adjusted to 6-7 using 1N HCl, and the mixture was extracted with DCM (50 mL x 3). The organic liquid was collected, dried on anhydrous Na2SO4, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash chromatography (PE / siRNA=5 / 1) to obtain methyl 6-chloro-2-methoxynicotinate (4 g, yield 77%) as a bright yellow oil. LC-MS: m / z 202.0 (M+H) +

[0377] Step C (6-chloro-2-methoxypyridine-3-yl)methanol [ka]

[0378] To a solution of methyl 6-chloro-2-methoxynicotinate (4 g, 19.84 mmol) in THF (30 mL), DIBAL-H (1 M, 70.00 mL) was added at -78°C, and the mixture was stirred at 20°C for 1 hour. The reaction product was diluted with saturated aqueous solution of sodium potassium tartrate (300 mL) and extracted with siRNA (200 mL). The organic extracts were combined, dried on anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by flash chromatography (PE / siRNA = 4 / 1) to obtain (6-chloro-2-methoxypyridine-3-yl)methanol (3.5 g, yield 98%) as a white solid. LC-MS: m / z 173.8 (M + H) +

[0379] Step D: 6-Chloro-3-(chloromethyl)-2-methoxypyridine [ka]

[0380] To a solution of (6-chloro-2-methoxypyridine-3-yl)methanol (505 mg, 2.91 mmol) in DCM (10 mL), SOCl2 (865.22 mg, 7.27 mmol) was added dropwise at 0°C, and the mixture was stirred at 20°C for 1 hour. The reaction product was diluted with H2O (50 mL) and then extracted with DCM (30 mL x 3). The organic solution was collected, dried on anhydrous Na2SO4, and concentrated under reduced pressure to obtain 6-chloro-3-(chloromethyl)-2-methoxypyridine (525 mg, crude product) as a white solid. LC-MS: m / z 191.7 (M+H) +

[0381] Step E: 2-(6-chloro-2-methoxypyridine-3-yl)acetonitrile [ka]

[0382] 6-chloro-3-(chloromethyl)-2-methoxypyridine (525 mg, 2.72 mmol) was dissolved in DMSO (10 mL), to which NaCN (173 mg, 3.44 mmol) was added, and the mixture was stirred at 20°C for 2.5 hours. The reaction product was diluted with H2O (10 mL) and then extracted with siRNA (10 mL x 3). The organic solution was collected, dried on anhydrous Na2SO4, and concentrated under reduced pressure to obtain 2-(6-chloro-2-methoxypyridine-3-yl)acetonitrile (460 mg, yield 70%) as a bright yellow solid. LC-MS: m / z 182.9 (M+H) +

[0383] Process F: Methyl 2-(6-chloro-2-methoxypyridine-3-yl)acetate [ka]

[0384] To a solution of 2-(6-chloro-2-methoxypyridine-3-yl)acetonitrile (3.22 g, 17.63 mmol) in MeOH (15 mL), HCl / MeOH (15 mL) was added, and the mixture was stirred at 50°C for 16 hours. The reaction products were combined and concentrated under reduced pressure to obtain a residue. The residue was diluted with H2O (50 mL), and its pH was adjusted to 7-8 using 1 M NaOH. The mixture was extracted with  (30 mL x 3). The organic layers were combined, washed with brine (30 mL x 3), dried on anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography (PE /  = 5 / 1) to obtain methyl 2-(6-chloro-2-methoxypyridine-3-yl)acetate (2.3 g, yield 46%) as a colorless oil. LC-MS: m / z 215.8 (M+H) +

[0385] Step G: 2-(6-((2S,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-phenethoxypropyl)-2-methoxypyridine-3-yl)acetic acid (compound 130a) [ka]

[0386] Example 12 (compound 130a) was synthesized by using methyl 2-(6-chloro-2-methoxypyridine-3-yl)acetate (12-7) in step B, following the procedure described for the production of Example 11 (steps A to D of Scheme 1). 1 H NMR(400MHz, CD3OD)δ 7.35(d,J=7.2Hz,1H), 7.18-7.04(m,3H), 6.97-6.90(m,2H), 6.68-6.61(m,3H), 4.62(d,J=5.6Hz,1H), 3.99-3.92(m,1H), 3.87(s, 3H), 3.76(s,6H), 3.50(s,2H), 3.43-3.35(m,2H), 2.98-2.91(m,1H), 2.83-2.73(m,1H), 2.59-2.48(m,2H), 2.00(s,3H);LC-MS:m / z 496.2(M+H) +

[0387] Example 13 2-(6-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-2-methoxypyridine-3-yl)acetic acid (compound 110a) [ka]

[0388] Example 13 (compound 110a) was synthesized according to the procedure described for the production of Example 11 (procedures A to D of Scheme 1), by using [(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl]methanesulfonate in step A and methyl 2-(6-chloro-2-methoxypyridine-3-yl)acetate in step B. 1 H NMR(400MHz, CD3OD)δ 7.40(d,J=8.0Hz,1H), 6.72(d,J=8.0Hz,1H), 6.64(s,2H), 4.55(d,J=8.0Hz,1H), 3.96-3.91(m,1H), 3.89(s,3H), 3.79(s,6 LC-MS: m / z 460.2(M+H) +

[0389] Example 14 2-(2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)thiazole-4-yl)acetic acid (compound 112a) [ka]

[0390] Process A: (3S,4R)-4-((tert-butyldimethylsilyl)oxy)-3-(cyclopentyloxy)-4-(3,5-dimethoxy-4-methylphenyl)butanenitrile [ka] To a solution of [(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl]methanesulfonate (1 g, 1.99 mmol) (synthesized in step C using cyclopentanol according to the procedure described for the preparation in Example 1) in DMSO (10 mL), NaCN (487 mg, 9.95 mmol) was added, and the mixture was stirred at 90°C for 1.5 hours. The reaction mixture was diluted with H2O (30 mL) and then extracted with ELISA (20 mL x 3). The organic layers were combined, washed with brine (10 mL x 2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by flash chromatography (PE / siRNA = 8 / 1) to obtain (3S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-3-(cyclopentoxy)-4-(3,5-dimethoxy-4-methylphenyl)butanenitrile (849 mg, yield 97%) as a colorless oil. LC-MS: m / z 456.3 (M+Na) +

[0391] Process B: (3S,4R)-4-((tert-butyldimethylsilyl)oxy)-3-(cyclopentyloxy)-4-(3,5-dimethoxy-4-methylphenyl)butanamide [ka]

[0392] (3S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-3-(cyclopentoxy)-4-(3,5-dimethoxy-4-methylphenyl)butanenitrile (495 mg, 1.14 mmol) was dissolved in DMSO (4 mL), to which K2CO3 (316 mg, 2.28 mmol) and H2O2 (1.29 g, 11.41 mmol, 30% purity) were added at 0°C. The mixture was stirred at 25°C for 44 hours. The reaction product was diluted with H2O (50 mL) and extracted with ELISA (30 mL x 3). The organic layers were combined, washed with H2O (20 mL x 2), dried on anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by flash chromatography (PE / siRNA=3 / 1) to obtain (3S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-3-(cyclopentoxy)-4-(3,5-dimethoxy-4-methylphenyl)butanamide (383 mg, yield 74%) as a white solid. LC-MS: m / z 474.2 (M+Na) +

[0393] Process C(3S,4R)-4-((tert-butyldimethylsilyl)oxy)-3-(cyclopentyloxy)-4-(3,5-dimethoxy-4-methylphenyl)butanthioamide [ka]

[0394] (3S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-3-(cyclopentoxy)-4-(3,5-dimethoxy-4-methylphenyl)butanamide (383 mg, 847.96 micromoles) was dissolved in THF (15 mL) and Lawesson's reagent (202 mg, 498.60 micromoles) was added. The mixture was stirred at 80°C for 2 hours. The reaction product was concentrated under vacuum, and the residue was purified by flash chromatography (PE / siRNA=5 / 1) to obtain (3S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-3-(cyclopentoxy)-4-(3,5-dimethoxy-4-methylphenyl)butanthioamide (216 mg, yield 53%) as a bright yellow oil. LC-MS: m / z 490.2 (M+Na) +

[0395] Process D: Ethyl 2-(2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)thiazole-4-yl)acetate [ka]

[0396] (3S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-3-(cyclopentoxy)-4-(3,5-dimethoxy-4-methylphenyl)butanthioamide (216 mg, 461.80 micromoles) was dissolved in EtOH (5 mL), to which ethyl 4-chloro-3-oxo-butanoate (76 mg, 461.80 micromoles) was added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by flash chromatography (PE / siRNA=16 / 1) to obtain ethyl 2-[2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl]thiazole-4-yl]acetate (36 mg, yield 12%) as a colorless oil. LC-MS: m / z 578.2 (M+H) +

[0397] Step E: 2-(2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)thiazole-4-yl)acetic acid [ka]

[0398] Ethyl 2-[2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl]thiazole-4-yl]acetate (36 mg, 62.30 micromoles) was dissolved in THF (0.5 mL), EtOH (0.5 mL), and H2O (0.5 mL), to which LiOH·H2O (13 mg, 311.50 micromoles) was added. The mixture was stirred at 25°C for 0.5 hours. The reaction product was acidified with 1N HCl and then diluted with H2O (10 mL). The mixture was extracted with ELISA (10 mL x 4). The organic layers were combined, dried over anhydrous Na2SO4, and filtered. 2-[2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl]thiazole-4-yl]acetic acid (25 mg, yield 69%) was obtained as a red oil. LC-MS: m / z 550.2 (M+H) +

[0399] Step F: 2-(2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)thiazole-4-yl)acetic acid (compound 112a) [ka]

[0400] To a solution of 2-[2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl]thiazole-4-yl]acetic acid (25 mg, 45.47 micromoles) in THF (2 mL), TBAF (1 M, 0.46 mL) was added, and the mixture was stirred at 40°C for 2 hours. The reaction product was diluted with ELISA (20 mL). The mixture was washed with H2O (10 mL x 6), dried on anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80x30mmx3μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 10%-80%, 9 minutes) to obtain 2-[2-[(2S,3R)-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-propyl]thiazole-4-yl]acetic acid (compound 112a) (3.92 mg, yield 20%) as a white solid. 1 H NMR(400MHz, CD3OD)δ 7.22-7.14(m,1H), 6.67(s,2H), 4.67-4.65(m,1H), 3.88-3.79(m,8H), 3. 69(s,2H), 3.27-3.15(m,2H), 2.03(s,3H), 1.52-1.32(m,8H);LC-MS:m / z 436.1(M+H) +

[0401] Example 15 2-(2-((2S,3R)-2-((2,3-dihydro-1H-inden-2-yl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)thiazole-4-yl)acetic acid (compound 129a) [ka]

[0402] Example 15 (Compound 129a) was synthesized by following the procedure described for the production of Example 14 (procedures A to F of Scheme 14), by using (2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((2,3-dihydro-1H-inden-2-yl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl methanesulfonate in step A. 1 H NMR(400MHz, CD3OD)δ 7.18(s,1H), 7.09-6.94(m,3H), 6.93-6.92(m,1H), 6.60(s,2H), 4.55-4.46(m,1H), 4.11-4.04(m,1H), 3.94-3 .88(m,1H), 3.72-3.70(m,8H)3.37-3.09(m,2H), 2.86-2.76(m,2H), 2.56-2.50(m,2H), 2.02(s,3H);LC-MS:m / z 484.3(M+H) +

[0403] Example 16 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-1H-benzo[d]imidazole-5-carboxylic acid (compound 109a) [ka]

[0404] Process A: (3S,4R)-4-((tert-butyldimethylsilyl)oxy)-3-(cyclopentyloxy)-4-(3,5-dimethoxy-4-methylphenyl)butanal [ka]

[0405] (3S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-3-(cyclopentoxy)-4-(3,5-dimethoxy-4-methylphenyl)butanenitrile (730 mg, 1.68 mmol) was dissolved in toluene (10 mL), to which DIBAL-H (1 M, 3.37 mL) was added under N2 at -78 °C, and the mixture was stirred at -78 °C for 10 minutes. The resulting mixture was stirred under N2 at 0 °C for 50 minutes. The reaction product was diluted with H2O (50 mL) and extracted with ELISA (30 mL x 3). The organic layers were combined, washed with brine (20 mL x 3), dried on anhydrous Na2SO4, and filtered. (3S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-3-(cyclopentoxy)-4-(3,5-dimethoxy-4-methylphenyl)butanal (721 mg, yield 98%) was obtained as a colorless oil. LC-MS: m / z 459.2 (M+Na) +

[0406] Step B: Methyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-1H-benzo[d]imidazole-5-carboxylate [ka]

[0407] (3S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-3-(cyclopentoxy)-4-(3,5-dimethoxy-4-methylphenyl)butanal (400 mg, 916.06 micromoles) was dissolved in MeOH (5 mL), to which methyl 3,4-diaminobenzoate (152 mg, 916.06 micromoles) and AcOH (2.60 g, 43.30 mmol) were added. The mixture was stirred at 25°C for 0.5 hours. The pH was adjusted to 7 using a saturated aqueous solution of NaHCO3. The mixture was diluted with H2O (30 mL), and then extracted with ELISA (20 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by flash chromatography (PE / Â=4 / 1) to obtain methyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl]-1H-benzimidazole-5-carboxylate (163 mg, yield 30%) as an orange oil. LC-MS: m / z 583.2(M+H) +

[0408] Step C 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-1H-benzo[d]imidazole-5-carboxylic acid [ka]

[0409] 163 mg (279.68 micromoles) of methyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl]-1H-benzimidazole-5-carboxylate was dissolved in THF (1.5 mL), MeOH (1.5 mL), and H2O (1.5 mL), to which NaOH (56 mg, 1.40 mmol) was added. The mixture was stirred at 50°C for 16 hours. The pH was adjusted to 2-3 using 1N HCl. The mixture was diluted with H2O (30 mL) and extracted with ELISA (20 mL x 3). The organic layers were combined, dried over anhydrous sodium 2SO4, filtered, and concentrated to obtain 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl]-1H-benzimidazole-5-carboxylic acid (160 mg, crude) as an orange solid. LC-MS: m / z 569.2 (M+H) +

[0410] Step D 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-1H-benzo[d]imidazole-5-carboxylic acid (compound 109a) [ka]

[0411] To a solution of 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl]-1H-benzimidazole-5-carboxylic acid (160 mg, 281.31 micromoles) in THF (2 mL), TBAF (1 M, 2.81 mL) was added, and the mixture was stirred at 40°C for 2 hours. The reaction product was diluted with ELISA (15 mL) and then washed with H2O (8 mL x 6). The organic matter was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under vacuum, and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80x30mmx3μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 10%-80%, 9 minutes) to obtain 2-[(2S,3R)-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl]-1H-benzimidazole-5-carboxylic acid (53.94 mg, yield 42%) (compound 109a) as a white solid. 1 H NMR(400MHz, CD3OD)δ 8.22-8.21(m,1H), 7.94-7.93(m,1H), 7.56-7.52(m,1H), 6.71(s,2H), 4.78-4.76(m,1H), 4.01-3.94(m,1H), 3.84(s,6H) , 3.77-3.71(m,1H), 3.21-3.12(m,1H), 3.09-2.98(m,1H), 2.02(s,3H), 1.55-1.49(m,3H), 1.34-1.03(m,5H);LC-MS:m / z 455.1(M+H) +

[0412] Example 17 2-((2S,3R)-2-((2,3-dihydro-1H-inden-2-yl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-1H-benzo[d]imidazole-5-carboxylic acid (compound 114a) [ka]

[0413] Example 17 (Compound 114a) was synthesized according to the procedure described for the synthesis of Example 16 (Steps A to D in Scheme 165), by using (3S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-4-(3,5-dimethoxy-4-methylphenyl)-3-indan-2-yloxy-butanenitrile in step A. 1 H NMR(400MHz, CD3OD)δ 8.13(s,1H), 7.91(dd,J=8.4, 1.6Hz,1H), 7.46(d,J=8.4Hz,1H), 7.01-6.91(m,2 H), 6.89-6.78(m,1H), 6.67(s,2H), 6.46(d,J=7.2Hz,1H), 4.71(d,J=5.6,1H), 4 .04-3.94(m,2H), 3.76(s,6H), 3.21(dd,J=11.2, 3.2Hz,1H), 2.98-2.92(m,1H), 2.83-2.72(m,1H), 2.68-2.52(m,2H), 2.27-2.18(m,1H), 2.02(s,3H);LC-MS:m / z 503.1(M+H) +

[0414] Example 18 2-((2S,3R)-2-(cyclobutylmethoxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-1H-benzo[d]imidazole-5-carboxylic acid (compound 131a) [ka]

[0415] Example 18 (compound 131a) was synthesized according to the procedure described for the synthesis of Example 16 (steps A to D in Scheme 16), by using (3S,4R)-4-((tert-butyldimethylsilyl)oxy)-3-(cyclobutylmethoxy)-4-(3,5-dimethoxy-4-methylphenyl)butanenitrile in step A. 1H NMR (400MHz, DMSO-d6)δ 12.44(s,1H), 8.07-7.96(m,1H), 7.74(s,1H), 7.51-7.34(m,1H), 6.68(s,2H), 5.54(s,1H), 4.65(s,1H), 3.94-3.85(m,1H), 3.78(s,6H), 3.28-3.23(m,2H), 3.11-3.01(m,2H), 2.96-2.86(m,1H), 2.20-2.09(m,1H), 1.97(s,3H), 1.70-1.43(m,4H), 1.40-1.26(m,2H);LC-MS:m / z 455.2 (M+H) +

[0416] Example 19 2-[(2S,3R)-2-(cyclobutylmethoxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl]-1-methyl-benzimidazole-5-carboxylic acid (compound 119a) [ka]

[0417] Process A: Methyl 3-amino-4-(methylamino)benzoate [ka]

[0418] To a solution of methyl 4-(methylamino)-3-nitro-benzoate (500 mg, 2.38 mmol) in MeOH (5 mL), Pd / C (100 mg) was added. The mixture was stirred for 3 hours under 15 Psi of H2 at 25°C. The mixture was filtered, and the filtrate was concentrated under vacuum to obtain methyl 3-amino-4-(methylamino)benzoate (309 mg, yield 72.1%) as a brown solid. Without further purification, it was used in the next step. 1H NMR (400MHz, DMSO-d6)δ 7.25-7.22(dd,J=8.0, 1.6Hz,1H), 7.16(d,J=1.6Hz,1H), 6.39(d,J=8.0H z,1H), 5.44-5.40(m,1H), 4.69(s,2H), 3.72(s,1H), 2.77(d,J=4.8Hz,3H)

[0419] Step B: 2-[(2S,3R)-2-(cyclobutylmethoxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl]-1-methyl-benzimidazole-5-carboxylic acid (compound 119a) [ka]

[0420] Example 19 (compound 119a) was synthesized according to the procedure described for the synthesis of Example 16 (steps A to D in Scheme 16), by using (3S,4R)-4-((tert-butyldimethylsilyl)oxy)-3-(cyclobutylmethoxy)-4-(3,5-dimethoxy-4-methylphenyl)butanenitrile in step A and methyl 3-amino-4-(methylamino)benzoate in step B. 1 1H NMR (400 MHz, DMSO-d6)δ 8.09(d,J=0.8Hz,1H), 7.81(dd,J=8.4, 1.2Hz,1H), 7.55(d,J=8.4Hz,1H ), 6.70(s,2H), 5.57-5.53(m,1H), 4.73-4.69(m,1H), 3.88-3.81(m,1H), 3.78(s,6H), 3.76(s,3H), 3.27-3.18(m,2H), 3.05-2.95(m,2H), 2.21-2 .05(m,1H), 1.97(s,3H), 1.69-1.47(m,4H), 1.34-1.21(m,2H);LCMS:m / z 469.2 (M+H) +

[0421] Example 20 2-(2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-1H-benzo[d]imidazole-5-yl)acetic acid (compound 111a) [ka] [ka]

[0422] Process A: Methyl 2-(4-amino-3-nitrophenyl)acetate [ka]

[0423] A solution of methyl 2-(4-aminophenyl)acetate (2 g, 12.11 mmol) in TFA (20 mL) was cooled to -10°C. Next, HNO3 (0.57 mL, 12.71 mmol) was added dropwise. The reaction mixture was heated to 25°C and stirred for 18 hours. The reaction mixture was neutralized with 1N NaOH and extracted with siRNA (30 mL x 3). The organic layer was washed with H2O (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by flash chromatography (PE / siRNA = 5 / 1) to obtain methyl 2-(4-amino-3-nitrophenyl)acetate (930 mg, yield 37%) as a yellow solid. LC-MS: m / z 210.1 (M+H) +

[0424] Step B: Methyl 2-(3,4-diaminophenyl)acetate [ka]

[0425] A solution of methyl 2-(4-amino-3-nitrophenyl)acetate (500 mg, 2.38 mmol) in MeOH (5 mL) was mixed with Pd / C (0.2 g, purity 10%). The mixture was stirred for 3 hours under H2 (15 Psi) at 25°C. The mixture was filtered, the filtrate was concentrated under vacuum, and the residue was purified by flash chromatography (PE / Â=1 / 1) to obtain methyl 2-(3,4-diaminophenyl)acetate (384 mg, yield 89.5%) as a brown oil. 1 H NMR (400MHz, DMSO-d6)δ 6.44-6.37(m,2H), 6.25(d,J=6.8, 1H), 4.43-4.35(m,4H), 3.56(s,3H), 3.34(s,2H)

[0426] Step C 2-(2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-1H-benzo[d]imidazole-5-yl)acetic acid (compound 111a) [ka]

[0427] Example 20 (compound 111a) was synthesized by using methyl 2-(3,4-diaminophenyl)acetate in step B, following the procedure described for the synthesis of Example 16 (steps A to D in Scheme 16). 1 H NMR(400MHz, CD3OD)δ 7.50-7.43(m,2H), 7.24-7.17(d,J=8.8Hz,1H), 6.70(s,2H), 4.74(d,J=5.2Hz,1H), 3.99-3.90(m,1H), 3.84(s,6H), 3.77-3. 71(m,1H), 3.70(s,1H), 3.19-3.12(m,1H), 3.07-3.04(m,1H), 2.03(s,3H), 1.52-1.36(m,3H), 1.34-1.03(m,5H);LC-MS:m / z 469.1(M+H) +

[0428] Example 21 2-[2-[(2S,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-indan-2-yloxypropyl]-1H-benzimidazole-5-yl]acetic acid (compound 115a) [ka]

[0429] Example 21 (compound 115a) was synthesized according to the procedure described for the synthesis of Example 16 (steps A to D in Scheme 16), by using [(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(3,5-dimethoxy-4-methylphenyl)-2-indan-2-yloxypropyl]methanesulfonate in step A and methyl 2-(3,4-diaminophenyl)acetate in step B. 1 1H NMR (400 MHz, CD3OD) δ 7.44-7.34(m,2H), 7.20(d,J=5.6Hz,1H), 7.02-6.93(m,2H), 6.92-6.85 (m,1H), 6.66(s,2H), 6.51(d,J=7.6Hz,1H), 4.68(d,J=5.6Hz,1H), 4.02- 3.94(m,2H), 3.76(s,6H), 3.68(s,2H), 3.23-3.18(m,1H), 2.97-2.91(m ,1H), 2.80-2.72(m,1H), 2.66-2.55(m,2H), 2.28-2.20(m,1H), 2.02(s,3 H);LC-MS:m / z 517.1(M+H) +

[0430] Example 22 2-[2-[(2S,3R)-2-(cyclobutylmethoxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl]-1-methyl-benzimidazole-5-yl]acetic acid (compound 120a) [ka] [ka]

[0431] Step A: 2-(4-fluoro-3-nitrophenyl)acetic acid [ka]

[0432] To a solution of 2-(4-fluorophenyl)acetic acid (3.00 g, 19.5 mmol) in H2SO4 (20 mL), HNO3 (1.28 g, 19.3 mmol) was added dropwise at 0°C and the mixture was stirred for 1 hour. The reaction mixture was poured onto ice. The reaction mixture was extracted with ELISA (25 mL x 2). The organic phase was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to obtain 2-(4-fluoro-3-nitro-phenyl)acetic acid (4.11 g, crude) as a yellow solid. 1 H NMR(400MHz, CDCl3)δ 8.01(dd,J=6.8, 2.4Hz,1H), 7.64-7.53(m,1H), 7.32-7.22(m,1H), 3.74(s,2H)

[0433] Process B: 2-(4-fluoro-3-nitro-phenyl)acetate [ka]

[0434] 2-(4-fluoro-3-nitro-phenyl)acetic acid (4.11 g, 20.6 mmol) was dissolved in MeOH (20 mL), to which H2SO4 (376 mg, 3.75 mmol) was added dropwise. The mixture was then stirred at 80°C for 16 hours. The reaction mixture was poured over a mixture of saturated NaHCO3 aqueous solution and ice. The mixture was extracted with ELISA (30 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated to obtain methyl 2-(4-fluoro-3-nitro-phenyl)acetate (4.04 g, crude) as a brown gum. 1H NMR(400MHz, CDCl3)δ 8.01(dd,J=7.2, 2.4Hz,1H), 7.60-754(m,1H), 7.31-7.24(m,1H), 3.74(s,3H)

[0435] Process C: Methyl 2-[4-(methylamino)-3-nitrophenyl]acetate [ka]

[0436] To a solution of methyl 2-(4-fluoro-3-nitro-phenyl)acetate (2.00 g, crude) and methamine (425 mg, 6.29 mmol, HCl salt) in DMF (10 mL), Cs2CO3 (4.27 g, 13.1 mmol) was added at 25°C. The mixture was stirred at 25°C for 0.5 hours, then stirred at 60°C for 8 hours. The reaction mixture was diluted with saturated aqueous solution of NH4Cl (30 mL) and H2O (20 mL). The mixture was extracted with siRNA (30 mL x 3). The organic layers were combined, washed with brine (50 mL), and dried over Na2SO4. The solvent was removed to obtain a residue, which was purified by flash chromatography (PE / siRNA = 3 / 1) to obtain methyl 2-[4-(methylamino)-3-nitro-phenyl]acetate (0.957 g, 43.9% over 3 steps) as an orange solid. 1 H NMR (400MHz, CDCl3)δ 8.08(d,J=2.0Hz,1H), 8.03(brs,1H), 7.42(dd,J=8.8, 2.0Hz,1H), 6.84(d,J=8.8Hz,1H), 3.71(s,3H), 3.56(s,2H), 3.03(d,J=5.2Hz,3H)

[0437] Process D: Methyl 2-(3-amino-4-(methylamino)phenyl)acetate [ka]

[0438] 950 mg of methyl 2-[4-(methylamino)-3-nitrophenyl]acetate (4.24 mmol) was dissolved in 20 mL of MeOH, to which 200 mg of 10% Pd / C was added. The reaction mixture was stirred under 15 Psi of H2 for 16 hours. The reaction mixture was filtered and concentrated to obtain 800 mg of methyl 2-[3-amino-4-(methylamino)phenyl]acetate (crude) as a black oil. The residue was used in the next step without further purification. 1 H NMR(400MHz, CDCl3)δ 6.75(dd,J=8.0, 2.0Hz,1H), 6.67(d,J=2.0Hz,1H), 6.61(d,J=8.0Hz,1H), 3.68(s,3H), 3.50(s,2H), 3.33(brs,2H), 2.86(s,3H)

[0439] Step E: 2-[2-[(2S,3R)-2-(cyclobutylmethoxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl]-1-methyl-benzimidazole-5-yl]acetic acid (compound 120a) [ka]

[0440] Example 22 (Compound 120a) was synthesized according to the procedure described for the synthesis of Example 16 (Steps A to D in Scheme 165), by using (3S,4R)-4-((tert-butyldimethylsilyl)oxy)-3-(cyclobutylmethoxy)-4-(3,5-dimethoxy-4-methylphenyl)butanenitrile in step A and methyl 2-[3-amino-4-(methylamino)phenyl]acetate in step B. 1H NMR (400MHz, DMSO-d6)δ 7.48(d,J=6.0Hz,2H), 7.06(dd,J=7.6, 1.2Hz,1H), 6.69(s,2H), 5.56(brs,1 H), 4.67(d,J=5.2Hz,1H), 3.84-3.80(m,1H), 3.77(s,6H), 3.70(s,3H), 3.61( s,2H), 3.20(dd,J=9.4, 6.4Hz,1H), 3.06-2.97(m,3H), 2.15-2.12(m,1H), 1.9 8(s,3H), 1.71-1.57(m,3H), 1.57-1.47(m,1H), 1.38-1.25(m,2H);LC-MS:m / z 483.2(M+H) +

[0441] Example 23 2-((2S,3R)-3-(4-chloro-3-methoxyphenyl)-2-(cyclopentyloxy)-3-hydroxypropyl)-2H-indazole-7-carboxylic acid (compound 126a) [ka]

[0442] Example 23 (compound 126a) was synthesized according to the procedure described for the synthesis of Example 1 (steps C to N in Scheme 1), by using cyclopentanol in step C and 4-chloro-3-methoxybenzaldehyde in step F. 1 H NMR(400MHz, CD3OD)δ 8.33(s,1H), 8.02(dd,J=7.2, 1.2Hz,1H), 7.95(dd,J=8.4, 1.2Hz,1H), 7.33(d,J=8.0 Hz,1H), 7.20-7.14(m,2H), 7.01(dd,J=8.4, 2.0Hz,1H), 4.77(dd,J=13.6, 2.8Hz,1H), 4.63(d,J=4.0Hz,1H), 4.55(dd,J=14.0, 8.0Hz,1H), 4.06-3.98(m,1H), 4.01(s,3H), 3 .58-3.51(m,1H), 1.39-1.30(m,4H), 1.19-1.12(m,3H), 0.98-0.87(m,1H);LC-MS:m / z 445.1(M+H)+

[0443] Example 24 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)benzo[d]thiazole-4-carboxylic acid (compound 157) [ka] [ka]

[0444] Process A: (3S,4R)-4-((tert-butyldimethylsilyl)oxy)-3-(cyclopentyloxy)-4-(3,5-dimethoxy-4-methylphenyl)butanoic acid [ka]

[0445] (3S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-3-(cyclopentoxy)-4-(3,5-dimethoxy-4-methylphenyl)butanal (1.85 g, 4.24 mmol) was dissolved in t-BuOH (40 mL) and H2O (10 mL). NaH2PO4 (762.47 mg, 6.36 mmol), NaClO2 (1.38 g, 15.25 mmol), and 2-methylbuta-2-ene (1.34 g, 19.07 mmol) were added at 0°C. The mixture was stirred at 15°C for 1 hour. The mixture was diluted with H2O (40 mL) and extracted with ELISA (50 mL x 3). The organic layers were combined, washed with brine, dried over anhydrous sodium 2SO4, filtered, and concentrated to obtain (3S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-3-(cyclopentoxy)-4-(3,5-dimethoxy-4-methylphenyl)butanoic acid (1.9 g, crude product) as a yellow oil, which was used in the next step without further purification. LC-MS: m / z 475.2 (M+Na) +

[0446] Step B: Methyl 3-(tert-butylthio)-2-nitrobenzoate [ka]

[0447] To a solution of methyl 3-fluoro-2-nitro-benzoate (2 g, 10.04 mmol) in DMF (30 mL), Cs2CO3 (6.54 g, 20.09 mmol) and 2-methylpropane-2-thiol (815 mg, 9.04 mmol) were added. The solution was stirred at 25°C for 12 hours. The solution was diluted with H2O (100 mL) and extracted with siRNA (30 mL x 2). The organic matter was combined, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column (PE / siRNA = 5 / 1) to obtain methyl 3-tert-butylsulfanyl-2-nitro-benzoate (2.3 g, yield 85.0%). 1 H NMR(400MHz, CD3OD)δ 8.07(dd,J=9.8, 1.4Hz,1H), 7.96(dd,J=8.0, 1.6Hz,1H), 7.63(t,J=8.0Hz,1H), 3.86(s,3H), 1.28(s,9H)

[0448] Step C: Dimethyl 3,3'-disulfanediylbis(2-nitrobenzoate) [ka]

[0449] A solution of methyl 3-tert-butylsulfanyl-2-nitro-benzoate (7 g, 25.99 mmol) in TFA (70 mL) was stirred at 70°C for 3 hours. The solvent was removed under vacuum. The residue was dissolved in siRNA (200 mL) and washed with aqueous NaHCO3 (100 mL). The organic matter was added, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column (PE / siRNA=0 / 1) to obtain methyl 3-[(3-methoxycarbonyl-2-nitrophenyl)disulfanyl]-2-nitro-benzoate (2.7 g, crude) as a yellow solid. LC-MS: m / z 447.0 (M+Na) +

[0450] Step D: Dimethyl 3,3'-disulfanediylbis(2-aminobenzoate) [ka]

[0451] To a solution of methyl 3-[(3-methoxycarbonyl-2-nitrophenyl)disulfanyl]-2-nitrobenzoate (2.7 g, 6.36 mmol) in AcOH (20 mL), Fe (1.78 g, 31.81 mmol) was added. The solution was stirred at 60°C for 12 hours. The reaction mixture was filtered. The filtrate was collected and concentrated. The residue was dissolved in siRNA (200 mL) and washed with aqueous NaHCO3 (100 mL). The organic matter was combined, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column (PE / siRNA = 10 / 1) to obtain methyl 2-amino-3-[(2-amino-3-methoxycarbonylphenyl)disulfanyl]benzoate (1.86 g, yield 74.0%) as a yellow solid. LC-MS: m / z 364.7 (M+H) +

[0452] Step E: Methyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)benzo[d]thiazole-4-carboxylate [ka]

[0453] Tributylphosphan (2.28 g, 11.27 mmol) was added to a solution of methyl 2-amino-3-[(2-amino-3-methoxycarbonylphenyl)disulfanyl]benzoate (1.37 g, 3.76 mmol) in toluene (10 mL). The solution was stirred at 25°C for 10 minutes. Next, (3S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-3-(cyclopentoxy)-4-(3,5-dimethoxy-4-methylphenyl)butanoic acid (1.7 g, 3.76 mmol) was added. The solution was stirred at 80°C for 12 hours. The solvent was removed under vacuum to obtain the residue. The residue was purified by a silica gel column (PE / siRNA=5 / 1) to obtain methyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl]-1,3-benzothiazole-4-carboxylate (1.73 g, yield 48.4%) as a yellow oil. LC-MS: m / z 600.1(M+H) +

[0454] Step F: 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)benzo[d]thiazole-4-carboxylic acid [ka]

[0455] To a solution of methyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl]-1,3-benzothiazole-4-carboxylate (1.73 g, 2.88 mmol) in MeOH (8 mL), THF (8 mL), and H2O (8 mL), NaOH (1.73 g, 43.26 mmol) was added. The solution was stirred at 25°C for 2 hours. The pH of the solution was adjusted to 6 with 1N HCl, and the solution was extracted with SiO2 (30 mL x 3). The organic matter was combined, dried over Na2SO4, filtered, and concentrated to obtain 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl]-1,3-benzothiazole-4-carboxylic acid (1.4g, crude product) as a yellow oil, which was used directly in the next step without further purification.

[0456] Process G 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)benzo[d]thiazole-4-carboxylic acid (compound 157) [ka]

[0457] 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl]-1,3-benzothiazole-4-carboxylic acid (1.4 g, 2.39 mmol) was dissolved in THF (10 mL) and TBAF (1 M, 23.9 mL) was added. The solution was stirred at 25°C for 2 hours. The solution was diluted with H₂O (100 mL) and extracted with ELISA (200 mL). The organic liquid was collected and washed with H₂O (150 mL x 5). The organic compounds were combined, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by preparative HPLC (Neu) (column: Daisogel C18 250x50mmx8um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 5%-55%, 23 minutes) to obtain 2-[(2S,3R)-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-propyl]-1,3-benzothiazole-4-carboxylic acid (765.89 mg, yield 67.9%) as a white solid. 1 H NMR(400MHz, CD3OD)δ 8.11(d,J=8.0Hz,1H), 7.99(d,J=8.0Hz,1H), 7.50(t,J=8.0Hz,1H), 6.67(s,2H), 4.67(d,J=8.0Hz,1H), 4.03- 3.97(m,1H), 3.95-3.89(m,1H), 3.83(s,6H), 3.48(d,J=4.0Hz,2H), 2.01(s,3H), 1.55-1.32(m,8H);LC-MS:m / z 472.1(M+H) +

[0458] Example 25 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-2H-pyrazolo[4,3-b]pyridine-7-carboxylic acid (compound 160) [ka]

[0459] Example 25 (Compound 160) was synthesized by following the procedure described for the preparation of Example 1 (procedures A to N of Scheme 1), by using cyclopentanol in step C and methyl 2H-pyrazolo[4,3-b]pyridine-7-carboxylate in step L. 1 H NMR(400MHz, CD3OD)δ 8.55(d,J=4.4Hz,1H), 8.48(s,1H), 7.77(d,J=4.4Hz,1H), 6.60(s,2H), 4.72-4.66(m,1H), 4.57(d,J=6.0Hz,1H), 4.54-4.4 6(m,1H), 4.00-3.93(m,1H), 3.73(s,6H), 3.51-3.42(m,1H), 1.91(s,3H), 1.33-0.95(m,7H), 0.82-0.68(m,1H);LC-MS:m / z 456.4(M+H) +

[0460] Example 26 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-4-methoxypyrazolo[1,5-a]pyridine-7-carboxylic acid (compound 237) [ka] [ka]

[0461] Process A: 1-amino-5-methoxy-2-(methoxycarbonyl)pyridine-1-ium 2,4,6-trimethylbenzenesulfonate [ka]

[0462] To a solution of O-mesitylenesulfonylhydroxylamine (5.92 g, 27.5 mmol) in DCM (50 mL), methyl 5-methoxypyridine-2-carboxylate (2 g, 12.0 mmol) was added all at once, and the resulting mixture was stirred at 25°C for 2 hours. The solvent was removed under reduced pressure to obtain the product 1-amino-5-methoxy-2-(methoxycarbonyl)pyridine-1-ium 2,4,6-trimethylbenzenesulfonate (6 g, crude), which was used directly in the next step without further purification.

[0463] Step B (5-Methoxy-2-(Methoxycarbonyl)pyridine-1-ium-1-yl)(tosyl)amide [ka]

[0464] To a solution of methyl 1-amino-5-methoxypyridine-1-ium-2-carboxylate; 2,4,6-trimethylbenzenesulfonate (6 g, crude) in MeCN (100 mL), DMAP (192 mg, 1.6 mmol) and K2CO3 (6.5 g, 47.1 mmol) were added, followed by the gradual addition of p-TsCl (3.29 g, 17.3 mmol) at 0°C. The resulting mixture was stirred at 25°C for 12 hours. The mixture was diluted with MeOH (50 mL), filtered, and washed with MeOH (40 mL x 3). After concentrating the filtrate, the residue was purified by flash silica gel chromatography (ISCO®; 80g SepaFlash® silica flash column, eluate with a flow rate of 100 mL / min and a 0-3% MeOH / DCM gradient) to obtain (5-methoxy-2-(methoxycarbonyl)pyridine-1-ium-1-yl)(tosyl)amide (1.7g, yield 32.2%) as a white solid. LC-MS: m / z 336.9 (M+H) +

[0465] Process C tert-butyl(((1R,2S)-2-(cyclopentyloxy)-1-(3,5-dimethoxy-4-methylphenyl)penta-4-in-1-yl)oxy)dimethylsilane [ka]

[0466] At 0°C, a mixture of (3S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-3-(cyclopentoxy)-4-(3,5-dimethoxy-4-methylphenyl)butanal (7.2 g, 16.5 mmol) and K2CO3 (4.56 g, 33.0 mmol) in MeOH (70 mL) was added dropwise to dimethyl 1-(1-diazo-2-oxopropyl)phosphonate (3.8 g, 19.8 mmol). The mixture was stirred under nitrogen at 15°C for 16 hours. The mixture was concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 220g SepaFlash® silica flash column, eluate with a flow rate of 150 mL / min and a 0-4% ethyl acetate / petroleum ether gradient) to obtain tert-butyl-[(1R,2S)-2-(cyclopentoxy)-1-(3,5-dimethoxy-4-methylphenyl)penta-4-inoxy]-dimethylsilane (3.2g, yield 44.9%) as a colorless oil. 1 H NMR (400MHz, 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)

[0467] Step D: Methyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-4-methoxypyrazolo[1,5-a]pyridine-7-carboxylate [ka]

[0468] (5-methoxy-2-methoxycarbonylpyridine-1-ium-1-yl)-(p-tolylsulfonyl)azanide (296 mg, 881 micromoles) and tert-butyl-[(1R,2S)-2-(cyclopentoxy)-1-(3,5-dimethoxy-4-methylphenyl)penta-4-inoxy]-dimethylsilane (400 mg, 925 micromoles) were mixed in dioxane (5 mL) and tris(4-methoxyphenyl)phosphan (46.5 mg, 132 micromoles), silver benzoate (605 mg, 2.6 mmol), and dibromopalladium (11.7 mg, 44.0 micromoles) were added. The mixture was stirred under nitrogen at 120 °C for 3 hours. After cooling, the mixture was diluted with ethyl acetate (30 mL) and washed with 30% aqueous K2CO3 (30 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® silica flash column, eluate with a 0-22% ethyl acetate / petroleum ether gradient at a flow rate of 40 mL / min), and further purified by preparative HPLC to obtain methyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl]-4-methoxy-pyrazolo[1,5-a]pyridine-7-carboxylate (120 mg, yield 22.2%) as a colorless oil. 1 H NMR (400MHz, CDCl3)δ 8.04(s,1H), 7.54-7.51(m,1H), 6.60(s,2H), 6.35(d,J=8.0Hz,1H), 4.66-4.65(m,1H), 4.00(s,3H), 3.97(s,3H), 3.82-3.80(m,7H) ), 3.64-3.62(m,1H), 3.25-3.21(m,1H), 2.99-2.93(m,1H), 2.06(s,3H), 1.47-1.19(m,8H), 0.91(s,9H), 0.07(s,3H), -0.13(s,3H)

[0469] Step E 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-4-methoxypyrazolo[1,5-a]pyridine-7-carboxylic acid (compound 237) [ka]

[0470] A mixture of methyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl]-4-methoxy-pyrazolo[1,5-a]pyridine-7-carboxylate (80 mg, 131 micromoles) in MeOH (6 mL) and THF (2 mL) was mixed with NaOH (1.57 g, 39.2 mmol) / H2O (2 mL). The mixture was stirred at 60 °C for 20 hours. After removing the organic solvent, the aqueous layer was acidified to pH 4-5 with 6N HCl. The mixture was extracted with ethyl acetate (30 mL x 3). The organic layers were combined, dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Kromasil 100-5-C18; eluate: 65%~100% water (0.1% HCOOH)-ACN) to obtain 2-[(2S,3R)-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-propyl]-4-methoxy-pyrazolo[1,5-a]pyridine-7-carboxylic acid (20.07 mg, yield 30.9%) as a white solid. 1 H NMR(400MHz, CD3OD)δ 7.68(d,J=8.0Hz,1H), 6.68(d,J=8.0Hz,1H), 6.58(s,1H), 6.52(s,2H), 4.51-4.49(m,1H), 3.97(s,3H) ), 3.76-3.70(m,8H), 3.12-3.07(m,1H), 2.99-2.96(m,1H), 1.87(s,3H), 1.21-1.36(m,8H);LC-MS:m / z 485.2(M+H) +

[0471] Example 27 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)pyrazolo[1,5-a]pyridine-7-carboxylic acid (compound 169) [ka]

[0472] Process A: O-(mesitylsulfonyl)hydroxylamine [ka]

[0473] A solution of tert-butyl (mesitylsulfonyl)oxycarbamate (18 g, 57.07 mmol) in TFA (80 mL) was stirred at 0°C for 1.5 hours. The mixture was poured into ice water, then filtered, the solid was washed with H2O, and dried to obtain O-(mesitylsulfonyl)hydroxylamine (12.49 g, crude product) as a white solid.

[0474] Step B: Methyl 6-(bromomethyl)picolinate [ka]

[0475] Methyl 6-methylpyridine-2-carboxylate (25 g, 165.39 mmol) and AIBN (2.72 g, 16.54 mmol) were dissolved in CCl4 (300 mL), to which NBS (32.38 g, 181.92 mmol) was added. The mixture was stirred at 80°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then diluted with H2O (300 mL) and extracted with DCM (300 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (PE / Â5=4 / 1) to obtain the product methyl 6-(bromomethyl)pyridine-2-carboxylate (10.09 g, yield 26.5%) as a bright yellow solid. LC-MS: m / z 231.7 (M+H) +

[0476] Process C: Methyl 6-(cyanomethyl)picolinate [ka]

[0477] To a solution of methyl 6-(bromomethyl)pyridine-2-carboxylate (10.09 g, 43.86 mmol) in DMSO (100 mL), NaCN (4.3 g, 87.72 mmol) was added. The mixture was stirred at 20°C for 3 hours. The mixture was diluted with H2O (150 mL) and extracted with siRNA (100 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (PE / siRNA = 0 / 1) to obtain the product methyl 6-(cyanomethyl)pyridine-2-carboxylate (4.64 g, yield 59.1%) as a yellow oil. LC-MS: m / z 176.7 (M + H) +

[0478] Process D: 1-amino-2-(cyanomethyl)-6-(methoxycarbonyl)pyridine-1-ium [ka]

[0479] To a solution of methyl 6-(cyanomethyl)pyridine-2-carboxylate (4.64 g, 26.34 mmol) in DCM (25 mL), O-(mesitylsulfonyl)hydroxylamine (10.21 g, 47.41 mmol) was added. The mixture was stirred at 25°C for 16 hours. This solution was used directly in the next step. LC-MS: m / z 191.7 (M+H) +

[0480] Step E: Methyl 2-aminopyrazolo[1,5-a]pyridine-7-carboxylate [ka]

[0481] To a solution of methyl 1-amino-6-(cyanomethyl)pyridine-1-ium-2-carboxylate (5.06 g, theoretical amount) in DCM (25 mL) and MeOH (100 mL), K2CO3 (7.28 g, 52.66 mmol) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with H2O (80 mL) and extracted with DCM (60 mL x 3). The organic layers were combined, washed with brine (60 mL x 2), dried on anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column (PE / Â=0 / 1) to obtain the product methyl 2-aminopyrazolo[1,5-a]pyridine-7-carboxylate (1.6 g, yield 31.8%) as a yellow solid. LC-MS: m / z 191.8(M) +

[0482] Process F: Methyl 2-iodopyrazolo[1,5-a]pyridine-7-carboxylate [ka]

[0483] To a solution of methyl 2-aminopyrazolo[1,5-a]pyridine-7-carboxylate (1.6 g, 8.37 mmol) in CH3CN (15 mL), 4-methylbenzenesulfonic acid hydrate (4.78 g, 25.11 mmol) was added, followed by the addition of a solution of NaNO2 (1.15 g, 16.74 mmol) in H2O (3 mL) dropwise at 0°C. The mixture was stirred at 0°C for 30 minutes, and then a solution of NaI (3.14 g, 20.92 mmol) in H2O (3 mL) dropwise was added. The mixture was stirred at 20°C for 3 hours. The mixture was diluted with H2O (60 mL) and extracted with SiO2 (40 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (PE / Â=3 / 1) to obtain methyl 2-iodopyrazolo[1,5-a]pyridine-7-carboxylate (323 mg, yield 12.8%) as a yellow solid. LC-MS: m / z 302.6 (M+H) +

[0484] Process G: Methyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)pyrazolo[1,5-a]pyridine-7-carboxylate [ka]

[0485] Methyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)pyrazole[1,5-a]pyridine-7-carboxylate was synthesized according to the procedure described for the synthesis of Example 11 (Compound 106a) (Steps A to B in Scheme 11), by using methyl [(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl]methanesulfonate in step A and methyl 2-iodopyrazole[1,5-a]pyridine-7-carboxylate in step B.

[0486] Step H 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)pyrazolo[1,5-a]pyridine-7-carboxylic acid (compound 169) [ka]

[0487] 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)pyrazolo[1,5-a]pyridine-7-carboxylic acid was synthesized by using methyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)pyrazolo[1,5-a]pyridine-7-carboxylate in step E, according to the procedure described for the synthesis of Example 26 (Compound 237) (step E in Scheme 26). 1 H NMR(400MHz, CD3OD)δ 7.90(dd,J=8.0, 1.2Hz,1H), 7.81(dd,J=7.2, 1.2Hz,1H), 7.40(dd,J=8.0, 7.2Hz,1H), 6.71(s,1H), 6.66(s,2H), 4.62(d,J=4.0 Hz,1H), 3.91-3.85(m,1H), 3.84-3.78(m,7H), 3.27-3.20(m,1H), 3.16-3.07(m,1H), 2.00(s,3H), 1.51-1.26(m,8H);LC-MS:m / z 455.0(M+H) +

[0488] Example 28 2-(2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-5-methylthiazole-4-yl)acetic acid (compound 177) [ka] [ka]

[0489] Process A: Methyl 4-chloro-3-oxopentanoate [ka]

[0490] To a suspension of (3-methoxy-3-oxo-propanoyl)oxypotassium (20 g, 128 mmol) in MeCN (150 mL), TEA (26.7 mL, 192 mmol) was added. Then MgCl2 (14.5 g, 152 mmol) was added little by little. After stirring for 3 hours, the mixture was cooled to 0°C and 2-chloropropanoyl chloride (9.21 mL, 95.0 mmol) was added dropwise. The resulting mixture was stirred at 25°C for 12 hours. The mixture was diluted with HCl (100 mL) and acidified to pH 6 using 5N HCl. Organic matter was separated, dried on anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column (PE / HCl = 10 / 1) to obtain the product methyl 4-chloro-3-oxo-pentanoate (9 g, yield 42.7%) as a yellow liquid. 1 H NMR (400MHz, CDCl3)δ 4.56-4.36(m,1H), 3.89-3.64(m,5H), 1.73-1.60(m,3H)

[0491] Process B: Methyl 2-(2-amino-5-methylthiazole-4-yl)acetate [ka]

[0492] A mixture of methyl 4-chloro-3-oxo-pentanoate (7 g, 42.5 mmol) and thiourea (3.56 g, 46.8 mmol) in MeOH (50 mL) was stirred at 90°C for 12 hours. The solvent was removed under reduced pressure to obtain a residue. The residue was purified by passing it through a silica gel column (PE / siRNA=2 / 1) to obtain the product methyl 2-(2-amino-5-methylthiazole-4-yl)acetate (5.3 g, yield 66.9%) as a white solid. 1 H NMR(400MHz, CDCl3)δ 4.77(brs,2H), 3.71(s,3H), 3.50(s,2H), 2.22(s,3H)

[0493] Process C: Methyl 2-(2-bromo-5-methylthiazole-4-yl)acetate [ka]

[0494] To an ice-cold suspension of tert-butyl nitrite (1.92 mL, 16.1 mmol) and CuBr2 (3.60 g, 16.11 mmol) in MeCN (100 mL), methyl 2-(2-amino-5-methylthiazole-4-yl) acetate (2 g, 10.7 mmol) was added at -20°C. The resulting mixture was stirred at 15°C for 2 hours. The mixture was poured into H2O (250 mL) and extracted with siRNA (120 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and evaporated to obtain the residue. The residue was purified by silica gel column (PE / siRNA = 20 / 1) to obtain the product methyl 2-(2-bromo-5-methylthiazole-4-yl) acetate (1.06 g, yield 39.5%) as a colorless oil. 1 H NMR (400MHz, CDCl3)δ 3.72-3.71(m,5H), 2.37(s,3H)

[0495] Process D: Methyl 2-(2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-5-methylthiazole-4-yl)acetate [ka]

[0496] Methyl 2-(2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-5-methylthiazole-4-yl) acetate was synthesized according to the procedure described for the synthesis of Example 11 (Compound 106a) (Steps A to B in Scheme 11), by using methyl [(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl]methanesulfonate in Step A of Scheme 11 and methyl 2-(2-bromo-5-methylthiazole-4-yl) acetate in Step B of Scheme 11. LC-MS: m / z 578.1 (M+H) +

[0497] Step E: 2-(2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-5-methylthiazole-4-yl)acetic acid [ka]

[0498] 2-(2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-5-methylthiazole-4-yl)acetic acid was synthesized according to the procedure described in step M of the manufacturing process in Example 1. LC-MS: m / z 564.6 (M+H) +

[0499] Process F: 2-(2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-5-methylthiazole-4-yl)acetic acid [ka]

[0500] 2-(2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-5-methylthiazole-4-yl)acetic acid was synthesized according to the procedure described in step N of the manufacturing process in Example 1. 1 H NMR(400MHz, CD3OD)δ 6.67(s,2H), 4.67(d,J=5.2Hz,1H), 3.83(s,6H), 3.82-3.77(m,2H), 3.68(s,2H), 3.18- 3.06(m,2H), 2.38(s,3H), 2.03(s,3H), 1.52-1.37(m,7H), 1.36-1.32(m,1H);LC-MS:m / z 450.5(M+H) +

[0501] Example 29 2-((2S,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-isobutoxypropyl)-6-methylbenzo[d]thiazole-4-carboxylic acid (compound 234) [ka] [ka]

[0502] Process A: Methyl 2-amino-3-bromo-5-methylbenzoate [ka]

[0503] To a solution of methyl 2-amino-5-methylbenzoate (5 g, 30.27 mmol) in AcOH (30 mL), NBS (5.39 g, 30.27 mmol) was added, and the mixture was stirred at 25°C for 2 hours. The pH was adjusted to 6-7 using a saturated aqueous solution of NaHCO3. The mixture was extracted with siRNA (80 mL x 3). The organic layers were combined, dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by passing it through a silica gel column (PE / siRNA = 49 / 1) to obtain the product methyl 2-amino-3-bromo-5-methylbenzoate (6.84 g, yield 92.2%) as a colorless oil. 1 H NMR (400MHz, CD3OD) δ 7.59(d,J=1.2Hz,1H), 7.52(d,J=2.0Hz,1H), 6.49(s,2H), 3.81(s,3H), 2.17(s,3H);LC-MS:m / z 243.8(M+H) +

[0504] Process B: Methyl 2-amino-3-((3-((2-ethylhexyl)oxy)-3-oxopropyl)thio)-5-methylbenzoate [ka]

[0505] To a solution of methyl 2-amino-3-bromo-5-methylbenzoate (6.84 g, 28.02 mmol) in toluene (50 mL), 2-ethylhexyl 3-sulfanylpropanoate (6.73 g, 30.83 mmol), DIEA (14.6 mL, 84.07 mmol), xanthophos (3.24 g, 5.60 mmol), and Pd2(dba)3 (2.57 g, 2.80 mmol) were added. The mixture was stirred under N2 at 100°C for 16 hours. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by passing it through a silica gel column (PE / SiO=24 / 1) to obtain the product methyl 2-amino-3-((3-((2-ethylhexyl)oxy)-3-oxopropyl)thio)-5-methylbenzoate (6.88 g, yield 61.7%) as a yellow oil. LC-MS: m / z 382.4(M+H) +

[0506] Step C: Diethyl 3,3'-disulfanediylbis(2-amino-5-methylbenzoate) [ka]

[0507] To a solution of methyl 2-amino-3-((3-((2-ethylhexyl)oxy)-3-oxopropyl)thio)-5-methylbenzoate (1 g, 2.62 mmol) in EtOH (10 mL), EtONa (445.90 mg, 6.55 mmol) was added at 0°C. After addition, the reaction mixture was stirred at 25°C for 12 hours. The mixture was diluted with H2O (40 mL) and its pH was adjusted to 7 using 1N HCl. The mixture was extracted with ELISA (30 mL x 3). The organic layers were combined, dried on anhydrous Na2SO4, and concentrated under reduced pressure to obtain a residue. The residue was purified by passing it through a silica gel column (PE / ELISA = 28 / 1) to obtain the product diethyl 3,3'-disulfanediylbis(2-amino-5-methylbenzoate) (264 mg, yield 23.5%) as a yellow solid. LC-MS: m / z 421.4 (M+H) +

[0508] Step D: Ethyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-2-isobutoxypropyl)-6-methylbenzo[d]thiazole-4-carboxylate [ka]

[0509] Ethyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-2-isobutoxypropyl)-6-methylbenzo[d]thiazole-4-carboxylate was synthesized by using diethyl 3,3'-disulfanediylbis(2-amino-5-methylbenzoate) and (3S,4R)-4-((tert-butyldimethylsilyl)oxy)-4-(3,5-dimethoxy-4-methylphenyl)-3-isobutoxybutanoic acid in step E, according to the procedure described for the synthesis of Example 24 (Compound 157).

[0510] Step E 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-2-isobutoxypropyl)-6-methylbenzo[d]thiazole-4-carboxylic acid [ka]

[0511] 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-2-isobutoxypropyl)-6-methylbenzo[d]thiazole-4-carboxylic acid was synthesized by using ethyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-2-isobutoxypropyl)-6-methylbenzo[d]thiazole-4-carboxylate in step F, according to the procedure described for the synthesis of Example 24 (Compound 157).

[0512] Process F 2-((2S,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-isobutoxypropyl)-6-methylbenzo[d]thiazole-4-carboxylic acid (compound 234) [ka]

[0513] 2-((2S,3R)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxy-2-isobutoxypropyl)-6-methylbenzo[d]thiazole-4-carboxylic acid was synthesized by using 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-3-(3,5-dimethoxy-4-methylphenyl)-2-isobutoxypropyl)-6-methylbenzo[d]thiazole-4-carboxylic acid in step G, according to the procedure described for the synthesis of Example 24. 1 H NMR(400MHz, CD3OD)δ 7.92(d,J=4.0Hz,2H), 6.57(s,2H), 4.67(d,J=4.0Hz,1H), 3.90-3.79(m,1H), 3.71(s,6H), 3.44-3.28(m, 2H), 3.06(d,J=8.0Hz,2H), 2.44(s,3H), 1.87(s,3H), 1.62-1.54(m,1H), 0.63(t,J=7.2Hz,6H);LC-MS:m / z 474.2(M+H) +

[0514] Example 30 (S)-2-(2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-5-methylthiazole-4-yl)propanoic acid (compound 239) and (R)-2-(2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-5-methylthiazole-4-yl)propanoic acid (compound 240) [ka] [ka]

[0515] Process A: Methyl 2-methyl-3-oxopentanoate [ka]

[0516] To a solution of methyl 3-oxopentanoate (3.5 g, 26.89 mmol) in THF (10 mL), K2CO3 (7.43 g, 53.79 mmol) and MeI (2.1 mL, 33.62 mmol) were added under an N2 atmosphere at 20°C. The mixture was stirred at 70°C for 5 hours. The reaction product was concentrated under reduced pressure to remove THF. The residue was diluted with H2O (10 mL) and extracted with siRNA (20 mL x 2). The organic layers were combined, washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated to obtain the crude product methyl 2-methyl-3-oxopentanoate (3.7 g, yield 95.4%) as a yellow oil, which was used directly in the next step without further purification. 1 H NMR (400MHz, DMSO-d6)δ 3.78-3.70(m,1H), 3.63(s,3H), 2.57(q,J=7.2Hz,2H), 1.18(d,J=7.1Hz,3H), 0.92(t,J=7.2Hz,3H)

[0517] Process B: Methyl 4-bromo-2-methyl-3-oxopentanoate [ka]

[0518] To a solution of methyl 2-methyl-3-oxopentanoate (4.79 g, 33.25 mmol) in DCM (50 mL), pyridinium tribromide (11.70 g, 36.58 mmol) was added at 0°C, and the mixture was stirred at 25°C for 3 hours. The reaction mixture was quenched with H2O (30 mL), and the mixture was extracted with DCM (20 mL x 3). The organic layers were combined and concentrated under reduced pressure to obtain the crude product methyl 4-bromo-5-methyl-3-oxohexanoate (8.14 g, yield 86.6%) as a bright yellow oil. 1 H NMR (400MHz, DMSO-d6)δ 5.04-4.91(m,1H), 4.17-3.93(m,1H), 3.61(s,3H), 1.62-1.58(m,3H), 1.24-1.20(m,3H)

[0519] Process C: Methyl 2-(2-amino-5-methylthiazole-4-yl)propanoate [ka]

[0520] Methyl 2-(2-amino-5-methylthiazole-4-yl)propanoate was synthesized by using methyl 4-bromo-2-methyl-3-oxopentanoate in step B, according to the procedure described for the synthesis of Example 28. 1 H NMR (400MHz, DMSO-d6)δ 6.69(s,2H), 3.73-3.67(m,1H), 3.54(s,3H), 2.13(s,3H), 1.24(d,J=7.0Hz,3H)

[0521] Process D: Methyl 2-(2-bromo-5-methylthiazole-4-yl)propanoate [ka]

[0522] Methyl 2-(2-bromo-5-methylthiazole-4-yl)propanoate was synthesized by using methyl 2-(2-amino-5-methylthiazole-4-yl)propanoate in step C, according to the procedure described for the synthesis of Example 28. 1 H NMR (400MHz, DMSO-d6)δ 4.02(q,J=6.8Hz,1H), 3.58(s,3H), 2.36(s,3H), 1.34(d,J=7.2Hz,3H);LC-MS:m / z 266.1(M+H) +

[0523] Process E: Methyl 2-(2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-5-methylthiazole-4-yl)propanoate [ka]

[0524] Methyl 2-(2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-5-ethylthiazole-4-yl)acetate was synthesized by using methyl 2-(2-bromo-5-methylthiazole-4-yl)propanoate in step D, according to the procedure described for the synthesis of Example 28. LC-MS: m / z 592.3 (M+H) +

[0525] Process F: 2-(2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-5-methylthiazole-4-yl)propanoic acid [ka]

[0526] 2-(2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-5-methylthiazole-4-yl)propanoic acid was synthesized by using methyl 2-(2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-5-methylthiazole-4-yl)propanoate in step M, according to the procedure described for the synthesis of Example 1. LC-MS: m / z 578.3(M+H) +

[0527] Process G: 2-(2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-5-methylthiazole-4-yl)propanoic acid [ka]

[0528] 2-(2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-5-methylthiazole-4-yl)propanoic acid was synthesized by using 2-(2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-5-methylthiazole-4-yl)propanoic acid in step N, according to the procedure described for the synthesis of Example 1. LC-MS: m / z 464.1(M+H) +

[0529] Step H (S)-2-(2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-5-methylthiazole-4-yl)propanoic acid (compound 239) and (R)-2-(2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-5-methylthiazole-4-yl)propanoic acid (compound 240) [ka]

[0530] 2-(2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-5-methylthiazole-4-yl)propanoic acid was further separated by SFC (column: DAISELCHIRALPAK IG (250mm x 30mm, 10μm); mobile phase: [Neu-MeOH]; B%: 25%-25%) to obtain two isomers. The chiral centers were randomly assigned.

[0531] Isomer 1: (S)-2-(2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-5-methylthiazole-4-yl)propanoic acid (compound 239); 1 H NMR(400MHz, CD3OD)δ 6.67(s,2H), 4.65(d,J=5.6Hz,1H), 3.94-3.89(m,1H), 3.84(s,6H), 3.82-3.77(m,2H), 3.21-3.13(m, 1H), 3.11-3.02(m,1H), 2.40(s,3H), 2.04(s,3H), 1.46(d,J=8.0Hz,3H), 1.42-1.30(m,8H);LC-MS:m / z 464.1(M+H) + SFC analysis conditions: Column: ChiralPak IG-3 100x4.6mm ID, 3μm; Mobile phase: A: CO2 B: Methanol (0.05% DEA); Gradient: 5% to 40% B over 4.5 minutes, then 5% B over 1.5 minutes; Flow rate: 2.5 mL / min; Retention time: 3.202 min

[0532] Isomer 2 (R)-2-(2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)-5-methylthiazole-4-yl)propanoic acid (compound 240) [ka]

[0533] 1 H NMR(400MHz, CD3OD)δ 6.67(s,2H), 4.66(d,J=5.6Hz,1H), 3.94-3.89(m,1H), 3.84(s,6H), 3.83-3.79(m,2H), 3.19 -3.04(m,2H), 2.40(s,3H), 2.04(s,3H), 1.46(d,J=8.0Hz,3H), 1.42-1.31(m,8H);LC-MS:m / z 464.1(M+H) + SFC analysis conditions: Column: ChiralPak IG-3 100x4.6mm ID, 3μm; Mobile phase: A: CO2 B: Methanol (0.05% DEA); Gradient: 5% to 40% B over 4.5 minutes, then 5% B over 1.5 minutes; Flow rate: 2.5 mL / min; Retention time: 3.371 min

[0534] Example 31 2-((2S,3R)-3-(4-cyano-3,5-diethoxyphenyl)-2-(cyclopentyloxy)-3-hydroxypropyl)benzo[d]thiazole-4-carboxylic acid (compound 257) [ka] [ka]

[0535] (3S,4R)-4-(4-bromo-3,5-diethoxyphenyl)-4-((tert-butyldimethylsilyl)oxy)-3-(cyclopentyloxy)butanoic acid is used in step F by using 2-(2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)-5-methylthiazole-4-yl)propanoic acid in step F, according to the procedure described for the synthesis in Example 1 (steps F to K in Scheme 1), and (2S,3R)-3-(4-bromo-3,5-diethoxyphenyl)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)propyl in step A, according to the procedure described in Example 14 (step A in Scheme 14). It was synthesized by using methanesulfonate and by using (3S,4R)-4-(4-bromo-3,5-diethoxyphenyl)-4-((tert-butyldimethylsilyl)oxy)-3-(cyclopentyloxy)butanal in step A, according to the procedure described in Example 24 (step A in Scheme 24).

[0536] Process A: (3S,4R)-4-((tert-butyldimethylsilyl)oxy)-4-(4-cyano-3,5-diethoxyphenyl)-3-(cyclopentyloxy)butanoic acid [ka]

[0537] (3S,4R)-4-(4-bromo-3,5-diethoxyphenyl)-4-[tert-butyl(dimethyl)silyl]oxy-3-(cyclopentoxy)butanoic acid (200 mg, 366.58 micromoles) was dissolved in DMF (2 mL) to which Zn(CN)2 (129.14 mg, 1.10 mmol) and Pd(PPh3)4 (42.36 mg, 36.66 micromoles) were added. The mixture was stirred under microwave at 120°C for 1 hour. The reaction mixture was diluted with H2O (10 mL) and extracted with ELISA (10 mL x 3). The organic layers were combined, washed with brine (10 mL x 3), dried on anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column (PE / siRNA=3 / 1) to obtain (3S,4R)-4-((tert-butyldimethylsilyl)oxy)-4-(4-cyano-3,5-diethoxyphenyl)-3-(cyclopentyloxy)butanoic acid (70 mg, yield 38.8%) as a brown oil. LC-MS: m / z 492.2(M+H) +

[0538] Step B: Ethyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-3-(4-cyano-3,5-diethoxyphenyl)-2-(cyclopentyloxy)propyl)benzo[d]thiazole-4-carboxylate [ka]

[0539] To a solution of ethyl 2-amino-3-[(2-amino-3-ethoxycarbonylphenyl)disulfanyl]benzoate (55.88 mg, 142.37 micromoles) in toluene (1 mL), tributylphosphan (86.41 mg, 427.11 micromoles) was added. Next, (3S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-4-(4-cyano-3,5-diethoxyphenyl)-3-(cyclopentoxy)butanoic acid (70.00 mg, 142.37 micromoles) was added. The solution was stirred at 80°C for 12 hours. The reaction mixture was diluted with H2O (30 mL) and extracted with ELISA (30 mL x 3). The organic layers were combined, washed with brine (30 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated to obtain ethyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(4-cyano-3,5-diethoxyphenyl)-2-(cyclopentoxy)propyl]-1,3-benzothiazole-4-carboxylate (100 mg, crude) as a yellow oil, which was used in the next step without further purification. LC-MS: m / z 653.2 (M+H) +

[0540] Step C: Ethyl 2-((2S,3R)-3-(4-cyano-3,5-diethoxyphenyl)-2-(cyclopentyloxy)-3-hydroxypropyl)benzo[d]thiazole-4-carboxylate [ka]

[0541] To a solution of ethyl 2-[(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-3-(4-cyano-3,5-diethoxyphenyl)-2-(cyclopentoxy)propyl]-1,3-benzothiazole-4-carboxylate (100 mg, 153.16 micromoles) in THF (1 mL), TBAF (1 M THF solution, 1.53 mL) was added. The mixture was stirred at 20°C for 2 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with ELISA (10 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated to obtain ethyl 2-[(2S,3R)-3-(4-cyano-3,5-diethoxyphenyl)-2-(cyclopentoxy)-3-hydroxypropyl]-1,3-benzothiazole-4-carboxylate (80 mg, yield 97.0%) as a yellow oil, which was used in the next step without further purification. LC-MS: m / z 539.0 (M+H) +

[0542] Step D 2-((2S,3R)-3-(4-cyano-3,5-diethoxyphenyl)-2-(cyclopentyloxy)-3-hydroxypropyl)benzo[d]thiazole-4-carboxylic acid (compound 257) [ka]

[0543] Ethyl 2-[(2S,3R)-3-(4-cyano-3,5-diethoxyphenyl)-2-(cyclopentoxy)-3-hydroxypropyl]-1,3-benzothiazole-4-carboxylate (80 mg, 148.52 micromoles) was dissolved in THF (0.8 mL), MeOH (0.2 mL), and H2O (0.2 mL), to which LiOH (17.78 mg, 742.59 micromoles) was added. The mixture was stirred at 20°C for 0.5 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with ELISA (10 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Kromasil 100-5-C18; eluate: 50%~90% water (0.1% HCOOH)-ACN) to obtain the product 2-[(2S,3R)-3-(4-cyano-3,5-diethoxyphenyl)-2-(cyclopentoxy)-3-hydroxy-propyl]-1,3-benzothiazole-4-carboxylic acid (15 mg, yield 19.78%) as a yellow solid. 1 H NMR(400MHz, CD3OD)δ 8.28-8.16(m,2H), 7.59(t,J=7.8Hz,1H), 6.76(s,2H), 4.84-4.82(m,1 LC-MS:m / z 511.1(M+H) +

[0544] Example 32 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)benzo[b]thiophene-4-carboxylic acid (compound 265) [ka]

[0545] Step A: Methylbenzo[b]thiophene-4-carboxylate [ka]

[0546] To a solution of 4-bromobenzothiophene (5 g, 23.46 mmol) in MeOH (50 mL), TEA (9.8 mL, 70.39 mmol) and Pd(dppf)Cl2 (1.72 g, 2.35 mmol) were added. The mixture was stirred for 16 hours under 40 psi of CO gas at 55°C. The reaction product was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by passing it through a silica gel column (PE / siRNA=24 / 1) to obtain the product methylbenzo[b]thiophene-4-carboxylate (3.32 g, yield 73.6%) as a bright yellow oil. 1 H NMR(400MHz, CD3OD)δ 8.20-8.00(m,3H), 7.73(d,J=3.6Hz,1H), 7.38(t,J=8.0Hz,1H), 3.95(s,3H)

[0547] Step B: Methyl 2-iodobenzo[b]thiophene-4-carboxylate [ka]

[0548] To a solution of diisopropylamine (0.26 mL, 1.79 mmol) in THF (4 mL), n-BuLi (2.5 M in hexane) (0.66 mL, 1.65 mmol) was added at 0°C, and the mixture was stirred at 0°C for 10 minutes. A solution of methylbenzo[b]thiophene-4-carboxylate (260 mg, 1.35 mmol) in THF (2 mL) was added under N2 conditions at -78°C. After 30 minutes, a solution of I2 (412 mg, 1.62 mmol) in THF (1 mL) was added. The mixture was stirred at 25°C for 5 hours. The reaction product was quenched with H2O (40 mL) and extracted with RINKAN (30 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by passing it through a silica gel column (PE / siRNA=32 / 1) to obtain methyl 2-iodobenzo[b]thiophene-4-carboxylate (240 mg, yield 27.1%) as a bright yellow oil. LC-MS: m / z 318.5 (M+H) +

[0549] Process C: Methyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)benzo[b]thiophene-4-carboxylate [ka]

[0550] Methyl 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)benzo[b]thiophene-4-carboxylate was synthesized according to the procedure described for the production of Example 11 (Compound 106a) (Steps A to B of Scheme 11), by using methyl [(2S,3R)-3-[tert-butyl(dimethyl)silyl]oxy-2-(cyclopentoxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl]methanesulfonate in step A and methyl 2-iodobenzo[b]thiophene-4-carboxylate in step B.

[0551] Step D: 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)benzo[b]thiophene-4-carboxylic acid [ka]

[0552] 2-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)propyl)benzo[b]thiophene-4-carboxylic acid was synthesized according to the procedure described in step M of the preparation of Example 1 (compound 113a). LC-MS: m / z 607.3 (M+Na) +

[0553] Step E: 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)benzo[b]thiophene-4-carboxylic acid [ka]

[0554] 2-((2S,3R)-2-(cyclopentyloxy)-3-(3,5-dimethoxy-4-methylphenyl)-3-hydroxypropyl)benzo[b]thiophene-4-carboxylic acid was synthesized according to the procedure described in step N of the preparation of Example 1 (compound 113a). 1 H NMR(400MHz, CD3OD)δ 8.09-7.95(m,3H), 7.35(t,J=8.0Hz,1H), 6.67(s,2H), 4.58(d,J=4.0Hz,1H), 3.89-3.78 (m,7H), 3.77-3.72(m,1H), 3.29-3.16(m,2H), 2.04(s,3H), 1.52-1.27(m,8H);LC-MS:m / z 493.1(M+Na) +

[0555] Example A: Assay In vitro LPA1 functional antagonist assay Human LPA1-overexpressing CHO-K1 cells were seeded in a total volume of 20 μL in a 384-well microplate coated with poly-D-lysine, with black sidewalls and a clear bottom, and incubated at 37°C for an appropriate time before testing. The assay was performed in 1x Dye Loading Buffer consisting of 1x dye, 1x Additive A, and 2.5 mM probenecid in HBSS / 20 mM Hepes. Probenecid was freshly prepared. The cells were loaded with dye before testing. The culture medium was aspirated from the cells and replaced with 20 μL of dye-loaded buffer. The cells were incubated at 37°C for 30–60 minutes. After dye loading, the cells were removed from the incubator and 10 μL of 3x test compound was added. Cells were incubated in the dark at room temperature for 30 minutes, the plate temperature was brought to equilibrium, and then subjected to the oleoyl LPA challenge at 0.018 μM. The antagonist activity of the compound was measured by FLIPR Tetra (MDS). Calcium mobilization was monitored for 2 minutes, and 10 μL of oleoyl LPA in HBSS / 20 mM Hepes was added to the cells 5 seconds before the assay. The activity of the compound was analyzed using the CBIS data analysis suite (ChemInnovation, CA). The inhibition percentage is given by the following formula:

number

[0556] Table B1 shows the biological activity of the compounds in an in vitro LPA1 functional antagonist assay. [Table 79] [Table 80]

[0557] In vitro LPA1 calcium flux antagonist assay - Bioduro protocol CHO-K1 cells overexpressing human LPA1 and G15a were seeded in 20 μL total volume (15,000 cells / well) in 384-well plates pre-coated with Matrigel and incubated at 37°C. After overnight incubation, cells were serum-starved for 4 hours. The assay was performed in a dye-loaded buffer containing 1x Fluo-8 AM (AAT Bioquest, 21080) and 2.5 mM probenecid (Thermo Fisher, 36400) in HBSS / 20 mM Hepes. After starving the cells, the medium was replaced with 20 μL of dye-loaded buffer and incubated at 37°C for 30 minutes. Then, 5 μL of 5x compound titrated in dye-loaded buffer was added to the cells, incubated for 30 minutes, and subsequently subjected to the LPA challenge at EC80. Calcium recruitment was measured using FLIPR Tetra (MDS). To measure LPA EC80, starved cells were incubated with 20 μL of dye-loaded buffer for 1 hour, and then 5 μL of 5x LPA titrated in dye-loaded buffer was added to the cells. The calcium signal induced by LPA was monitored using FLIPR.

[0558] The inhibition percentage is calculated using the following formula:

number

[0559] Table B2 shows the biological activity of the compounds in the in vitro LPA1 calcium flux antagonist assay-bioduro protocol. [Table 81] [Table 82] [Table 83] [Table 84]

[0560] Example B: X-ray crystallographic operation as an example for measuring absolute configuration Equipment: HyPix-6000HE area detector; Rigaku Oxford XtaLAB Synergy quadra-axis diffractometer equipped with microfocus tubes / Cu. 1. Cultivation of single crystals The solution was evaporated at room temperature to cultivate the single crystal. 2. X-ray testing and analysis We collected the reflected light, solved its structure using SHELXT, and refined it using SHELXL.

[0561] Other Embodiments The present invention is described in conjunction with its detailed description, but it should be understood that the above description is intended to illustrate, not to limit, the scope of the invention as defined by the attached claims. Other aspects, advantages, and modifications are within the scope of the following claims.

[0562] Numbered items The compounds, compositions, methods, and other subjects of invention described herein are further explained by the following numbered sections:

[0563] 1. Equation (I): [ka] [In formula: L 1 teeth: · Joint; and ·C 1-6 Alkylene (1-6 R a This may be replaced as desired); Selected from the group consisting of; R 1 R b ;C 2-6 Alkenyl (1-6 R aThis may be replaced as desired; and C 2-6 Alkinyl (1-6 R a Selected from the group consisting of (which may be substituted as desired); Ar 1 teeth: ·C 6-10 Aryl (1 to 4, each of which is R) c1 and -(L b ) b -R b A substituent, which may be optionally substituted, is independently selected from the group consisting of; and • Heteroaryl (containing 5-10 ring atoms, where each of the 1-4 ring atoms is N, N(H), N(R) d A ring heteroatom independently selected from the group consisting of ), O, and S, wherein the heteroaryl is R c1 and -(L b ) b -R b (Each of the substituents may be optionally substituted with 1 to 4 substituents independently selected from the group consisting of the above.) Selected from the group consisting of; Ar 2 teeth: ·C 6-10 Arrine (1 to 4 R c2 This may be replaced as desired); and Heteroarylenes (containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are N, N(H), and N(R) respectively) d A ring heteroatom independently selected from the group consisting of ), O, and S, where 1 to 4 R c2 (May be replaced as desired) Selected from the group consisting of; n is either 0 or 1; R 3a and R 3b These are independently H, -halo, and C. 1-6 Alkyl, or C 1-4 It is a haloalkyl; or R 3a and R 3b Each of them, together with the carbon atom to which it is bonded, C 3-6Forms a cycloalkyl group; R a Each time it appears, -OH;-HALO;-NR e R f ;C 1-4 Alkoxy; C 1-4 Haloalkoxy;-C(=O)O(C 1-4 Alkyl);-C(=O)(C 1-4 alkyl);-C(=O)OH;-CONR'R'';-S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 Independently selected from the group consisting of alkyl and cyano; R b Each time it appears, ·C 3-10 Cycloalkyl, or C 3-10 Cycloalkenyl (each of which contains 1 to 4 R g This may be replaced as desired); Heterocyclyls, or heterocycloalkenyls (containing 3 to 10 ring atoms, with 1 to 3 ring atoms each being N, N(H), and N(R) d ), O, and S(O) 0-2 Independently selected from the group consisting of 1 to 4 R g This may be replaced as desired); • Heteroaryl (contains 5 to 10 ring atoms, where 1 to 4 ring atoms are heteroatoms, each being N, N(H), and N(R) d ), O, and S(O) 0-2 Independently selected from the group consisting of 1 to 4 R g This may be replaced as desired); and ·C 6-10 Aryl (1 to 4 R g (May be replaced as desired) Selected independently from the group consisting of; b is 0, 1, 2, or 3; L b Each time it appears, :C 1-3 Alkilen;-N(H)-;N(R) d )-;-O-;-S-;C(=O);and S(O) 1-2Selected from the group consisting of; R c1 and R c2 Each time it appears, Halo;Cyan;C 1-10 Alkyl (1 to 6 independently selected R a This may be replaced as desired); C 2-6 Alkenil; C 2-6 Alkinyl; C 1-4 Alkoxy; C 1-4 Haloalkoxy;-S(O) 0-2 (C 1-4 Alkyl);-NR e R f ;-OH;-S(O) 1-2 NR'R'';-NO2;-C(=O)(C 1-10 Alkyl);-C(=O)O(C 1-4 Independently selected from the group consisting of alkyl;-C(=O)OH; and-C(=O)NR'R''; R d Each time it appears, C 1-6 Alkyl (1 to 3 independently selected R a (This may be substituted as desired);-C(O)(C 1-4 Al...

Claims

1. Equation (I): 【Chemistry 1】 [In the formula: L １ teeth, - Joints; and ・C １－６ Alkylene (1 to 6 R as appropriate) ａ (May be replaced with) Selected from the group consisting of; R １ is R ｂ ; C １－６ alkyl (optionally substituted with 1 to 6 R ａ ); C ２－６ alkenyl (optionally substituted with 1 to 6 R ａ ); and C ２－６ alkynyl (optionally substituted with 1 to 6 R ａ ); and is selected from the group consisting of; Ar １ teeth, ・C ６－１０ aryl (1 to 4, each of which is R) ｃ１ and -(L ｂ ) ｂ -R ｂ Independently selected from the group consisting of (which may be appropriately substituted with substituents); and - Heteroaryl compounds (containing 5 to 10 ring atoms, where each of 1 to 4 ring atoms is N, N(H), N(R) ｄ A ring heteroatom independently selected from the group consisting of ), O, and S, wherein the heteroaryl is R ｃ１ and -(L ｂ ) ｂ -R ｂ (Each of the substituents may be appropriately substituted with one to four substituents independently selected from the group consisting of the above.) Selected from the group consisting of; Ar ２ teeth, ・C ６－１０ Arielene (R ｃ２ and -(L ｂ ) ｂ -R ｂ (Each of the substituents may be appropriately substituted with one to four substituents independently selected from the group consisting of the above); and Heteroarylenes (containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are N, N(H), and N(R) respectively) ｄ A ring heteroatom independently selected from the group consisting of ), O, and S, R ｃ２ and -(L ｂ ) ｂ -R ｂ (Each of the substituents may be appropriately substituted with one to four substituents independently selected from the group consisting of the above.) Selected from the group consisting of; R ２ is -C(=O)OH; n is either 0 or 1; R ３ａ and R ３ｂ These are independently H, -halo, and C. １－６ Alkyl, or C １－４ It is a haloalkyl; or R ３ａ and R ３ｂ Each of them, together with the carbon atom to which it is bonded, C ３－６ Forms a cycloalkyl group; R ａ Each time it appears, -OH; -HALO; -NR ｅ R ｆ ; C １－４ Alkoxy; C １－４ Haloalkoxy; -C(=O)O(C １－４ Alkyl); -C (=O) (C １－４ Alkyl); -C(=O)OH; -CONR'R''; -S(O) １－２ NR'R'';-S(O) １－２ (C １－４ Independently selected from the group consisting of alkyl and cyano; R ｂ Each time it appears, ・C ３－１０ Cycloalkyl or C ３－１０ Cycloalkenyl (each of which has 1 to 4 R ｇ (This may be replaced as appropriate); - Heterocyclyl or heterocycloalkenyl (containing 3 to 10 ring atoms, with 1 to 3 ring atoms each being N, N(H), and N(R) ｄ ), O, and S(O) ０－２ Independently selected from the group consisting of 1 to 4 R ｇ (This may be replaced as appropriate); - Heteroaryl compounds (containing 5 to 10 ring atoms, where 1 to 4 ring atoms are heteroatoms, each being N, N(H), and N(R) ｄ ), O, and S(O) ０－２ Independently selected from the group consisting of, where the heteroaryl has 1 to 4 R ｇ (This may be replaced as appropriate); and ・C ６－１０ Aryl (1 to 4 R ｇ (This may be replaced as appropriate.) Selected independently from the group consisting of; b is 0, 1, 2, or 3; L ｂ Each time it appears, C １－３ Alkylene; -N(H)-; N(R) ｄ )-;-O-;-S-;C(=O);and S(O) １－２ Selected from the group consisting of; R ｃ１ and R ｃ２ Each time it appears, Halo; Cyano; C １－１０ Alkyl (1 to 6 independently selected R ａ (May be replaced as appropriate); C ２－６ Alkenil; C ２－６ Alkinyl; C １－４ Alkoxy; C １－４ Haloalkoxy; -S(O) ０－２ (C １－４ Alkyl); -NR ｅ R ｆ ;-OH;-S(O) １－２ NR'R''; -NO ２ ;-C(=O)(C １－１０ Alkyl); -C(=O)O(C １－４ Independently selected from the group consisting of alkyl; -C(=O)OH; and -C(=O)NR'R''; R ｄ is, each time it appears, C １－６ alkyl (optionally substituted with 1 to 3 independently selected R ａ ); -C(O)(C １－４ alkyl); -C(O)O(C １－４ alkyl); -CONR'R''; -S(O) １－２ NR'R''; -S(O) １－２ (C １－４ alkyl); -OH; and C １－４ is independently selected from the group consisting of alkoxy; R ｅ and R ｆ each time it appears, is independently selected from the group consisting of H; C １－６ alkyl; -C(O)(C １－４ alkyl); -C(O)O(C １－４ alkyl); -CONR'R''; -S(O) １－２ NR'R''; -S(O) １－２ (C １－４ alkyl); -OH; and C １－４ alkoxy; R ｇ Each time it appears, Halo; Cyano; C １－６ Alkyl; C １－６ Haloalkyl; C １－４ Alkoxy; C １－４ Independently selected from the group consisting of haloalkoxys; -OH; and NR'R''; and Each time R' and R'' appear, H; -OH; and C １－４ Independently selected from the group consisting of alkyls; The compound is given by formula (I-A): 【Chemistry 2】 [The compound shown, or a pharmaceutically acceptable salt thereof, may be used.] The compound indicated by or a pharmaceutically acceptable salt thereof.

2. Ar １ C ６－１０ Aryl (may be appropriately substituted with 1 to 4 substituents, each substituent being R) ｃ１ and -(L ｂ ) ｂ -R ｂ (Selected independently from the group consisting of) or; Ar １ is phenyl (which may be appropriately substituted with 1 to 4 substituents, each of which substituents is R ｃ１ and -(L ｂ ) ｂ -R ｂ (Selected independently from the group consisting of ); R as appropriate ｃ１ However, every time it appears, Halo;C １－６ Alkyl; C １－６ Alkyl (substituted with 1 to 6 independently selected halos); -C (=O) (C １－１０ Alkyl); C １－４ Alkoxy; C １－４ Haloalkoxys; and cyanos may be independently selected from this group; and / or - (L ｂ ) ｂ -R ｂ However, each time it appears, an independently selected C ３－６ Cycloalkyl (1-2 R ｇ (This may be replaced as appropriate.) The compound according to claim 1.

3. Ar １ but 【Transformation 3】 And where m1 is 0, 1, 2, or 3; R Ａａ and R Ａｂ However, each of them, R ｃ１ and -(L ｂ ) ｂ -R ｂ Independently selected from the group consisting of; as appropriate, (a) R Ａａ But, Hello; C １－６ Alkyl; C １－６ Alkyl (substituted with 1 to 6 independently selected halos); -C (=O) (C １－１０ Alkyl); C １－４ Alkoxy; C １－４ Haloalkoxys; cyanos; and C ３－６ Cycloalkyl (1-2 R ｇ Selected from the group consisting of (which may be substituted as appropriate); or (b) R Ａａ C １－６ Alkyl; or (c) R Ａａ C １－３ Alkyl; or (d) R Ａａ is methyl; or (e) R Ａａ C １－６ Alkyl (substituted with 1 to 6 independently selected halos); or (f) R Ａａ C １－３ Alkyl (substituted with 1 to 6 F), and R as appropriate. Ａａ ga CF ３ or CHF ２ is; or (g) R Ａａ is cyano; or (h)R Ａａ is a halo; or (i) R Ａａ C ３－６ It is cycloalkyl; or (j) Caution Ａａ It is cyclopropyl. The compound according to claim 1 or 2.

4. (a) m1 is 2; or m1 is 1 or 3; or, If m1 is 1 or 2, then R that appears in one or both Ａｂ However, R Ａａ A ring atom bonded to a ring atom in the ortho position relative to the ring atom bonded to it; and / or, (b) R Ａｂ However, each of them, Haro;C １－６ Alkyl; C １－６ Alkyl (substituted with 1 to 6 independently selected halos); C １－４ Alkoxy; C １－４ Haloalkoxys; cyanos; and C ３－６ Cycloalkyl (1-2 R ｇ Independently selected from the group consisting of (which may be substituted as appropriate); or, R Ａｂ However, each is independent, C １－４ Alkoxy or C １－４ It is a haloalkoxy; or R Ａｂ However, each of them is C １－４ It is an alkoxy; or, R Ａｂ However, each of them is methoxy. The compound according to claim 3.

5. The compound according to claim 3, wherein m1 is 0.

6. Ar １ but 【Chemistry 4】 is; or Ar １ but 【Transformation 5】 Selected from the group consisting of, The compound according to claim 1 or 2.

7. Ar 1 is (i) Heteroaryl compounds (containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are N, N(H), and N(R) respectively) ｄ A ring heteroatom independently selected from the group consisting of ), O, and S, wherein the heteroaryl may be appropriately substituted with 1 to 4 substituents, each of which substituents is R ｃ１ and -(L ｂ ) ｂ -R ｂ Independently selected from the group consisting of; or, (ii) Heteroaryl (containing 5 to 6 ring atoms, of which 1 to 4 ring atoms are N, N(H), and N(R) ｄ A ring heteroatom independently selected from the group consisting of ), O, and S, wherein the heteroaryl may be appropriately substituted with 1 to 4 substituents, each of which substituents is R ｃ１ and -(L ｂ ) ｂ -R ｂ Independently selected from the group consisting of; or, (iii) A heteroaryl compound (containing six ring atoms, of which one or two are ring nitrogen atoms), wherein the heteroaryl compound may be substituted with one to four substituents, each of which is R ｃ１ and -(L ｂ ) ｂ -R ｂ Independently selected from the group consisting of; or, (iv)R ｃ１ and -(L ｂ ) ｂ -R ｂ It is a pyridyl which may be substituted with 1 to 3 substituents selected from the group consisting of; or, (v) 3-pyridyl or Ar １ It is 4-pyridyl, and each of them is R ｃ１ and -(L ｂ ) ｂ -R ｂ They may be appropriately substituted with 1 to 3 substituents selected from the group consisting of; or, (vi) Ar １ 3-pyridyl (1 to 3 independently selected C １－６ (substituted with alkyl) or Ar １ 4-pyridyl (1 to 3 independently selected C １－６ (substituted with alkoxy); or (vii) Ar １ but 【Transformation 6】 is or Ar １ but 【Transformation 7】 And, Each time R c1 appears, it is independently selected from the group consisting of halo; C1-6 alkyl; C1-6 alkyl (substituted with 1 to 6 independently selected halos); C1-4 alkoxy; C1-4 haloalkoxy; and cyano; or Each instance of -(L b) b-R b is an independently selected C3-6 cycloalkyl (which may be substituted with 1-2 R g groups). The compound according to claim 1.

8. (a) L １ is a joint; or (b) L １ C １－６ Alkylene (1 to 6 R ａ (This may be replaced as appropriate) and; or (c) L １ C １－３ Alkylene (1 to 6 R ａ (This may be replaced as appropriate) and; or (d) L １ is a non-substituted C １－３ It is alkylene; or (e) L １ ga CH ２ CH ２ is; or (f) L １ ga CH ２ That is, The compound according to any one of claims 1 to 7.

9. (i) R １ R ｂ is; or (ii) R １ but ・C ３－１０ Cycloalkyl or C ３－１０ Cycloalkenyl (each of which has 1 to 4 R ｇ (This may be replaced as appropriate); and ・C ６－１０ Aryl (1 to 4 R ｇ (This may be replaced as appropriate.) Selected from the group consisting of; or (iii) R １ C ６－１０ Aryl (1 to 4 R ｇ (This may be replaced as appropriate) and; or (iv)R １ Phenyl (1 to 4 R ｇ (This may be replaced as appropriate) and; or (v) R １ Phenyl (1-2 R ｇ (This may be replaced as appropriate) and; or (vi)R １ is an unsubstituted phenyl; or (vii)R １ C ８－１０ Biring aryl (1 to 4 R) ｇ (This may be replaced as appropriate) and; or (viiii)R １ C ９－１０ Double ring aryl (1-2 R ｇ (This may be replaced as appropriate) and; or (ix)R １ is indanyl (1-2 R ｇ (This may be replaced as appropriate) and; or (x)R １ However, 1 to 2 R ｇ This may be substituted as appropriate. 【Transformation 8】 And; or (xi)R １ but 【Chemistry 9】 And; or (xi)R １ C ３－１０ Cycloalkyl or C ３－１０ A cycloalkenyl, each having 1 to 4 R ｇ This may be replaced as appropriate; or (xiii)R １ is 1 to 4 R ｇ C may be replaced by ３－１０ It is cycloalkyl; or (xiv)R １ However, 1 to 2 R ｇ C may be replaced as appropriate. ３－６ It is cycloalkyl; or (xv)R １ is cyclobutyl or cyclopentyl, each having 1 to 2 R ｇ This may be replaced as appropriate; or (xvi)R １ is unsubstituted cyclobutyl or cyclopentyl; or (xvii)R １ C ２－６ Alkinyl (1 to 6 R ａ (This may be replaced as appropriate) and; or (xviiii)R １ C ２－４ Alkinyl (1-3 R ａ (May be replaced as appropriate) or (xix)R １ but 【Chemistry 10】 Yes; or (xx)R １ C １－６ Alkyl (1 to 6 R ａ (This may be replaced as appropriate) and; or (xxi)R １ C １－６ It is alkyl; or (xxii)R １ C ２－４ It is alkyl; or (xxiii)R １ C ３ It is alkyl; or (xxiv)R １ is i-propyl; or (xxv)R １ C ３－５ It is alkyl; or (xxvi)R １ C ４ Alkyl; or (xxvii)R １ is i-butyl, The compound according to any one of claims 1 to 8.

10. L １ The compound according to any one of claims 1 to 8, wherein the bond is a binding site.

11. (a) Ar ２ Heteroarylenes contain 5 to 10 ring atoms, of which 1 to 4 ring atoms are N, N(H), and N(R). ｄ A ring heteroatom independently selected from the group consisting of ), O, and S, wherein the heteroarylene has 1 to 4 ring heteroatoms, each of which is R ｃ２ and -(L ｂ ) ｂ -R ｂ A substituent, independently selected from the group consisting of, may be appropriately substituted with; or (b) Ar ２ Heteroarylenes contain 5 to 6 ring atoms, of which 1 to 4 ring atoms are N, N(H), and N(R). ｄ A ring heteroatom independently selected from the group consisting of ), O, and S, wherein the heteroarylene has 1 to 4 ring heteroatoms, each of which is R ｃ２ and -(L ｂ ) ｂ -R ｂ A substituent, independently selected from the group consisting of, may be appropriately substituted with; or (c) Ar ２ Heteroarylene (contains 5 ring atoms, of which 1 to 4 are N, N(H), and N(R) respectively) ｄ A ring heteroatom independently selected from the group consisting of ), O, and S, wherein the heteroarylene has 1 to 4 such heteroarylenes, each of which is R ｃ２ and -(L ｂ ) ｂ -R ｂ A substituent, independently selected from the group consisting of, may be appropriately substituted with; or (d) Ar ２ The group is selected from pyrrolylene, pyrazolylene, thiazoylene, and 1,3,4-oxadiazoylene, and each of them has 1 to 4 R ｃ２ and -(L ｂ ) ｂ -R ｂ A substituent, independently selected from the group consisting of, may be appropriately substituted with; or (e) Ar ２ but 【Chemistry 11】 And here aa is -(CR ３ａ R ３ｂ ) ｎ - This is the junction point with R 2, and as appropriate, R ｃ２ is C(O)OC １－４ Alkyl may be used; or (f) Ar ２ but 【Chemistry 12】 And here: 【Chemistry 13】 However, each is independently either a single bond or a double bond: where B １ , B ２ , B ３ , B ４ , and B ５ The ring containing the heteroaryl is a heteroaryl; aa is - (CR ３ａ R ３ｂ ) ｎ -R ２ It is the junction point with; B ２ and B ４ is C or N; and B １ , B ３ , and B ５ However, independently, O, S, N, N(H), N(R) ｄ ), CH, CR ｃ２ , or C-(L ｂ ) ｂ -R ｂ This is the case where 1 to 4 B １ , B ２ , B ３ , B ４ , and B ５ These are independently selected heteroatoms, Here, as appropriate, (i) B ２ N is; and / or B ４ C is; and / or B １ , B ３ , and B ５ However, CH and CR became independent. ｃ２ , or C-(L ｂ ) ｂ -R ｂ B is; and / or, ５ CR ｃ２ B １ and B ３ It may be CH; or (ii) B ２ N is B ４ C is; and B １ , B ３ , and B ５ However, CH and CR became independent. ｃ２ , or C-(L ｂ ) ｂ -R ｂ It is fine; or (iii) B ２ C is; B as appropriate. ４ It may be C; or (iv) B ５ CH, CR ｃ２ , or C-(L ｂ ) ｂ -R ｂ B １ and B ３ One of them is N; and B １ and B ３ The other one of them is NH, N(R ｄ ), O, S; and / or Ar ２ but 【Chemistry 14】 A group consisting of is selected, where aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ It is the point of connection with, R as appropriate ｃ２ ga C(=O)C １－４ Alkyl is also acceptable; or R as appropriate ｃ２ C １－６ Alkyl is also acceptable; or -(L ｂ ) ｂ -R ｂ C ３－１０ It may also be a cycloalkyl; or (v)Ar ２ が、 【Chemistry 15】 And here aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ It is the junction point with; or (vi) B ２ C is B ４ is N; or, (vii) B ３ N is B １ and B ５ However, CH and CR became independent. ｃ２ , or C-(L ｂ ) ｂ -R ｂ And; or (viiii｡r ２ が 【Chemistry 16】 And here aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ The point of connection with, The compound according to any one of claims 1 to 10.

12. (a) Ar ２ This is a heteroarylene (containing six ring atoms, of which one or two are ring nitrogen atoms), where the heteroarylene is 1 to 4, each of which is R ｃ２ and -(L ｂ ) ｂ -R ｂ A substituent may be appropriately substituted, independently selected from the group consisting of; or, (b) Ar ２ There are 1 to 4 of them, each of which is R ｃ２ and -(L ｂ ) ｂ -R ｂ A pyridylene independently selected from the group consisting of the following, which may be appropriately substituted with substituents; or, (c) Ar ２ but 【Chemistry 17】 And here aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ The connection point with, appropriately, R ｃ２ C １－４ Alkoxy or C １－４ It may also be a haloalkoxy. The compound according to any one of claims 1 to 10.

13. (a) Ar ２ This is a bicyclic heteroarylene (containing 9 to 10 ring atoms, of which 1 to 4 ring atoms are N, N(H), and N(R) respectively). ｄ A ring heteroatom independently selected from the group consisting of ), O, and S, where the heteroarylene comprises 1 to 4 such heteroarylenes, each of which is R ｃ２ and -(L ｂ ) ｂ -R ｂ A substituent may be appropriately substituted, independently selected from the group consisting of; or, (b) Ar ２ The group is selected from benzimidazolylene, indazolylene, benzothiazolylen, and imidazo[1,2-a]pyridylene, and each of them has 1 to 4 R ｃ２ and -(L ｂ ) ｂ -R ｂ The substituents may be appropriately substituted with substituents independently selected from the group consisting of: or (c) Ar ２ but [Chemistry 18] And here 【Chemistry 19】 However, each is independently either a single bond or a double bond: where B ６ , B ７ , B ８ , B ９ , and B １０ The five-membered ring containing B is a heteroaryl, ８ , B ９ , B １１ , B １２ , and B １３ The six-membered ring containing the ring is aryl or heteroaryl; aa is - (CR ３ａ R ３ｂ ) ｎ -R ２ It is the junction point with; B ６ , B ８ , and B ９ However, independently, it is either C or N; B ７ and B １０ However, O, S, N, N(H), N(R) ｄ ), CH, CR ｃ２ and C-(L ｂ ) ｂ -R ｂ Selected independently from the group consisting of; B １１ , B １２ , and B １３ However, independently, N, CH, CR ｃ２ , or C-(L ｂ ) ｂ -R ｂ However, B ６ , B ７ , B ８ , B ９ , B １０ , B １１ , B １２ , and B １３ One to four of these are independently selected heteroatoms; B ７ , B １０ , B １１ , B １２ , and B １３ Three or fewer of them are CR ｃ２ , or C-(L ｂ ) ｂ -R ｂ It is; Here, as appropriate, (i) B ８ and B ９ C is; and / or B １１ , B １２ , and B １３ However, CH and CR became independent. ｃ２ , or C-(L ｂ ) ｂ -R ｂ is; and / or, B １１ , B １２ , and B １３ is CH; and / or, B ６ is N; and / or, B ７ is N; and / or, B １０ CH, CR ｃ２ , or C-(L ｂ ) ｂ -R ｂ is; and / or, B １０ is CH; and / or, Ar 2 is 【Chemistry 20】 And there are 1 to 2 of them, each of which is R ｃ２ and -(L ｂ ) ｂ -R ｂ A substituent independently selected from the group consisting of, which may be appropriately substituted with a substituent, where aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ It is the point of connection with; or (ii) B ７ is N; and / or, B １０ S is; and / or, Ar 2 is 【Chemistry 21】 And there are 1 to 2 of them, each of which is R ｃ２ and -(L ｂ ) ｂ -R ｂ A substituent independently selected from the group consisting of, which may be appropriately substituted with a substituent, where aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ It is the point of connection with; or (iii) B ８ C is B ９ is N; and / or, B ７ is N; and / or, B １０ , B １１ , B １２ , and B １３ CH, CR ｃ２ , or C-(L ｂ ) ｂ -R ｂ and / or, Ar ２ but 【Chemistry 22】 And there are 1 to 2 of them, each of which is R ｃ２ and -(L ｂ ) ｂ -R ｂ A substituent independently selected from the group consisting of, which may be appropriately substituted with a substituent, where aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ It is the junction point with; or (ii) Ar ２ but 【Chemistry 23】 A group is selected from the group consisting of, each of which has 1 to 2, each of which is R ｃ２ and -(L ｂ ) ｂ -R ｂ A substituent independently selected from the group consisting of, which may be appropriately substituted with a substituent, where aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ It is the junction point with; or (v)Ar ２ が 【Chemistry 24】 A group is selected from the group consisting of, each of which has 1 to 2, each of which is R ｃ２ and -(L ｂ ) ｂ -R ｂ A substituent independently selected from the group consisting of, which may be appropriately substituted with a substituent, where aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ It is the junction point with; or (vi)r ２ が 【Chemistry 25】 A group is selected from the group consisting of, each of which has 1 to 2, each of which is R ｃ２ and -(L ｂ ) ｂ -R ｂ A substituent independently selected from the group consisting of, which may be appropriately substituted with a substituent, where aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ It is the junction point with; (d) Ar ２ but 【Chemistry 26】 And here: 【Chemistry 27】 However, each is independently either a single bond or a double bond: where B １４ , B １５ , B １６ , B １７ , and B １８ The five-membered ring containing B is a heteroaryl, １６ , B １７ , B １９ , B ２０ , and B ２１ A six-membered ring containing this ring is either aryl or heteroaryl; aa is - (CR ３ａ R ３ｂ ) ｎ -R ２ It is the junction point with; B １６ , B １７ , and B １４ However, independently, it is either C or N; B １５ and B １８ However, O, S, N, N(H), N(R) ｄ ), CH, and CR ｃ２ Selected independently from the group consisting of; B １９ , B ２０ , and B ２１ However, independently, N, CH, CR ｃ２ , or C-(L ｂ ) ｂ -R ｂ However, B １４ , B １５ , B １６ , B １７ , B １８ , B １９ , B ２０ , and B ２１ One to four of these are independently selected heteroatoms; B １５ , B １８ , B １９ , B ２０ , and B ２１ Three or fewer of them are CR ｃ２ or C-(L ｂ ) ｂ -R ｂ And; Here, as appropriate, B １６ and B １７ C is; and / or, B １９ , B ２０ , and B ２１ However, independently, N, CH, CR ｃ２ , or C-(L ｂ ) ｂ -R ｂ and / or, B １４ C is; and / or, B １５ and B １８ One of them is N; B １５ and B １８ The other of these is O, S, NH, or N(R) ｄ ) and; or (e) Ar ２ but 【Chemistry 28】 And each of them has 1 to 2 R ｃ２ It may be replaced as appropriate, where aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ It is the junction point with; or (f) Ar ２ but 【Chemistry 29】 And there are 1 to 2 of them, each of which is R ｃ２ and -(L ｂ ) ｂ -R ｂ A substituent independently selected from the group consisting of, which may be appropriately substituted with a substituent, where aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ The compound according to any one of claims 1 to 10, which is a bonding site with the compound.

14. (a) n is 0; or (b) n is 1, R ３ａ and R ３ｂ It may be H; or, (c) n is 1, where R ３ａ and R ３ｂ One of them is H, and R ３ａ and R ３ｂ The other of them is C １－６ It is alkyl; or (d) n is 1, where R ３ａ and R ３ｂ And, together with the carbon atom to which each of them is bonded, C ３－６ Forms a cycloalkyl group, The compound according to any one of claims 1 to 13.

15. Equation (I-1): 【Transformation 30】 [In the formula: 【Chemistry 31】 Each of these is independently either a single bond or a double bond: however, B １ , B ２ , B ３ , B ４ , and B ５ The ring containing the heteroaryl is a heteroaryl; B ２ and B ４ is C or N; B １ , B ３ , and B ５ These are independently O, S, N, N(H), N(R) ｄ ), CH, CR ｃ２ , or C-(L ｂ ) ｂ -R ｂ This is the case where 1 to 4 B １ , B ２ , B ３ , B ４ , and B ５ These are independently selected heteroatoms; Ar １ teeth: Phenyl (1-4, halo; C) １－６ Alkyl; C １－６ Alkyl (substituted with 1 to 6 independently selected halos); C １－４ Alkoxy; C １－４ Haloalkoxys; cyanos; and C ３－６ Cycloalkyl (1-2 R ｇ From the group consisting of (which may be appropriately substituted with), each is independently selected (which is substituted with a substituent); and Heteroaryl (containing six ring atoms, of which one or two are ring nitrogen atoms, where the heteroaryl is composed of 1 to 4 halo atoms; C) １－６ Alkyl; C １－６ Alkyl (substituted with 1 to 6 independently selected halos); C １－４ Alkoxy; C １－４ Haloalkoxys; cyanos; and C ３－６ Cycloalkyl (1-2 R ｇ From the group consisting of (which may be appropriately substituted with), each is independently selected, which may be appropriately substituted with substituents. Selected from the group consisting of; Here, as appropriate, (a) B ２ N is B ４ C is; and / or, B １ , B ３ , and B ５ However, CH and CR became independent. ｃ２ or C-(L ｂ ) ｂ -R ｂ and / or, B １ -B ５ A ring containing 【Chemistry 32】 And here aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ The connection point with R ｃ２ C(O)OC as appropriate １－４ It may also be alkyl; or, (b) B ２ C is B ４ is N; and / or, B ３ N is B １ and B ５ However, CH and CR became independent. ｃ２ or C-(L ｂ ) ｂ -R ｂ and / or, B １ -B ５ A ring containing, 【Transformation 33】 And here aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ It is the junction point with; or (c) B ２ C is B ４ C is; and / or, B ５ is CH or CR ｃ２ B １ and B ３ One of them is N; B １ and B ３ The other of these is NH, N(R ｄ ), O, or S; and / or, B １ -B ５ A ring containing (i) Formula: 【Transformation 34】 And here aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ It is the junction point with; or (ii) Formula: 【Chemistry 35】 And here aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ The connection point with, appropriately, R ｃ２ C(O)OC １－４ Alkyl, C １－４ Alkyl, C １－４ Alkoxy, or C １－４ It may also be a haloalkoxy; or Formula (iii): 【Transformation 36】 And here aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ The connection point with, appropriately, -(L ｂ ) ｂ -R ｂ C ３－１０ It may be a cycloalkyl group; or, (iv) Formula: 【Chemistry 37】 And here aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ This is the point of connection with [the other]. The compound according to claim 1, which is a compound represented by or a pharmaceutically acceptable salt thereof.

16. Equation (I-2): 【Transformation 38】 [In the formula: 【Chemistry 39】 Each of these is independently either a single bond or a double bond: however, B ６ , B ７ , B ８ , B ９ , and B １０ The five-membered ring containing B is a heteroaryl, ８ , B ９ , B １１ , B １２ , and B １３ A six-membered ring containing this ring is either aryl or heteroaryl; B ６ , B ８ , and B ９ It is independently C or N; B ７ and B １０ O, S, N, N(H), N(R) ｄ ), CH, CR ｃ２ , or C-(L ｂ ) ｂ -R ｂ Selected independently from the group consisting of; B １１ , B １２ , and B １３ These are independently N, CH, CR ｃ２ , or C-(L ｂ ) ｂ -R ｂ However, B ６ , B ７ , B ８ , B ９ , B １０ , B １１ , B １２ , and B １３ One to four of these are independently selected heteroatoms; B ７ , B １０ , B １１ , B １２ , and B １３ Three or fewer of them are CR ｃ２ or C-(L ｂ ) ｂ -R ｂ And; Ar １ teeth Phenyl (1-4, halo; C) １－６ Alkyl; C １－６ Alkyl (substituted with 1 to 6 independently selected halos); C １－４ Alkoxy; C １－４ Haloalkoxys; cyanos; and C ３－６ Cycloalkyl (1-2 R ｇ From the group consisting of (which may be appropriately substituted with), each is independently selected (which is substituted with a substituent); and Heteroaryl (containing six ring atoms, of which one or two are ring nitrogen atoms, where the heteroaryl is composed of 1 to 4 halo atoms; C) １－６ Alkyl; C １－６ Alkyl (substituted with 1 to 6 independently selected halos); C １－４ Alkoxy; C １－４ Haloalkoxys; cyanos; and C ３－６ Cycloalkyl (1-2 R ｇ From the group consisting of (which may be appropriately substituted with), each is independently selected, which may be appropriately substituted with substituents. Selected from the group consisting of; Here, as appropriate, (a) B ８ and B ９ C is; and / or, B １１ , B １２ , and B １３ However, independently, CH or CR ｃ２ and / or, B ６ N is B ７ N is B １０ is CH or CR ｃ２ and / or, B ６ ~B １３ A ring containing 【Chemistry 40】 And that is 1 to 2 R ｃ２ It may be replaced as appropriate, where aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ It is the junction point with; or (b) B ７ is N; and / or, B １０ is S; and / or, B ６ ~B １３ A ring containing 【Chemistry 41】 And there are 1 to 2 of them, each of which is R ｃ２ and -(L ｂ ) ｂ -R ｂ A substituent independently selected from the group consisting of, which may be appropriately substituted with a substituent, where aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ It is the junction point with; or (c) B ８ C is B ９ is N; and / or, B ７ is N; and / or, B １０ , B １１ , B １２ , and B １３ CH, CR ｃ２ , or C-(L ｂ ) ｂ -R ｂ and / or, B ６ ~B １３ A ring containing 【Chemistry 42】 And there are 1 to 2 of them, each of which is R ｃ２ and -(L ｂ ) ｂ -R ｂ A substituent independently selected from the group consisting of, which may be appropriately substituted with a substituent, where aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ It is the junction point with; or (d) B ６ ~B １３ A ring containing 【Chemistry 43】 A group is selected from the group consisting of, each of which has 1 to 2, each of which is R ｃ２ and -(L ｂ ) ｂ -R ｂ A substituent independently selected from the group consisting of, which may be appropriately substituted with a substituent, where aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ It is the junction point with; or (e) B ６ ~B １３ A ring containing 【Chemistry 44】 A group is selected from the group consisting of, each of which has 1 to 2, each of which is R ｃ２ and -(L ｂ ) ｂ -R ｂ A substituent independently selected from the group consisting of, which may be appropriately substituted with a substituent, where aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ It is the junction point with; or (f) B ６ ~B １３ A ring containing 【Chemistry 45】 A group is selected from the group consisting of, each of which has 1 to 2, each of which is R ｃ２ and -(L ｂ ) ｂ -R ｂ A substituent independently selected from the group consisting of, which may be appropriately substituted with a substituent, where aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ This is the point of connection with [the other]. The compound according to claim 1, which is a compound represented by or a pharmaceutically acceptable salt thereof.

17. Equation (I-3): 【Chemistry 46】 [In the formula: 【Chemistry 47】 is, independently of each other, a single bond or a double bond: provided that B １４ B １５ B １６ B １７ and B １８ the 5-membered ring containing is heteroaryl, and B １６ B １７ B １９ B ２０ and B ２１ the 6-membered ring containing is aryl or heteroaryl; B １６ , B １７ , and B １４ It is independently C or N; B １５ and B １８ are independently selected from the group consisting of O, S, N, N(H), N(R ｄ ), CH, CR ｃ２ , and C-(L ｂ ) ｂ -R ｂ ; and are independently selected from the group consisting of B １９ , B ２０ , and B ２１ These are independently N, CH, CR ｃ２ , or C-(L ｂ ) ｂ -R ｂ However, B １４ , B １５ , B １６ , B １７ , B １８ , B １９ , B ２０ , and B ２１ One to four of these are independently selected heteroatoms; B １５ , B １８ , B １９ , B ２０ , and B ２１ Three or fewer of them are CR ｃ２ or C-(L ｂ ) ｂ -R ｂ and Ar １ teeth: Phenyl (1-4, halo; C) １－６ Alkyl; C １－６ Alkyl (substituted with 1 to 6 independently selected halos); C １－４ Alkoxy; C １－４ Haloalkoxys; cyanos; and C ３－６ Cycloalkyl (1-2 R ｇ From the group consisting of (which may be appropriately substituted with), each is independently selected (which is substituted with a substituent); and Heteroaryl (containing six ring atoms, of which one or two are ring nitrogen atoms, where the heteroaryl is composed of one to four halo atoms; C) １－６ Alkyl; C １－６ Alkyl (substituted with 1 to 6 independently selected halos); C １－４ Alkoxy; C １－４ Haloalkoxys; cyanos; and C ３－６ Cycloalkyl (1-2 R ｇ From the group consisting of (which may be appropriately substituted with), each is independently selected, which may be appropriately substituted with substituents. Selected from the group consisting of; Here, as appropriate, (a) B １６ and B １７ C is; (b) B １９ , B ２０ , and B ２１ However, CH and CR became independent. ｃ２ , or C-(L ｂ ) ｂ -R ｂ And; (c) B １４ C is B １５ and B １８ One of them is N; B １５ and B １８ The other of these is O, S, NH, or N(R) ｄ ) and; (d) B １４ ~B ２１ A ring containing 【Chemistry 48】 and each of them has 1 to 2 Rs ｃ２ may be appropriately replaced by, where aa is -(CR ３ａ R ３ｂ ) ｎ -R ２ is the bonding point with The compound according to claim 1, which is a compound represented by or a pharmaceutically acceptable salt thereof.

18. (a) n is 1, and R appropriately ３ａ and R ３ｂ It may also be H; or n is 1, R ３ａ and R ３ｂ One of them is H, and R ３ａ and R ３ｂ The other of them is C １－６ It is alkyl; or n is 1, and here R ３ａ and R ３ｂ However, each of them, together with the carbon atom it is bonded to, C ３－６ Forming a cycloalkyl group; or, n is 0; and / or, (b) Ar １ but 【Chemistry 49】 and; m1 is 0, 1, 2, or 3; R Ａａ and R Ａｂ However, each time it appears, halo; -C (=O) (C １－１０ Alkyl); C １－６ Alkyl; C １－６ Alkyl (substituted with 1 to 6 independently selected halos); C １－４ Alkoxy; C １－４ Haloalkoxys; cyanos; and C ３－６ Cycloalkyl (1-2 R ｇ Independently selected from the group consisting of (which may be substituted as appropriate); Here, as appropriate, m1 is 0; or m1 is 1 or 2, and each R Ａｂ is R Ａａ It may be in the ortho position as appropriate; and / or, As appropriate, each R Ａｂ However, if it exists, C １－４ Alkoxy or C １－４ It is a haloalkoxy; and / or R as appropriate Ａａ C １－３ Alkyl; C １－３ Alkyl (substituted with 1 to 6 F); halo; or C ３－６ It is cycloalkyl; and / or, (c) Ar １ but [Transformation 50] And; or Ar １ but 【Chemistry 51】 Selected from the group consisting of; and / or, (d) L １ is a joint; or, L １ C １－３ Alkylene (1 to 6 R ａ (This may be replaced as appropriate) or L １ ga CH ２ or CH ２ CH ２ and / or, (e) R １ but (i) Phenyl (1-2 R ｇ (This may be replaced as appropriate); or, (ii) C ９－１０ Double ring aryl (1-2 R ｇ (This may be replaced as appropriate); or, Formula (iii): 【Chemistry 52】 And, 1 to 2 R ｇ This may be replaced as appropriate; or, (iv) C ３－６ Cycloalkyl (1-2 R ｇ (This may be replaced as appropriate); (v) Cyclobutyl or cyclopentyl, each having 1 to 2 R ｇ This may be replaced as appropriate; or, (vi) C １－６ Alkyl (1 to 6 R ａ (This may be replaced as appropriate); or, (vii) C １－６ alkyl; or, (viiii) C ２－４ Alkyl; (ix) C ３ Alkyl; (x) i-propyl; or, (xi)C ３－５ alkyl; or, (xi)C ４ alkyl; or, (xiiii)i-butyl; and / or, (f) Formula: 【Chemistry 53】 The part indicated by is the following equation: 【Chemistry 54】 As shown, The compound according to any one of claims 15 to 17.

19. Compounds selected from the group consisting of compounds listed in Tables C1 and C2 below, or their pharmaceutically acceptable salts: Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 Table 33 Table 34 Table 35 Table 36 Table 37 Table 38 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 Table 45 Table 46 Table 47 Table 48 Table 49 Table 50 Table 51 Table 52 Table 53 Table 54 Table 55 Table 56 Table 57 Table 58 Table 59 Table 60 Table 61 Table 62 Table 63 Table 64 Table 65 Table 66 Table 67 Table 68 Table 69 Table 70 Table 71 Table 72 Table 73 Alternatively, the compound is selected from the group consisting of compounds 101 to 437 and 101a-131a, or pharmaceutically acceptable salts thereof. compound.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

21. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 20, for use in a method of treatment or prevention of LPA-related disease in a subject requiring treatment or prevention of such disease, wherein the method comprises administering to a subject a therapeutically effective amount of the compound or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition. Here, As appropriate, LPA-related diseases １ It is a related disease; or Depending on the circumstances, LPA-related diseases are selected from the group consisting of fibrosis, transplant rejection, cancer, osteoporosis, or inflammatory disorders. Here, where appropriate, cancer is cancer of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gallbladder, genitals, reproductive tract, head, kidney, pharynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovaries, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testes, or thyroid; or, Depending on the circumstances, the fibrosis may be pulmonary, hepatic, renal, cardiac, cutaneous, ocular, or pancreatic fibrosis; or, Depending on the circumstances, LPA-related diseases may be selected from the group consisting of idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, and systemic sclerosis. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 20.

22. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 20, for use in a method of treatment or prevention of fibrosis in a subject requiring treatment or prevention of such fibrosis, wherein the method comprises administering to a subject a therapeutically effective amount of the compound or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition. Here, As appropriate, fibrosis may be idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, and systemic sclerosis, and as appropriate, fibrosis may be IPF. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 20.

Images