Pharmaceutical agent containing fused-ring compound or salt thereof

Abstract

To provide a pharmaceutical agent that has STAT6 inhibitory activity and is effective for the treatment of allergic diseases and inflammatory diseases such as atopic dermatitis.SOLUTION: A pharmaceutical agent contains, as an active ingredient, a compound represented by the general formula (I) in the figure or a pharmaceutically acceptable salt thereof, which has STAT6 inhibitory activity.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical comprising a novel fused ring compound or a salt thereof as an active ingredient. More specifically, the present invention relates to a pharmaceutical having an inhibitory effect on Signal Transducer and Activator of Transcription 6 (hereinafter referred to as STAT6). [Background technology]

[0002] Interleukin-4 (IL-4) and interleukin-13 (IL-13) are cytokines that bind to receptors expressed on the cell membrane and transmit signals intracellularly. These two cytokines are deeply involved in the induction of type 2 inflammatory responses, which are thought to play an important role in the pathogenesis of inflammatory and allergic diseases such as bronchial asthma and atopic dermatitis. These cytokines are important in the pathogenesis of mouse airway hyperresponsiveness models and mouse contact dermatitis models (Non-Patent Document 1). Therefore, inhibiting intracellular signal transduction by IL-4 and IL-13 is expected to lead to the treatment of various diseases caused by type 2 inflammatory responses. Indeed, dupilumab (human IgG4 monoclonal antibody), an antibody drug that binds to the IL-4 receptor α subunit (IL-4Rα), which mediates intracellular signal transduction by IL-4 and IL-13, has excellent therapeutic effects against inflammatory and allergic diseases, such as atopic dermatitis, bronchial asthma, and chronic sinusitis with nasal polyps. STAT6 is a transcription factor responsible for the intracellular signal transduction of IL-4 and IL-13. When IL-4 and IL-13 bind to their receptors on the cell membrane, IL-4Rα, a subunit common to the receptors for these two cytokines, is phosphorylated. STAT6 then binds to the phosphorylated IL-4Rα and phosphorylates itself. The phosphorylated STAT6 forms a dimer, translocates into the nucleus, and acts as a transcription factor to promote the expression of various genes. Thus, STAT6 plays an important role in the intracellular signal transduction mediated by IL-4 and IL-13. Therefore, inhibiting STAT6 activation and function is expected to lead to the treatment of inflammatory and allergic diseases involving IL-4 and IL-13. Indeed, it has been reported that STAT6 knockout mice are unable to transmit IL-4 signals and exhibit suppressed allergic responses (Non-Patent Documents 2, 3, and 4), as well as alleviation of pathologies such as contact dermatitis (Non-Patent Document 5), bronchial asthma (Non-Patent Document 6), and food allergies (Non-Patent Document 7), which are induced by various inflammatory and allergy-inducing substances. In addition, a clinical study in which a decoy oligonucleotide against STAT6 was administered to patients with atopic dermatitis reported an improvement in erythema and itching symptoms (Non-Patent Document 8). Furthermore, it has been reported that a compound that inhibits the binding of phosphorylated IL-4Rα to STAT6 alleviates the pathology of a mouse allergic lung disease model (Non-Patent Document 9 and Patent Document 1).

[0003] Based on the above, STAT6 inhibitors that suppress the activation and function of STAT6 are thought to be extremely useful as preventive or therapeutic agents for various pathologies involving IL-4 and IL-13. None of the prior art documents discloses or suggests the compounds of general formula (I) of the present invention described below.

[0004] Incidentally, the following compounds are known as known 5,6-fused ring derivatives in a technical field different from that of the present invention. Patent Document 2 discloses a compound of the formula: [ka] (wherein each symbol is as defined in Patent Document 2), a compound represented by the formula: Patent Document 3 discloses a material for use in imaging huntingtin protein, which is a compound of the formula: [ka] (wherein each symbol is as defined in Patent Document 3) is described.

[0005] However, Patent Document 2 and Patent Document 3 do not specifically disclose the compound of general formula (I) of the present invention, and do not state or suggest at all that it has a STAT6 inhibitory activity, much less that it is useful in treating STAT6-related diseases. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2014 / 182928 [Patent Document 2] International Publication No. 2010 / 003048 [Patent Document 3] International Publication No. 2016 / 033445 [Non-patent literature]

[0007] [Non-Patent Document 1] American journal of respiratory cell and molecular biology. 2013:49,p.37-46. [Non-patent document 2] Nature. 1996:380,pp.627-630. [Non-patent document 3] Nature. 1996:380,pp.630-633. [Non-patent document 4] Immunity. 1996:4,p.313-319. [Non-Patent Document 5] International Immunology. 2004:16, p.685-695. [Non-patent document 6] Journal of experimental medicine. 1998:187, p.1537-1542. [Non-Patent Document 7] Allergologia et Immunopathologia. 2019:47,p535-543. [Non-patent document 8] British Journal of Dermatology. 2009:160,p.1124-1126. [Non-Patent Document 9] Journal of Biological Chemistry. 2018:293,p.10026-10040. Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention addresses the problem of providing a pharmaceutical comprising, as an active ingredient, a novel compound or a salt thereof that has a STAT6 inhibitory effect and is effective in treating inflammatory diseases such as atopic dermatitis and allergic diseases. [Means for solving the problem]

[0009] As a result of intensive research to solve the above problems, the present inventors have found that a novel compound represented by the following general formula (I) has excellent STAT6 inhibitory activity, and have completed the present invention based on this finding.

[0010] That is, the present invention (1) General formula (I):

[0011] [ka]

[0012] [In the formula, R 1 represents an optionally substituted 5-membered heteroaryl group, an optionally substituted 5- to 6-membered non-aromatic heterocyclic group, an optionally substituted pyridonyl group, -C(=O)-NR a R b or -NR c -C(=O)R d where R a , R b , R c and R d are each independently a hydrogen atom or a C1-C6 alkyl group, R 2 is a hydrogen atom, an optionally substituted C1-C6 alkyl group, or an optionally substituted C1-C6 haloalkyl group, Alternatively, R 1 and R 2 may form, together with the carbon atom to which they are attached, an optionally substituted 5- or 6-membered non-aromatic heterocyclic group, R 3 is a hydrogen atom, an optionally substituted C1-C6 alkyl group, or an optionally substituted C1-C6 haloalkyl group, R 4 is a hydrogen atom, an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 haloalkyl group, an optionally substituted C1-C3 alkoxy-C2-C6 alkyl group, an optionally substituted C1-C3 haloalkoxy-C2-C6 alkyl group, or an optionally substituted C3-C6 cycloalkyl-C1-C6 alkyl group; Q 1 is C(=O) or CH2, Q 2 is NH or O, X 1 is N or CR 5 where R 5 is a hydrogen atom or a halogen atom, X 2 , X 3 and X 4 are each independently N or CR 6where R 6 is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 haloalkyl group, an optionally substituted hydroxy-C1-C6 alkyl group, an optionally substituted cyano-C1-C6 alkyl group, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted C1-C6 alkoxy-C1-C6 alkyl group, an optionally substituted C2-C6 alkenyl group, an optionally substituted C2-C6 alkynyl group, or an optionally substituted phenyl group; Y 1 and Y 2 are each independently N or CR 7 where R 7 is a hydrogen atom, an optionally substituted C1-C6 alkyl group, or an optionally substituted C1-C6 haloalkyl group, Ring A is an optionally substituted phenyl group or an optionally substituted 5- or 6-membered heteroaryl group, and the phenyl group or the 5- or 6-membered heteroaryl group may be further fused with another ring to form an optionally substituted 8- or 10-membered fused ring. A pharmaceutical comprising, as an active ingredient, a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.

[0013] (2) In the general formula (I), Q 1 is C(=O) and Q 2 A medicine containing the compound according to (1) or a pharmaceutically acceptable salt thereof, wherein (3) In the general formula (I), X 1 , X 2 and X 4 are each independently CH or N, or a pharmaceutically acceptable salt thereof. (4) In the general formula (I), (i)X 1 is CH and X 2 is CH, and X 4 is CH, (ii) X 1 is N and X 2is CH, and X 4 is CH, or (iii)X 1 is CH and X 2 is CH, and X 4 is N, A pharmaceutical composition comprising the compound according to any one of (1) to (3) or a pharmaceutically acceptable salt thereof. (5) In the general formula (I), Y 1 and Y 2 are each independently CH or N, or a pharmaceutically acceptable salt thereof. (6) In the general formula (I), (i)Y 1 is CH and Y 2 is CH, (ii) Y 1 is N and X 2 is CH, or (iii) Y 1 is CH and Y 2 is N, A medicine containing the compound according to any one of (1) to (5) or a pharmaceutically acceptable salt thereof. (7) A medicine containing the compound according to any one of (1) to (6) or a pharmaceutically acceptable salt thereof, wherein in the general formula (I), ring A is an optionally substituted phenyl group, an optionally substituted pyridinyl group, an optionally substituted pyrazolyl group, or an optionally substituted thiadiazolyl group. (8) In the general formula (I), ring A is represented by the following formula:

[0014] [ka]

[0015] (In the formula, R 8is a hydrogen atom, cyano group, hydroxyl group, amino group, methanesulfonylamino group, sulfonamido group, C1-C6 alkyl group, C1-C6 haloalkyl group, hydroxy-C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 alkoxy-C1-C6 alkyl group, C1-C6 alkylcarbonyl group, amino-C1-C6 alkyl group, N-acetylamino-C1-C6 alkyl group, C1-C6 alkylcarbamoyl group, N-methyl-C1-C6 alkylcarbamoyl group, imidazolyl group, thiazolyl group, or -C(=O)NHR e where R e represents a hydrogen atom, a C1-C6 alkyl group optionally substituted with a cyano group, a C1-C6 alkylcarbonyl group optionally substituted with a dimethylamino group, or an optionally substituted 5- or 6-membered heteroaryl group, R 9 is a hydrogen atom, a halogen atom, or a C1-C6 alkyl group. A pharmaceutical composition comprising the compound according to any one of (1) to (7) or a pharmaceutically acceptable salt thereof, wherein the ring is selected from the group consisting of: (9) In the general formula (I), ring A is represented by the following formula:

[0016] [ka]

[0017] (In the formula, R 8 and R 9 is the same as above.) A pharmaceutical composition comprising the compound according to any one of (1) to (7) or a pharmaceutically acceptable salt thereof, wherein the ring is selected from the group consisting of: (10) In the general formula (I), ring A is represented by the following formula:

[0018] [ka]

[0019] [In the formula, R 8is a hydrogen atom, a cyano group, a C1-C6 alkyl group, an imidazolyl group, a thiazolyl group, or -C(=O)-NHR e and R e represents a hydrogen atom, a C1-C6 alkyl group optionally substituted with a cyano group, a C1-C6 alkylcarbonyl group optionally substituted with a dimethylamino group, or a group represented by the following formula:

[0020] [ka]

[0021] {where, R 10 is a hydrogen atom, a C1-C6 alkyl group optionally substituted with a cyano group, a C1-C6-alkyl group optionally substituted with a C3-C6 cycloalkyl group, a C1-C6 alkoxy-C1-C6 alkylcarbonyl group or a C3-C6 cycloalkyl group, and R 11 is a hydrogen atom, a halogen atom, or a cyano group, and R 12 is a hydrogen atom or a C1-C6 alkyl group, and R 13 is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 alkyl group optionally substituted with a halogen atom, and R 14 is a hydrogen atom or a C1-C6 alkyl group, and R 15 is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 alkoxy-C1-C6 alkyl group}. A pharmaceutical composition comprising the compound according to any one of (1) to (7) or a pharmaceutically acceptable salt thereof, wherein (11) In the general formula (I), R 1 is expressed as follows:

[0022] [ka]

[0023] {In the formula, R 16 is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. a ring selected from the group consisting of: —C(═O)—NR a R b or -NR c -C(=O)R d where R a , R b , R c and R d are each independently a hydrogen atom or a C1-C6 alkyl group. Alternatively, R 1 and R 2 together with the carbon atoms to which they are attached, form the following formula:

[0024] [ka]

[0025] {In the formula, * 1 is R 1 is the carbon atom to which * 2 is R 2 is the carbon atom to which A pharmaceutical composition comprising the compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof, which forms a ring represented by the following formula: (12) R 4 is a C1-C6 alkyl group optionally substituted with deuterium, cyano, hydroxyl, amino, or oxo; a C1-C6 haloalkyl group optionally substituted with deuterium, cyano, hydroxyl, amino, or oxo; a C1-C3 alkoxy-C2-C6 alkyl group optionally substituted with deuterium, cyano, hydroxyl, amino, or oxo; a C1-C3 haloalkoxy-C2-C6 alkyl group optionally substituted with deuterium, cyano, hydroxyl, amino, or oxo; a C1-C3 haloalkoxy-C2-C6 alkyl group optionally substituted with deuterium, cyano, hydroxyl, amino, or oxo; a C1-C3 haloalkoxy-C2-C6 alkyl group optionally substituted with deuterium, cyano, hydroxyl, amino, or oxo; a C3-C6 cycloalkyl-C1-C6 alkyl group optionally substituted with deuterium, a halogen atom, cyano, hydroxyl, amino, C1-C6 alkyl group, a C1-C6 haloalkyl group, or oxo. (13) In the general formula (I), R 4 is a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C3 alkoxy-C2-C6 alkyl group, a C1-C3 haloalkoxy-C2-C6 alkyl group, or a C3-C6 cycloalkyl-C1-C6 alkyl group optionally substituted with a cyano group, or a pharmaceutically acceptable salt thereof. (14) In the general formula (I), X 2 is CH and X 3 is CR 6 where R 6 is a hydrogen atom, a halogen atom, a cyano group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a hydroxy-C1-C6 alkyl group, a cyano-C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy-C1-C6 alkyl group, a C1-C6 alkenyl group, a C1-C6 alkynyl group, or a phenyl group, a pharmaceutical comprising the compound according to any one of (1) to (13) or a pharmaceutically acceptable salt thereof. (15) The compound represented by the general formula (I)

[0026] [ka]

[0027] [ka]

[0028] A pharmaceutical composition comprising the compound according to (1) or a pharmaceutically acceptable salt thereof, wherein (16) The pharmaceutical agent according to any one of (1) to (15), which is a preventive or therapeutic agent for a disease in which STAT6 is involved. (17) The pharmaceutical according to (16), wherein the disease in which STAT6 is involved is an allergic disease or an inflammatory disease. (18) The pharmaceutical according to (16) or (17), wherein the disease associated with STAT6 is one or more diseases selected from the group consisting of chronic obstructive pulmonary disease, atopic dermatitis, bronchial asthma, bullous pemphigoid, nasal polyps, chronic sinusitis, allergic rhinitis, eosinophilic esophagitis, prurigo, and urticaria. (19) Use of the compound according to any one of (1) to (15) or a pharmaceutically acceptable salt thereof for the manufacture of an agent for the prophylaxis or treatment of a disease in which STAT6 is involved. (20) The use according to (19), wherein the disease in which STAT6 is involved is an allergic disease or an inflammatory disease. (21) The use according to (19) or (20), wherein the disease in which STAT6 is involved is one or more diseases selected from the group consisting of chronic obstructive pulmonary disease, atopic dermatitis, bronchial asthma, bullous pemphigoid, nasal polyps, chronic sinusitis, allergic rhinitis, eosinophilic esophagitis, prurigo, and urticaria. [Effects of the Invention]

[0029] According to the present invention, it is possible to provide a pharmaceutical comprising a novel compound or a salt thereof which has an excellent STAT6 inhibitory effect and is particularly effective in treating allergic diseases and inflammatory diseases in which STAT6 is involved. DETAILED DESCRIPTION OF THE INVENTION

[0030] The present invention will be described in detail below. In this specification, "n-" means normal, "sec-" means secondary, and "tert-" means tertiary. First, each substituent in the general formula (I) will be explained, but the present invention is not limited to those exemplified as specific examples. Specific examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The term "C1-C6 alkyl group" refers to a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, an n-pentyl group, a tert-pentyl group, a 3-methylbutyl group (an isopentyl group), a neopentyl group, and an n-hexyl group. The term "C2-C6 alkyl group" refers to a linear or branched alkyl group having 2 to 6 carbon atoms, and specific examples include an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, an n-pentyl group, a tert-pentyl group, a 3-methylbutyl group (an isopentyl group), a neopentyl group, and an n-hexyl group. A "C1-C6 haloalkyl group" is a "C1-C6 alkyl group" in which one or more hydrogen atoms have been substituted with a halogen atom. These groups may be bonded to any substitutable position. Specific examples include a trifluoromethyl group, a difluoromethyl group, a monofluoromethyl group, a 2-fluoroethyl group, a 2,2-difluoroethyl group, a 1,1-difluoroethyl group, a 2,2,2-trifluoroethyl group, a 1,1,2-trifluoroethyl group, a 1,1,2,2,2-pentafluoroethyl group, a 2-bromo-1,1-difluoroethyl group, a 1,1,1-trifluoropropan-2-yl group, a 1,1-difluoropropan-2-yl group, a 3,3,3-trifluoro-2-methylpropyl group, and a 1,1-difluoro-2-methylpropyl group. A "hydroxy-C1-C6 alkyl group" is a "C1-C6 alkyl group" in which one of the hydrogen atoms has been substituted with a hydroxy group. This group can be bonded at any substitutable position. Specific examples include a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 1-hydroxy-n-propyl group, a 2-hydroxy-n-propyl group, a 3-hydroxy-n-propyl group, a 2-hydroxy-2-methyl-n-propyl group, a 3-hydroxy-2-methyl-n-propyl group, a 3-hydroxy-2,2-dimethyl-n-propyl group, a 1-hydroxy-n-propan-2-yl group, a 1-hydroxy-2-methyl-n-propan-2-yl group, a 2- Examples thereof include a hydroxy-n-propan-2-yl group, a 4-hydroxy-n-butyl group, a 3-hydroxy-n-butyl group, a 3-hydroxy-3-methyl-n-butyl group, a 2-hydroxy-n-butyl group, a 2-hydroxy-2-methyl-n-butyl group, a 2-hydroxy-2-ethyl-n-butyl group, a 3-hydroxy-n-butan-2-yl group, a 3-hydroxy-3-methyl-n-butan-2-yl group, and a 3-hydroxy-2,3-dimethyl-n-butan-2-yl group. A "cyano-C1-C6 alkyl group" is a "C1-C6 alkyl group" in which one of the hydrogen atoms has been substituted with a cyano group. This group may be bonded to any substitutable position. Specific examples include a cyanomethyl group, a 1-cyanoethyl group, a 2-cyanoethyl group, a 1-cyano-n-propyl group, a 2-cyano-n-propyl group, a 3-cyano-n-propyl group, a 2-cyano-2-methyl-n-propyl group, a 3-cyano-2-methyl-n-propyl group, a 3-cyano-2,2-dimethyl-n-propyl group, a 1-cyano-n-propan-2-yl group, a 1-cyano-2-methyl-n-propan-2-yl group, a 2 ... Examples thereof include an ano-n-propan-2-yl group, a 4-cyano-n-butyl group, a 3-cyano-n-butyl group, a 3-cyano-3-methyl-n-butyl group, a 2-cyano-n-butyl group, a 2-cyano-2-methyl-n-butyl group, a 2-cyano-2-ethyl-n-butyl group, a 3-cyano-n-butan-2-yl group, a 3-cyano-3-methyl-n-butan-2-yl group, and a 3-cyano-2,3-dimethyl-n-butan-2-yl group.

[0031] The term "C3-C6 cycloalkyl group" refers to a monocyclic or bridged saturated carbocyclic group having 3 to 6 carbon atoms. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a bicyclo[1.1.1]pentyl group. The term "5- or 6-membered non-aromatic heterocyclic group" refers to a monovalent substituent formed by removing one hydrogen atom from any position of a 5- or 6-membered monocyclic, bridged, or spirocyclic non-aromatic heterocycle containing one or two heteroatoms selected from oxygen, sulfur, and nitrogen atoms as ring-constituting atoms. Specific examples of such non-aromatic heterocycles include azetidine, pyrrolidine, piperidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperazine, morpholine, thiomorpholine, azepine, diazepine, oxetane, tetrahydrofuran, 1,3-dioxolane, tetrahydropyran, dihydropyran, and 1,4-dioxane.

[0032] The term "C2-C6 alkenyl group" refers to a linear or branched alkenyl group having one or more double bonds and having 2 to 6 carbon atoms. Specific examples include vinyl, 1-propenyl, isopropenyl, 1-butenyl, isobutenyl, 2-methyl-1-propenyl, 1-methyl-1-propenyl, 1-pentenyl, and 1-hexenyl groups. The term "C2-C6 alkynyl group" refers to a straight-chain or branched alkynyl group having one or more triple bonds and having 2 to 6 carbon atoms. Specific examples include an ethynyl group, a 1-propynyl group, a 1-butynyl group, a 3-methyl-1-butynyl group, a 1-pentynyl group, a 3-methyl-1-pentynyl group, and a 1-hexynyl group.

[0033] The term "5- or 6-membered heteroaryl group" refers to a monovalent substituent formed by removing one hydrogen atom from any position of a 5- or 6-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen atoms as ring-constituting atoms. Specific examples of such aromatic heterocycles include pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, uracil, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, furan, thiophene, thiazole, isothiazole, oxazole, isoxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, and 1,3,4-thiadiazole. The "5-membered heteroaryl group" refers to a monovalent substituent obtained by removing one hydrogen atom from any position of a 5-membered aromatic heterocycle among the "5- to 6-membered heteroaryl groups." Specific examples of such aromatic heterocycles include pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, furan, thiophene, thiazole, isothiazole, oxazole, isoxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, and 1,3,4-thiadiazole.

[0034] The term "C1-C6 alkoxy group" refers to an alkoxy group in which the alkyl portion is the above-mentioned "C1-C6 alkyl group", and specific examples include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentyloxy group, and an n-hexyloxy group. The term "C1-C3 alkoxy group" refers to an alkoxy group in which the alkyl portion is a linear or branched alkyl having 1 to 3 carbon atoms, and specific examples include a methoxy group, an ethoxy group, an n-propoxy group, and an isopropoxy group. A "C1-C3 haloalkoxy group" is a "C1-C3 alkoxy group" in which one or more hydrogen atoms have been substituted with a halogen atom. These groups may be bonded at any substitutable position. Specific examples include a trifluoromethoxy group, a difluoromethoxy group, a 2,2,2-trifluoroethoxy group, a 2,2-difluoroethoxy group, a 3,3,3-trifluoro-n-propoxy group, a 3,3-difluoro-n-propoxy group, and a 2,2-difluoro-n-propoxy group.

[0035] A "C1-C6 alkoxy-C1-C6 alkyl group" is the above-mentioned "C1-C6 alkyl group" substituted with a "C1-C6 alkoxy group." These can be bonded at any substitutable position. Specific examples include a methoxymethyl group, an ethoxymethyl group, an n-propoxymethyl group, a 2-methoxyethyl group, a 2-ethoxyethyl group, a 2-n-propoxyethyl group, a 2-isopropoxyethyl group, a 3-methoxy-n-propyl group, and a 2-methoxy-n-propyl group. A "C1-C3 alkoxy-C2-C6 alkyl group" is the above-mentioned "C2-C6 alkyl group" substituted with a "C1-C3 alkoxy group." These can be bonded at any substitutable position. Specific examples include a 2-methoxyethyl group, a 2-ethoxyethyl group, a 2-n-propoxyethyl group, a 2-isopropoxyethyl group, a 3-methoxy-n-propyl group, and a 2-methoxy-n-propyl group. A "C1-C3 haloalkoxy-C2-C6 alkyl group" is the above-mentioned "C2-C6 alkyl group" substituted with a "C1-C3 haloalkoxy group." These may be bonded at any substitutable position. Specific examples include a 2-(trifluoromethoxy)ethyl group, a 2-(difluoromethoxy)ethyl group, a 2-(2,2,2-trifluoroethoxy)ethyl group, a 2-(2,2-difluoromethoxy)ethyl group, a 2-(3,3,3-trifluoro-n-propoxy)ethyl group, a 2-(3,3-difluoro-n-propoxy)ethyl group, and a 2-(2,2-difluoro-n-propoxy)ethyl group. A "C3-C6 cycloalkyl-C1-C6 alkyl group" is the above-mentioned "C1-C6 alkyl group" substituted with a "C3-C6 cycloalkyl group." These can be bonded at any substitutable position. Specific examples include a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, a 2-cyclopropylethyl group, and a 3-cyclopropylpropyl group.

[0036] The term "C1-C6 alkylcarbonyl group" refers to a group in which any carbon atom in the "C1-C6 alkyl group" that can be substituted with a carbonyl group is substituted with a carbonyl group, and specific examples include a formyl group, an acetyl group, a 2-oxoethyl group, a propionyl group, a 2-oxopropyl group, and a 3-oxopropyl group. A "C1-C6 alkoxy-C1-C6 alkylcarbonyl group" is the aforementioned "C1-C6 alkylcarbonyl group" substituted with the aforementioned "C1-C6 alkoxy group." These can be bonded at any substitutable position. Specific examples include a methoxycarbonyl group, an ethoxycarbonyl group, and a 2-methoxy-2-oxoethyl group.

[0037] In this specification, the term "8- to 10-membered fused ring" refers to a ring formed by sharing two atoms constituting each ring between any of the ring structures represented by the group consisting of a phenyl group or the "5- to 6-membered heteroaryl group" and the "C3-C6 cycloalkyl group," "5- to 6-membered non-aromatic heterocyclic group," "5- to 6-membered heteroaryl group," and a phenyl group. The combination of the two ring structures may be the same or different, and may include, for example, a fused ring formed by a phenyl group and a phenyl group, a fused ring formed by a phenyl group and a "5- to 6-membered non-aromatic heterocyclic group," or a fused ring formed by a phenyl group and a "5- to 6-membered heteroaryl group." Specific examples include naphthalene, tetrahydronaphthalene, quinoline, chroman, isochroman, indoline, isoindoline, tetrahydroquinoline, and tetrahydroisoquinoline.

[0038] In general formula (I), R1 In the above, the substituents of the "optionally substituted 5-membered heteroaryl group", "optionally substituted 5- to 6-membered non-aromatic heterocyclic group" and "optionally substituted pyridonyl group" are substituents selected from the group consisting of deuterium, halogen atoms, cyano groups, hydroxyl groups, amino groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups and oxo groups. One or more of these may be substituted at all substitutable positions. In general formula (I), R 2 and R 3 In the above, the substituents of the "optionally substituted C1-C6 alkyl group" and the "optionally substituted C1-C6 haloalkyl group" are substituents selected from the group consisting of deuterium, cyano group, hydroxyl group, amino group, and oxo group. One or more of these may be substituted at all substitutable positions.

[0039] In general formula (I), R 4 In the formula (I), the substituents of "optionally substituted C1-C6 alkyl group," "optionally substituted C1-C6 haloalkyl group," "optionally substituted C1-C3 alkoxy-C2-C6 alkyl group," "optionally substituted C1-C3 haloalkoxy-C2-C6 alkyl group," and "optionally substituted C3-C6 cycloalkyl-C1-C6 alkyl group" are substituents selected from the group consisting of deuterium, halogen atoms, cyano group, hydroxyl group, amino group, C1-C6 alkyl group, C1-C6 haloalkyl group, and oxo group. One or more of these may be substituted at all substitutable positions. However, in the case of "optionally substituted C1-C6 alkyl group," "optionally substituted C1-C6 haloalkyl group," "optionally substituted C1-C3 alkoxy-C2-C6 alkyl group," or "optionally substituted C1-C3 haloalkoxy-C2-C6 alkyl group," halogen atoms, C1-C6 alkyl group, and C1-C6 haloalkyl group are excluded from the substituents.

[0040] In general formula (I), R 6In the above, the substituents of "optionally substituted C1-C6 alkyl group," "optionally substituted C1-C6 haloalkyl group," "optionally substituted hydroxy-C1-C6 alkyl group," "optionally substituted cyano-C1-C6 alkyl group," "optionally substituted C3-C6 cycloalkyl group," "optionally substituted C1-C6 alkoxy-C1-C6 alkyl group," "optionally substituted C2-C6 alkenyl group," and "optionally substituted C2-C6 alkynyl group" are selected from the group consisting of deuterium, halogen atoms, cyano groups, hydroxyl groups, amino groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and oxo groups. One or more of these may be substituted at all substitutable positions. However, in the case of "optionally substituted C1-C6 alkyl group," "optionally substituted C1-C6 haloalkyl group," or "optionally substituted C1-C3 alkoxy-C2-C6 alkyl group," halogen atoms, C1-C6 alkyl groups, and C1-C6 haloalkyl groups are excluded from the substituents. In general formula (I), R 6 In the above, the substituents of the "optionally substituted phenyl group" and the "optionally substituted 5- or 6-membered heteroaryl group" are substituents selected from the group consisting of deuterium, halogen atoms, cyano groups, hydroxyl groups, amino groups, C1-C6 alkyl groups, and C1-C6 haloalkyl groups. One or more of these may be substituted at all substitutable positions.

[0041] In general formula (I), R 7 In the formula, the substituents of the "optionally substituted C1-C6 alkyl group" and the "optionally substituted C1-C6 haloalkyl group" are substituents selected from the group consisting of deuterium, cyano group, hydroxyl group, and amino group. One or more of these may be substituted at all substitutable positions.

[0042] In general formula (I), substituents of the "optionally substituted phenyl group" and "optionally substituted 5- to 6-membered heteroaryl group" in ring A include deuterium, halogen atoms, cyano group, hydroxyl group, amino group, methanesulfonylamino group, sulfonamido group, C1-C6 alkyl group, C1-C6 haloalkyl group, hydroxy-C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 alkoxy-C1-C6 alkyl group, C1-C6 alkylcarbonyl group, amino-C1-C6 alkyl group, N-acetylamino-C1-C6 alkyl group, C1-C6 alkylcarbamoyl group, N-methyl-C1-C6 alkylcarbamoyl group, imidazolyl group, thiazolyl group and -C(=O)NHR e (R e represents hydrogen, deuterium, a cyano-C1-C6 alkyl group, a dimethylamino-C1-C6 alkylcarbonyl group, and an optionally substituted 5- or 6-membered heteroaryl group.) One or more of these may be substituted at all substitutable positions. In general formula (I), the substituent of the "optionally substituted fused ring" in ring A is a substituent selected from the group consisting of deuterium, a halogen atom, a cyano group, a hydroxyl group, an amino group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, and an oxo group, and one or more of these may be substituted at all substitutable positions.

[0043] R e In the above, the substituent of the "optionally substituted 5- or 6-membered heteroaryl group" is a substituent selected from the group consisting of deuterium, halogen atoms, cyano, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy-C1-C6 alkyl, cyano-C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, and C1-C6 alkoxy-C1-C6 alkylcarbonyl. One or more of these may be substituted at all substitutable positions.

[0044] When the compound represented by formula (I) has an asymmetric carbon atom, the present invention encompasses all of its racemates, diastereoisomers and individual optically active substances. Furthermore, the compounds represented by general formula (I) or pharmaceutically acceptable salts thereof can form hydrates or solvates, which are also included within the scope of the present invention.

[0045] In the compound of general formula (I) or a pharmaceutically acceptable salt thereof included in the pharmaceutical of the present invention, preferred atoms or substituents are explained below. Q 1 A preferred example of is C(=O). Q 2 A preferred example of is NH. A more preferred example is Q 1 is C(=O) and Q 2 is NH. X 1 Preferred examples of are CH or N. X 2 Preferred examples of are CH or N. X 3 A preferred example of 6 or N, where R 6 is a hydrogen atom, a halogen atom, a cyano group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a hydroxy-C1-C6 alkyl group, a cyano-C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy-C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, or a phenyl group. X 4 Preferred examples of are CH or N. Y 1 Preferred examples of are N or CR 7 where R 7 is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. Y 2 Preferred examples of are N or CR 7 where R 7 is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. A more preferred example is (i)Y 1 is CH and Y 2 is CH, (ii) Y 1 is N and X 2 is CH, or (iii) Y 1 is CH and Y 2 is N. Even more preferably, Y 1 is CH and Y 2 is CH. Preferred examples of ring A include the following formula:

[0046] [ka]

[0047] (In the formula, R 8 is a hydrogen atom, cyano group, hydroxyl group, amino group, methanesulfonylamino group, sulfonamido group, C1-C6 alkyl group, C1-C6 haloalkyl group, hydroxy-C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 alkoxy-C1-C6 alkyl group, C1-C6 alkylcarbonyl group, amino-C1-C6 alkyl group, N-acetylamino-C1-C6 alkyl group, C1-C6 alkylcarbamoyl group, N-methyl-C1-C6 alkylcarbamoyl group, imidazolyl group, thiazolyl group, or -C(=O)NHR e where R e represents a hydrogen atom, a C1-C6 alkyl group optionally substituted with a cyano group, a C1-C6 alkylcarbonyl group optionally substituted with a dimethylamino group, or a group represented by the following formula:

[0048] [ka]

[0049] {where, R 10is a hydrogen atom, a C1-C6 alkyl group optionally substituted with a cyano group, a C1-C6 alkyl group optionally substituted with a C3-C6 cycloalkyl, a C1-C6 alkoxy-C1-C6 alkylcarbonyl group or a C3-C6 cycloalkyl group, and R 11 is a hydrogen atom, a halogen atom, or a cyano group, and R 12 is a hydrogen atom or a C1-C6 alkyl group, and R 13 is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 alkyl group optionally substituted with a halogen atom, and R 14 is a hydrogen atom or a C1-C6 alkyl group, and R 15 is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 alkoxy-C1-C6 alkyl group; R 9 is a hydrogen atom, a halogen atom, or a C1-C6 alkyl group. and more preferably, a ring selected from the group consisting of the following formula:

[0050] [ka]

[0051] (In the formula, R 8 is an imidazolyl group, a thiazolyl group, or -C(=O)NHR e where R e represents a hydrogen atom, a C1-C6 alkyl group optionally substituted with a cyano group, a C1-C6 alkylcarbonyl group optionally substituted with a dimethylamino group, or a group represented by the following formula:

[0052] [ka]

[0053] {where, R 10is a hydrogen atom, a C1-C6 alkyl group optionally substituted with a cyano group, a C1-C6 alkyl group optionally substituted with a C3-C6 cycloalkyl, a C1-C6 alkoxy-C1-C6 alkylcarbonyl group or a C3-C6 cycloalkyl group, and R 11 is a hydrogen atom, a halogen atom, or a cyano group, and R 12 is a hydrogen atom or a C1-C6 alkyl group, and R 13 is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 alkyl group optionally substituted with a halogen atom, and R 14 is a hydrogen atom or a C1-C6 alkyl group, and R 15 is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 alkoxy-C1-C6 alkyl group; R 9 is a hydrogen atom or a halogen atom. is a ring selected from the group consisting of: In another embodiment of the present invention, preferred examples of ring A include the following formula:

[0054] [ka]

[0055] (In the formula, R 8 is a hydrogen atom, cyano group, hydroxyl group, amino group, methanesulfonylamino group, sulfonamido group, C1-C6 alkyl group, C1-C6 haloalkyl group, hydroxy-C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 alkoxy-C1-C6 alkyl group, C1-C6 alkylcarbonyl group, amino-C1-C6 alkyl group, N-acetylamino-C1-C6 alkyl group, C1-C6 alkylcarbamoyl group, N-methyl-C1-C6 alkylcarbamoyl group, imidazolyl group, thiazolyl group, or -C(=O)NHR e where R e represents a hydrogen atom, a C1-C6 alkyl group optionally substituted with a cyano group, a C1-C6 alkylcarbonyl group optionally substituted with a dimethylamino group, or a group represented by the following formula:

[0056] [ka]

[0057] {where, R 10 is a hydrogen atom, a C1-C6 alkyl group optionally substituted with a cyano group, a C1-C6 alkyl group optionally substituted with a C3-C6 cycloalkyl, a C1-C6 alkoxy-C1-C6 alkylcarbonyl group or a C3-C6 cycloalkyl group, and R 11 is a hydrogen atom, a halogen atom, or a cyano group, and R 12 is a hydrogen atom or a C1-C6 alkyl group, and R 13 is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 alkyl group optionally substituted with a halogen atom, and R 14 is a hydrogen atom or a C1-C6 alkyl group, and R 15 is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 alkoxy-C1-C6 alkyl group; R 9 is a hydrogen atom, a halogen atom, or a C1-C6 alkyl group. and more preferably, a ring selected from the group consisting of the following formula:

[0058] [ka]

[0059] (In the formula, R 8 is an imidazolyl group, a thiazolyl group, or -C(=O)NHR e where R e represents a hydrogen atom, a C1-C6 alkyl group optionally substituted with a cyano group, a C1-C6 alkylcarbonyl group optionally substituted with a dimethylamino group, or a group represented by the following formula:

[0060] [ka]

[0061] {where, R 10 is a hydrogen atom, a C1-C6 alkyl group optionally substituted with a cyano group, a C1-C6 alkyl group optionally substituted with a C3-C6 cycloalkyl, a C1-C6 alkoxy-C1-C6 alkylcarbonyl group or a C3-C6 cycloalkyl group, and R 11 is a hydrogen atom, a halogen atom, or a cyano group, and R 12 is a hydrogen atom or a C1-C6 alkyl group, and R 13 is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 alkyl group optionally substituted with a halogen atom, and R 14 is a hydrogen atom or a C1-C6 alkyl group, and R 15 is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 alkoxy-C1-C6 alkyl group; R 9 is a hydrogen atom or a halogen atom. is a ring selected from the group consisting of: In another embodiment of the present invention, preferred examples of ring A include the following formula:

[0062] [ka]

[0063] (In the formula, R 8 is an imidazolyl group, a thiazolyl group, or -C(=O)-NHR e where R e represents a hydrogen atom, a C1-C6 alkyl group optionally substituted with a cyano group, a C1-C6 alkylcarbonyl group optionally substituted with a dimethylamino group, or a group represented by the following formula:

[0064] [ka]

[0065] {where, R 10is a hydrogen atom, a C1-C6 alkyl group optionally substituted with a cyano group, a C1-C6 alkyl group optionally substituted with a C3-C6 cycloalkyl, a C1-C6 alkoxy-C1-C6 alkylcarbonyl group or a C3-C6 cycloalkyl group, and R 11 is a hydrogen atom, a halogen atom, or a cyano group, and R 12 is a hydrogen atom or a C1-C6 alkyl group, and R 13 is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 alkyl group optionally substituted with a halogen atom, and R 14 is a hydrogen atom or a C1-C6 alkyl group, and R 15 is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 alkoxy-C1-C6 alkyl group; R 9 is a hydrogen atom or a halogen atom. This shows the ring represented by: R 1 Preferred examples of the formula

[0066] [ka]

[0067] {In the formula, R 16 is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. a ring selected from the group consisting of: —C(═O)—NR a R b or -NR c -C(=O)R d where R a , R b , R c and R d are each independently a hydrogen atom or a C1-C6 alkyl group. R 2 A preferred example of is a hydrogen atom. Alternatively, R 1 and R 2 together with the carbon atoms to which they are attached, form the following formula:

[0068] [ka]

[0069] {In the formula, * 1 is R 1 is the carbon atom to which * 2 is R 2 is the carbon atom to which It is also preferable that the ring is represented by the following formula: R 3 A preferred example of is a hydrogen atom. R 4 Preferred examples of R are a C1-C6 alkyl group optionally substituted with deuterium, cyano, hydroxyl, amino or oxo, a C1-C6 haloalkyl group optionally substituted with deuterium, cyano, hydroxyl, amino or oxo, a C1-C3 alkoxy-C2-C6 alkyl group optionally substituted with deuterium, cyano, hydroxyl, amino or oxo, a C1-C3 haloalkoxy-C2-C6 alkyl group optionally substituted with deuterium, cyano, hydroxyl, amino or oxo, a C1-C3 haloalkoxy-C2-C6 alkyl group optionally substituted with deuterium, cyano, hydroxyl, amino or oxo, and a C3-C6 cycloalkyl-C1-C6 alkyl group optionally substituted with deuterium, a halogen atom, cyano, hydroxyl, amino, C1-C6 alkyl group, a C1-C6 haloalkyl group or oxo. 4 More preferred examples are a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C3 alkoxy-C2-C6 alkyl group, a C1-C3 haloalkoxy-C2-C6 alkyl group, and a C3-C6 cycloalkyl-C1-C6 alkyl group optionally substituted with a cyano group, and even more preferred are a C1-C6 alkyl group, a C1-C3 alkoxy-C2-C6 alkyl group, and a C3-C6 cycloalkyl-C1-C6 alkyl group optionally substituted with a cyano group. Specifically, compounds selected from the following are particularly preferred:

[0070] [ka]

[0071] [ka]

[0072] [ka]

[0073] The "salt" of compound (I) is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, etc.; organic carboxylates such as acetate, oxalate, fumarate, maleate, malonate, citrate, succinate, malate, etc.; organic sulfonates such as methanesulfonate, benzenesulfonate, p-benzenesulfonate, etc.; alkali metal salts such as lithium salt, sodium salt, potassium salt, etc.; alkaline earth metal salts such as calcium salt, magnesium salt, etc.

[0074] Compound (I) or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition of the present invention can be prepared by various methods, including, for example, the general synthetic methods shown in Production Methods 1 to 27 below, methods similar to the production methods below, or an appropriate combination of synthetic methods well known to those skilled in the art. For example, other compounds of general formula (I) or pharmaceutically acceptable salts thereof can be derived by subjecting the compound to known reactions such as condensation, addition, oxidation, reduction, substitution, halogenation, dehydration, or hydrolysis, or by an appropriate combination thereof. Furthermore, unless otherwise specified, salts of compound (I) in each of the production methods below can be appropriately selected from the above-mentioned "salts" and can be prepared by methods well known to those skilled in the art.

[0075] When Compound (I) has one or more asymmetric carbon atoms, any of the steps described in Production Methods 1 to 27 may include a procedure for resolving stereoisomers. Methods commonly used by those skilled in the art can be applied to resolve stereoisomers, such as column chromatography. The starting materials and reaction reagents used in these syntheses are either commercially available or can be prepared using commercially available compounds according to methods well known to those skilled in the art.

[0076] The extraction, purification, and other treatments of the compound of general formula (I) or its pharmaceutically acceptable salt contained in the pharmaceutical composition of the present invention may be carried out in the same manner as in ordinary organic chemistry experiments. In each step of producing an intermediate for producing compound (I), the product may be carried to the next step as a crude product containing impurities without purification, or multiple steps may be carried out continuously, such as a one-pot reaction. In addition, compound (I) or the product of each step of producing compound (I) may be obtained in the form of a salt, solvate, or the like. In addition, the order of the steps described below may be changed as appropriate. The method for producing compound (I) contained in the pharmaceutical composition of the present invention is not limited to the examples shown below.

[0077] The abbreviations used in the production methods and examples in this specification are as follows. pin: pinacol MIDA: N-methyliminodiacetic acid THF: tetrahydrofuran DMF: N,N-dimethylformamide DMAc: N,N-dimethylacetamide DMSO: dimethyl sulfoxide tert:tertiary DABCO: 1,4-diazabicyclo[2.2.2.]octane DBU: 1,8-diazabicyclo[5.4.0]-7-undecene DCC: N,N'-dicyclohexylcarbodiimide DIC: N,N'-diisopropylcarbodiimide EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride HBTU: 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate COMU: (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate TCFH: chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate BOP: benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate PyBop: (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate PyBrop: Bromotripyrrolidinophosphonium hexafluorophosphate DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride T3P: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide HOBt: 1-hydroxybenzotriazole HOAt: 1-hydroxy-7-azabenzotriazole Oxyma: Ethyl cyanohydroxyiminoacetate DIPEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DEAD: Diethyl azodicarboxylate DIAD: Diisopropyl azodicarboxylate TMAD: 1,1'-azobis(N,N-dimethylformamide) ADDP: 1,1'-(azodicarbonyl)dipiperidine XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl Aphos-PD-G3: [4-(di-tert-butylphosphino)-N,N-dimethylaniline-2-(2'-aminobiphenyl)]palladium(II) methanesulfonate Xantphos-PD-G3: [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate SPhos-PD-G3: (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene SPhos: 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl tBuXPhos: 2-di-tertiary-butylphosphino-2',4',6'-triisopropylbiphenyl DavePhos: 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene BrettPhos: 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl QPhos: 1,2,3,4,5-pentaphenyl-1'-(di-tertiary-butylphosphino)ferrocene LDA: lithium diisopropylamide MTBE: Methyl tertiary butyl ether Boc: tertiary-butoxycarbonyl Cbz: benzyloxycarbonyl Fmoc: 9-fluorenylmethyloxycarbonyl TMS: trimethylsilyl LC: liquid chromatography MS: Mass spectrometry ESI: electrospray ionization UV: Ultraviolet light NMR: nuclear magnetic resonance TEA: Triethylamine TFA: Trifluoroacetic acid NIS: N-iodosuccinimide NMP: N-methylpyrrolidone TBAF: Tetrabutylammonium fluoride NBS: N-bromosuccinimide NCS: N-chlorosuccinimide DTT: dithiothreitol EDTA: Ethylenediaminetetraacetic acid

[0078] Compound (I) can be produced, for example, by Production Method 1 shown below. <Manufacturing method 1>

[0079] [ka]

[0080] [In the formula, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Q 1 , Q 2 and ring A are defined as above. 1 is a hydroxyl group or a chloro group, and M 1 are boronic acids and boronic acid-related structures such as B(OH)2, B(OMe)2, B(pin), B(MIDA), and BF3K, and Hal 1 is a chloro group, a bromo group, or an iodo group.

[0081] (Process 1-A) In (Step 1-A), compound (1-1) is subjected to a cyclization reaction with compound (1-2) in air or an oxygen atmosphere to produce compound (I). An acid may be present to facilitate the reaction, and examples of the acid include, but are not limited to, acetic acid, trifluoroacetic acid, ammonium acetate, paratoluenesulfonic acid, hydrochloric acid, phosphoric acid, and the like. Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, and DMSO; alcohols such as methanol and ethanol; water, and mixed solvents thereof. Furthermore, the reaction may be carried out in the absence of a solvent. The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature to 200° C. The reaction time is not particularly limited, and is preferably 1 to 24 hours.

[0082] (Process 1-B) In (Step 1-B), Compound (1-3) and Compound (1-4) are subjected to an addition-elimination reaction or substitution reaction in the presence or absence of a base to synthesize Compound (I). Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, and DMSO; and mixed solvents thereof. Examples of bases include, but are not limited to, metal bases such as potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, sodium carbonate, sodium bicarbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium fluoride, potassium bis(trimethylsilyl)amide, or sodium hydride; trimethylamine, triethylamine, diisopropylethylamine, tripropylamine organic bases such as triisopropylamine, tributylamine, N-methylmorpholine, 1-methylimidazole, pyridine, 4-(N,N-dimethylamino)pyridine, 2,6-dimethylpyridine, 2,6-di-tert-butylpyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,1,3,3-tetramethylguanidine, and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). Q 1 is a carbonyl group, and LG 1 When is a hydroxyl group, the reaction is carried out in the presence of a condensing agent. Examples of condensing agents include, but are not limited to, DCC, DIC, EDC, HBTU, HATU, COMU, TCFH, BOP, PyBOP, PyBrOP, DMT-MM, and T3P. In addition, an additive may be added to facilitate the reaction, and examples of the additive include HOBt, HOAt, Oxyma, and DMAP. Q 1 is a methylene group (-CH2-), and LG 1When is a hydroxyl group, the Mitsunobu reaction is carried out in the presence of an azodicarboxylic acid derivative and a phosphine derivative. Examples of azodicarboxylic acid derivatives include, but are not limited to, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), N,N,N',N'-tetramethylazodicarboxamide (TMAD), 1,1'-(azodicarbonyl)dipiperidine (ADDP), etc. Examples of phosphine derivatives include, but are not limited to, triphenylphosphine, tri-n-butylphosphine, etc. The reaction temperature is not particularly limited, and the reaction is usually carried out at 0° C. to 150° C. The reaction time is not particularly limited, and is preferably 0.5 to 24 hours.

[0083] (Process 1-C) In (Step 1-C), compound (I) can be produced by subjecting compound (1-5) and compound (1-6) to Suzuki-Miyaura coupling reaction in the presence of a palladium catalyst and a base. Palladium catalysts include metallic palladium such as palladium-carbon and palladium black; palladium salts such as palladium chloride and palladium acetate; tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, palladium chloride-1,1'-bis(diphenylphosphino)ferrocene, tris(dibenzylideneacetone)dipalladium, bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium, bis(acetonitrile)dichloropalladium, chloro(chloro)palladium, ...tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylpho Examples of suitable organic palladium complexes include, but are not limited to, organic palladium complexes such as (Xantphos-Pd-G3, Xantphos-PD-G3, and SPhos-PD-G3) and ... polymer-immobilized organic palladium complexes such as polymer-supported bis(acetate)triphenylphosphinepalladium and polymer-supported di(acetate)dicyclohexylphenylphosphinepalladium, and these may be used in combination. Examples of bases include, but are not limited to, metal bases such as potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, sodium carbonate, sodium bicarbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium fluoride, potassium bis(trimethylsilyl)amide, or sodium hydride; trimethylamine, triethylamine, diisopropylethylamine, tripotassium phosphate, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium fluoride, potassium bis(trimethylsilyl)amide, or sodium hydride; organic bases such as propylamine, triisopropylamine, tributylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, 2,6-dimethylpyridine, 2,6-di-tert-butylpyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,1,3,3-tetramethylguanidine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Additives may be used to facilitate the reaction, and examples of such additives include, but are not limited to, trialkylphosphines such as trimethylphosphine and tri-tert-butylphosphine; tricycloalkylphosphines such as tricyclohexylphosphine; triarylphosphines such as triphenylphosphine and tritolylphosphine; trialkylphosphites such as trimethylphosphite, triethylphosphite, and tributylphosphite; tricycloalkylphosphites such as tricyclohexylphosphite; triarylphosphites such as triphenylphosphite; imidazolium salts such as 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride; diketones such as acetylacetone and octafluoroacetylacetone; amines such as trimethylamine, triethylamine, tripropylamine, triisopropylamine, and tributylamine; 1,4-Bis(diphenylphosphino)butane;2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl (BINAP);2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos);2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos);2-(Di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl (tBuXPhos);2-Dicyclohexylphosphino-2'- (N,N-dimethylamino)biphenyl (DavePhos); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos); 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos); 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene (QPhos); and 2-(di-tert-butylphosphino)biphenyl. These additives may be used alone or in combination. Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as hexane and heptane; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, and DMSO; alcohols such as methanol and ethanol; water, and mixed solvents thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature to 150° C. The reaction time is not particularly limited, and is preferably 0.1 to 24 hours.

[0084] Compound (2-6), which is one of the compounds (1-1), can be produced, for example, by Production Method 2 shown below. <Manufacturing method 2>

[0085] [ka]

[0086] [In the formula, R 4 , X 2 , X 3 , X 4 and ring A are the same as defined above. 2 is a fluoro group or a chloro group.

[0087] (Process 2-1) In (Step 2-1), compound (2-3) can be produced by subjecting compound (2-1) and compound (2-2) to an aromatic nucleophilic substitution reaction in the presence of a base. Examples of bases include, but are not limited to, metal bases such as potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, sodium carbonate, sodium bicarbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, potassium bis(trimethylsilyl)amide, or sodium hydride; trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, Organic bases such as propylamine, tributylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, 2,6-dimethylpyridine, 2,6-di-tert-butylpyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,1,3,3-tetramethylguanidine, and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, and DMSO; water, and mixed solvents thereof. Furthermore, the reaction may be carried out in the absence of a solvent. The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature to 200° C. The reaction time is not particularly limited, and is preferably 0.5 to 24 hours.

[0088] (Step 2-2) In (Step 2-2), compound (2-5) can be produced by subjecting compound (2-3) and compound (2-4) to a condensation reaction using a condensing agent in the presence or absence of a base. Examples of condensing agents include, but are not limited to, DCC, DIC, EDC, HBTU, HATU, COMU, TCFH, BOP, PyBOP, PyBrOP, DMT-MM, and T3P. To facilitate the reaction, an additive may be added, and examples of the additive include HOBt, HOAt, Oxyma, and DMAP. Examples of the base include organic bases such as trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, tributylamine, N-methylmorpholine, 1-methylimidazole, pyridine, 4-(N,N-dimethylamino)pyridine, 2,6-dimethylpyridine, 2,6-di-tert-butylpyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,1,3,3-tetramethylguanidine, and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, and DMSO; and mixed solvents thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature to 100° C. The reaction time is not particularly limited, and is preferably 0.5 to 24 hours.

[0089] (Step 2-3A) In (Step 2-3A), the compound (2-5) is subjected to catalytic reduction in the presence of a transition metal catalyst and hydrogen to produce the compound (2-6). Transition metal catalysts include, but are not limited to, palladium on carbon, palladium hydroxide on carbon, palladium on fibroin, Raney nickel, platinum oxide, and the like. Examples of reaction solvents include, but are not limited to, alcohols such as methanol, ethanol, 2-propanol, and tert-butanol; esters such as methyl acetate and ethyl acetate; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, and DMSO; protic polar solvents such as acetic acid; water; and mixed solvents thereof. The reaction temperature is not particularly limited, and is usually room temperature to 100° C., and the reaction is carried out under normal pressure or increased pressure. The reaction time is not particularly limited, and is preferably 0.5 to 24 hours.

[0090] (Step 2-3B) In (Step 2-3B), compound (2-5) is subjected to a reduction reaction in the presence of reduced iron or zinc to produce compound (2-6). To facilitate the reaction, an additive may be present, and examples of the additive include, but are not limited to, acetic acid, hydrochloric acid, ammonium chloride, and the like. Examples of reaction solvents include, but are not limited to, alcohols such as methanol, ethanol, 2-propanol, and tert-butyl alcohol; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; protic polar solvents such as acetic acid; water; and mixed solvents thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out at 0° C. to 100° C. The reaction time is not particularly limited, and is preferably 0.5 to 24 hours.

[0091] The compound (1-2) can be produced, for example, by the following Production Method 3. <Manufacturing method 3>

[0092] [ka]

[0093] [In the formula, R 1 , R 2 , R 3 , Y1 and Y 2 The definition of is the same as above. 3 is a chloro group, a bromo group, or an iodo group.

[0094] (Step 3-1) In (Step 3-1), compound (3-2) can be produced by subjecting compound (3-1) and vinylboronic acid or a vinylboronic acid derivative to Suzuki-Miyaura coupling reaction in the presence of a palladium catalyst and a base. Examples of vinylboronic acid derivatives include pinacol vinylboronate, dibutyl vinylboronate, MIDA vinylboronate, and potassium vinyltetrafluoroborate. Examples of the palladium catalyst and base include the palladium catalyst and base described in Production Method 1 (Step 1-C). To facilitate the reaction, additives may be present, such as those described in Production Method 1 (Step 1-C). Examples of the reaction solvent include the solvents described in Production Method 1 (Step 1-C). The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature to 150° C. The reaction time is not particularly limited, and is preferably 0.1 to 24 hours.

[0095] (Step 3-2) In (Step 3-2), compound (3-2) is subjected to a double bond cleavage reaction using osmium tetroxide and sodium periodate to produce compound (1-2). To facilitate the reaction, an additive may be present, such as 2,6-lutidine. Examples of reaction solvents include, but are not limited to, halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; acetone, water, and mixed solvents thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out at 0° C. to 100° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

[0096] Compound (4-3), which is one of the compounds (3-1), can be produced, for example, by the following Production Method 4. <Manufacturing method 4>

[0097] [ka]

[0098] [In the formula, R 2 , R 3 , R 4 , Y 1 , Y 2 and Hal 3 The definition of is the same as above. 3 and Y 4 are each independently CH, C-Alkyl 2 or N, Alkyl 1 and Alkyl 2 are each independently an optionally substituted C1-C6 alkyl group, and LG 2 is a bromo group, an iodo group, or a trifluoromethanesulfonyloxy group.

[0099] (Step 4-1) In (step 4-1), compound (4-1) and compound (4-2) are subjected to a substitution reaction in the presence of a base to produce compound (4-3). Examples of the base include the bases described in (Step 2-1), and preferred are sodium hydride, tripotassium phosphate, and potassium tert-butoxide. Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and xylene; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, and DMSO; and mixed solvents thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out at 0° C. to 100° C. The reaction time is not particularly limited, and is preferably 0.5 to 24 hours.

[0100] Compound (5-5), which is one of the compounds (4-1), can be produced, for example, by the following Production Method 5. <Manufacturing method 5>

[0101] [ka]

[0102] [In the formula, R 2 , R 3 , Y 1 , Y 2 , Hal 3 and Alkyl 2 The definition of is the same as above. 3 is an optionally substituted C1-C3 alkyl group.

[0103] (Step 5-1) In (Step 5-1), compound (5-2) can be produced by subjecting compound (5-1) to a carbamate reaction with 4-nitrophenyl chloroformate in the presence of a base. Examples of the base include the bases described in (Step 2-2). Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; and mixed solvents thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out at 0° C. to 100° C. The reaction time is not particularly limited, and is preferably 0.5 to 24 hours.

[0104] (Step 5-2) In (Step 5-2), compound (5-3) can be produced by subjecting compound (5-2) to an addition-elimination reaction with hydrazine or hydrazine monohydrate in the presence or absence of a base. Examples of the base include the bases described in (Step 2-2). Examples of the reaction solvent include the solvents described in (Step 5-1). The reaction temperature is not particularly limited, and the reaction is usually carried out at 0° C. to 100° C. The reaction time is not particularly limited, and is preferably 0.5 to 24 hours.

[0105] (Step 5-3) In (Step 5-3), compound (5-5) can be produced by subjecting compound (5-3) and compound (5-4) to triazolone cyclization reaction in the presence of an acid. Examples of acids include, but are not limited to, paratoluenesulfonic acid. Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as hexane and heptane; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, normal butyl alcohol, and tert-butyl alcohol, and mixed solvents thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out at 0° C. to 100° C. The reaction time is not particularly limited, and is preferably 0.5 to 24 hours.

[0106] Compound (6-3), which is one of the compounds (3-1), can be produced, for example, by the following Production Method 6. <Manufacturing method 6>

[0107] [ka]

[0108] [In the formula, R 3 , Y 1 , Y 2 and Hal 3 The definition of is the same as above. 4 is an optionally substituted C1-C6 alkyl group.

[0109] (Step 6-1) In (step 6-1), compound (6-1) and compound (6-2) are subjected to an oxa-Pictet-Spengler reaction in the presence of an acid to produce compound (6-3). Acids include, but are not limited to, hydrochloric acid, sulfuric acid, trifluoroacetic acid, titanium (IV) chloride, boron trifluoride, and the like. Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as hexane and heptane; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butyl alcohol; nitromethane; water, and mixed solvents thereof. Furthermore, the reaction may be carried out under solvent-free conditions. The reaction temperature is not particularly limited, and the reaction is usually carried out at 0° C. to 100° C. The reaction time is not particularly limited, and is preferably 1 hour to 100 hours.

[0110] Compound (7-3), which is one of the compounds (3-1), can be produced, for example, by the following Production Method 7. <Manufacturing method 7>

[0111] [ka]

[0112] [In the formula, R 2 , R 3 , Y 1 , Y 2 and Hal 3 The definition of is the same as above. 5 and Alkyl 6 are each independently a hydrogen atom or an optionally substituted C1-C6 alkyl group.

[0113] (Step 7-1) In (Step 7-1), compound (7-3) can be produced by subjecting compound (7-1) and compound (7-2) to a lactam cyclization reaction in the presence of phenylsilane and indium acetate. The lactam cyclization reaction can be carried out, for example, according to the method described in Angewandte Chemie - International Edition 2016, 55, pp. 1864-1867.

[0114] Compound (8-2), which is one of the compounds (1-2), can be produced, for example, by the following Production Method 8. <Manufacturing method 8>

[0115] [ka]

[0116] [In the formula, R 2 , R 3 , Y 1 and Y 2The definition of is the same as above. 1 R is an amino group which may have a substituent, or an alkoxy group which may have a substituent. 2 and Het 1 may be joined together with the carbon atom to which they are attached to form a ring which may have a substituent.

[0117] (Step 8-1) In (Step 8-1), the compound (8-1) is subjected to a Duff reaction using an acid and hexamethylenetetramine to produce the compound (8-2). Examples of acids include, but are not limited to, acetic acid; trifluoroacetic acid; methanesulfonic acid; trifluoromethanesulfonic acid, and the like. The reaction solvent includes halogenated hydrocarbons such as dichloromethane; alcohols such as ethanol; water; and mixtures thereof. Alternatively, the reaction may be carried out without a solvent. The reaction temperature is not particularly limited, and the reaction is usually carried out at 0° C. to 100° C. The reaction time is not particularly limited, and is preferably 0.5 to 24 hours.

[0118] Compound (9-3), which is one of the compounds (1-2), can be produced, for example, by the following Production Method 9. <Manufacturing method 9>

[0119] [ka]

[0120] [In the formula, R 2 , R 3 , Y 1 and Y 2 The definition of is the same as above. 4 is a chloro group, a bromo group, or an iodo group. 7 is an optionally substituted C1-C6 alkyl group, and Alkyl 8 is a hydrogen atom or an optionally substituted C1-C6 alkyl group, and Alkyl7 and Alkyl 8 may be joined together with the carbon atom to which they are attached to form a ring which may have a substituent.

[0121] (Step 9-1) In (step 9-1), compound (9-1) and compound (9-2) are subjected to Goldberg amination in the presence of a copper catalyst and a base to produce compound (9-3). Copper catalysts include, but are not limited to, copper(I) iodide, copper(I) chloride, copper(II) chloride, copper(I) oxide, copper(I) thiocyanate, copper(II) sulfate pentahydrate, copper(II) acetate, copper(II) acetylacetonate, and the like. Examples of the base include, but are not limited to, metal bases such as potassium carbonate, sodium carbonate, cesium carbonate, tripotassium phosphate, potassium tert-butoxide, and sodium tert-butoxide. To facilitate the reaction, an additive may be present, such as N,N'-dimethylethylenediamine. Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as toluene; ethers such as THF and 1,4-dioxane; aprotic polar solvents such as DMF and N-methylpyrrolidone; and mixed solvents thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature to 150° C. The reaction time is not particularly limited, and is preferably 0.5 to 24 hours.

[0122] Compound (10-3), which is one of the compounds (1-6), and compound (10-6), which is one of the compounds (1-3), can be produced, for example, by Production Method 10 shown below. <Manufacturing method 10>

[0123] [ka]

[0124] [In the formula, R 1 , R2 , R 3 , R 4 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Hal 1 and Hal 3 The definition of is the same as above. 2 is a boronic acid or boronic ester, and Alkyl 9 is a methyl group, an ethyl group, or a benzyl group.

[0125] (Process 10-1A-1) In (Step 10-1A-1), the compound (10-2) can be produced by subjecting the compound (10-1) to a boronation reaction using a boric acid ester in the presence of LDA. Examples of borate esters include, but are not limited to, trimethyl borate, triethyl borate, triisopropyl borate, and the like. Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as toluene; ethers such as THF and 1,4-dioxane; and mixed solvents thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out at −78° C. to room temperature. The reaction time is not particularly limited, and is preferably 0.5 to 24 hours.

[0126] (Process 10-1A-2) In (Step 10-1A-2), compound (10-5) can be produced by subjecting compound (10-2) and compound (3-1) to Suzuki-Miyaura coupling reaction in the same manner as in Step (1-C).

[0127] (Process 10-1B-1) In (Step 10-1B-1), compound (10-3) can be produced by subjecting compound (3-1) and bis(pinacolato)diboron to Miyaura boration reaction in the presence of a palladium catalyst and potassium acetate. Examples of the palladium catalyst include the palladium catalysts described in Production Method 1 (Step 1-C). To facilitate the reaction, additives may be present, such as those described in Production Method 1 (Step 1-C). Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and xylene; aliphatic hydrocarbons such as hexane and heptane; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, and DMSO; and mixed solvents thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out at 80 to 150° C. The reaction time is not particularly limited, and is preferably 0.1 to 24 hours.

[0128] (Process 10-1B-2) In step 10-1B-2, compound (10-5) can be produced by subjecting compound (10-3) and compound (10-4) to Suzuki-Miyaura coupling reaction in the same manner as in (step 1-C) of production method 1.

[0129] (Step 10-2) In the step (10-2), the compound (10-5) is subjected to hydrolysis in the presence of a base to produce the compound (10-6). Examples of the base include lithium hydroxide, sodium hydroxide, and potassium hydroxide. Examples of reaction solvents include, but are not limited to, ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, 2-propanol, and tert-butyl alcohol; water; and mixed solvents thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out at 0° C. to 100° C. The reaction time is not particularly limited, and is preferably 0.5 to 24 hours.

[0130] The compound (10-6) can also be produced, for example, by the following Production Method 11. <Manufacturing method 11>

[0131] [ka]

[0132] [In the formula, R 1 , R 2 , R 3 , R 4 , X 2 , X 3 , X 4 , Y 1 and Y 2 The definition of is the same as above. 1 is an optionally substituted phenyl group.

[0133] (Step 11-1) In (Step 11-1), the compound (11-1) is subjected to catalytic reduction in the presence of a transition metal catalyst and hydrogen to produce the compound (10-6). The reaction may be carried out under the same reaction conditions as those described in Production Method 2 (Step 2-3A).

[0134] The compound (10-4) can be produced, for example, by the following Production Method 12. <Manufacturing method 12>

[0135] [ka]

[0136] [In the formula, R 1 , R 2 , R 3 , R 4 , X 2 , X 3 , X 4 , Y 1 , Y 2, Hal 1 and Alkyl 9 The definition of is the same as above. 5 is a chloro group, a bromo group, or an iodo group. 3 is a leaving group such as a chloro group, a bromo group, an iodo group, or a trifluoromethanesulfonyloxy group, and PG 1 is a protecting group selected from a carbamate protecting group such as a Boc group; an amide protecting group such as an acetyl group; a sulfonamide protecting group such as a paratoluenesulfonyl group, and the like.

[0137] (Step 12-1) In (Step 12-1), compound (12-2) can be produced by subjecting compound (12-1) and trimethylsilylacetylene to Sonogashira coupling reaction in the presence of a palladium catalyst and a base. Examples of the palladium catalyst include the palladium catalysts described in (Step 1-C). Examples of the base include the bases described in (Step 1-C). To facilitate the reaction, an additive may be present. Examples of the additive include the additives described in (Step 1-C) and copper salts such as copper(I) iodide. These additives may be used alone or in combination. Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as hexane and heptane; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, and DMSO; alcohols such as methanol and ethanol; and mixed solvents thereof.

[0138] (Step 12-2) In (Step 12-2), compound (12-2) is subjected to an indole cyclization reaction in the presence of a base or a transition metal catalyst to produce compound (12-3). Bases include, but are not limited to, sodium tert-butoxide, sodium hydride, and the like. Examples of transition metal catalysts include, but are not limited to, copper salts such as copper(I) iodide, silver complexes such as silver bis(trifluoromethanesulfonyl)imide, and gold salts such as chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)gold(I) and chloro(triphenylphosphine)gold(I). These catalysts may also be used in combination. Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as hexane and heptane; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, and DMSO; alcohols such as methanol and ethanol; acetonitrile, and mixed solvents thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature to 150° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

[0139] (Step 12-3) In (step 12-3), compound (12-5) can be produced by subjecting compound (12-3) and compound (12-4) to a substitution reaction in the presence of a base. Examples of the base include the bases described in step (1-B). Examples of the reaction solvent include the reaction solvents described in step (1-B). The reaction temperature is not particularly limited, and the reaction is usually carried out at 0° C. to 150° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

[0140] (Step 12-4) In (step 12-4), compound (12-5) is subjected to a halogenation reaction using LDA and a halogenating agent to produce compound (10-4). Examples of halogenating agents include iodinating agents such as N-iodosuccinimide, N-iodophthalimide, N-iodosaccharin, 1,3-diiodo-5,5-dimethylhydantoin, and iodine; brominating agents such as N-bromosuccinimide, N-bromophthalimide, N-bromosaccharin, 1,3-dibromo-5,5-dimethylhydantoin, carbon tetrabromide, and bromine; and chlorinating agents such as N-chlorosuccinimide, N-chlorophthalimide, N-chlorosaccharin, and 1,3-dichloro-5,5-dimethylhydantoin. Reaction solvents include, but are not limited to, ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane. The reaction temperature is not particularly limited, and the reaction is usually carried out at −78° C. to room temperature. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

[0141] (Step 12-5) In (Step 12-5), the compound (12-7) can be produced by subjecting the compound (12-6) and the compound (12-4) to a substitution reaction in the same manner as in (Step 12-3).

[0142] (Step 12-6) In (step 12-6), compound (12-5) can be produced by subjecting compound (12-7) to an esterification reaction using n-butyllithium and compound (12-8). Reaction solvents include, but are not limited to, ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, and MTBE. The reaction temperature is not particularly limited, and the reaction is usually carried out at −78° C. to room temperature. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

[0143] (Step 12-7) In step 12-7, the nitrogen forming the azole ring of compound (12-3) is protected by a protecting group PG 1 Compound (12-9) can be prepared by protecting the aryl group with . This reaction can be carried out according to methods well known to those skilled in the art (e.g., the method described in "Protective Groups in Organic Synthesis" by Green and Wuts, 5th ed., 2014).

[0144] (Step 12-8) In (Step 12-8), compound (12-9) is subjected to a halogenation reaction in the same manner as in (Step 12-4), to produce compound (12-10).

[0145] (Step 12-9) In step 12-9, compound (12-10) is reacted with a protecting group PG 1 Compound (12-11) can be produced by subjecting the resulting compound to a deprotection reaction to remove the following: Such a deprotection reaction may be carried out in accordance with a method well known to those skilled in the art (for example, the method described in "Protective Groups in Organic Synthesis" by Green and Wuts, 5th edition, 2014).

[0146] (Step 12-10) In (Step 12-10), the compound (10-4) can be produced by subjecting the compound (12-11) and the compound (12-4) to a substitution reaction in the same manner as in (Step 12-3).

[0147] The compound (10-5) can also be produced, for example, by the following Production Method 13. <Manufacturing method 13>

[0148] [ka]

[0149] [In the formula, R 1 , R 2 , R 3 , R 4 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Hal 1 , Hal 5 , L.G. 3 and Alkyl 9 The definitions are the same as above.]

[0150] (Step 13-1) In (Step 13-1), the compound (13-1) can be produced by subjecting the compound (3-1) and trimethylsilylacetylene to Sonogashira coupling reaction in the same manner as in (Step 12-1).

[0151] (Step 13-2) In step 13-2, compound (13-1) is subjected to a detrimethylsilylation reaction to produce compound (13-2). This detrimethylsilylation reaction may be carried out in accordance with methods well known to those skilled in the art (e.g., the method described in "Protective Groups in Organic Synthesis" by Green and Wuts, 5th edition, 2014).

[0152] (Step 13-3) In (Step 13-3), the compound (13-2) and the compound (12-1) are subjected to a Sonogashira coupling reaction in the same manner as in (Step 12-1), thereby producing the compound (13-3).

[0153] (Step 13-4) In (step 13-4), compound (13-4) can be produced by subjecting compound (13-3) to an indole cyclization reaction in the presence of a transition metal catalyst. Examples of transition metal catalysts include, but are not limited to, copper salts such as copper(I) iodide; silver complexes such as silver bis(trifluoromethanesulfonyl)imide; and gold salts such as chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)gold(I) and chloro(triphenylphosphine)gold(I). Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as hexane and heptane; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol and ethanol, and mixed solvents thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature to 150° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

[0154] (Step 13-5) In (Step 13-5), the compound (10-5) can be produced by subjecting the compound (13-4) and the compound (12-4) to a substitution reaction in the same manner as in (Step 12-3).

[0155] (Step 13-6) In (Step 13-6), compound (13-6) can be produced by subjecting compound (13-5) and compound (2-2) to an aromatic nucleophilic substitution reaction in the same manner as in (Step 2-1).

[0156] (Step 13-7) In (Step 13-7), the compound (13-7) can be produced by subjecting the compound (13-6) and the compound (13-2) to a Sonogashira coupling reaction in the same manner as in (Step 12-1).

[0157] (Step 13-8) In (Step 13-8), compound (10-5) can be produced by subjecting compound (13-7) to an indole cyclization reaction in the same manner as in (Step 13-4).

[0158] The compound (13-4) can also be produced, for example, by the following Production Method 14. <Manufacturing method 14>

[0159] [ka]

[0160] [In the formula, R 1 , R 2 , R 3 , R 4 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Hal 1 , P.G. 1 , M 2 and Alkyl 9 The definitions are the same as above.]

[0161] (Step 14-1) In (Step 14-1), the compound (12-9) is subjected to a boronation reaction in the same manner as in (Step 10-1A-1), thereby producing the compound (14-1).

[0162] (Step 14-2) In (Step 14-2), compound (14-1) is converted into a protecting group PG by the same method as in (Step 12-9). 1 Compound (14-2) can be prepared by subjecting the compound to a deprotection reaction to remove the protective group.

[0163] (Step 14-3) In (Step 14-3), compound (13-4) can be produced by subjecting compound (14-2) and compound (3-1) to Suzuki-Miyaura coupling reaction in the same manner as in (Step 1-C).

[0164] Compound (15-2), which is one of the compounds (1-3), can be produced, for example, by Production Method 15 shown below. <Manufacturing method 15>

[0165] [ka]

[0166] [In the formula, R 1 , R 2 , R 3 , R 4 , X 2 , X 3 , X 4 , Y 1 , Y 2 and Alkyl 9 The definitions are the same as above.]

[0167] (Step 15-1) In (step 15-1), compound (15-1) can be produced by subjecting compound (13-7) to indole cyclization reaction in the presence of copper(I) iodide. Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as hexane and heptane; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol and ethanol; and mixed solvents thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature to 150° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

[0168] (Step 15-2) In (Step 15-2), the compound (15-1) is subjected to a hydrolysis reaction in the same manner as in (Step 10-2), thereby producing the compound (15-2).

[0169] Compound (16-2), which is one of the compounds (1-3), can be produced, for example, by the following Production Method 16. <Manufacturing method 16>

[0170] [ka]

[0171] [In the formula, R 1 , R 2 , R 3 , R 4 , X 2 , X 3 , X 4 , Y 1 and Y 2 The definitions are the same as above.]

[0172] (Step 16-1) In (Step 16-1), compound (16-1) can be produced by subjecting compound (2-3) to a reduction reaction of the nitro group in the same manner as in (Step 2-3A) or (Step 2-3B) of Production Method 2.

[0173] (Step 16-2) In (Step 16-2), compound (16-2) can be produced by subjecting compound (16-1) to a cyclization reaction with compound (1-2) in the same manner as in (Step 1-A) of Production Method 1.

[0174] Compound (17-1), which is one of the compounds (1-3), can be produced, for example, by the following Production Method 17. <Manufacturing method 17>

[0175] [ka]

[0176] [In the formula, R 1 , R 2 , R 3 , R 4 , X 2 , X 3 , X 4 , Y 1 , Y 2 and Alkyl 9 The definitions are the same as above.]

[0177] (Step 17-1) In step 17-1, a reducing agent is used to convert the alkoxycarbonyl group (-CO2Alkyl) of compound (10-5) into 9 ) to a hydroxymethyl group to produce compound (17-1). Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, isobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, and the like. Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and xylene; alcohols such as methanol, ethanol, 2-propanol, and tert-butanol; ethers such as diethyl ether, THF, and 1,4-dioxane; and mixed solvents thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out at 0° C. to 100° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

[0178] Compound (18-1), which is one of the compounds (1-3), can be produced, for example, by the following Production Method 18. <Manufacturing method 18>

[0179] [ka]

[0180] [In the formula, R 1 , R 2 , R 3 , R 4 , X 2 , X 3 , X 4 , Y 1 and Y 2 The definitions are the same as above.]

[0181] (Step 18-1) In (Step 18-1), the hydroxymethyl group of compound (17-1) is converted to a chloromethyl group using methanesulfonyl chloride in the presence of a base to produce compound (18-1). Examples of the base include organic bases such as triethylamine, diisopropylethylamine, pyridine, and 4-(N,N-dimethylamino)pyridine. Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; and mixed solvents thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out at 0° C. to 50° C. The reaction time is not particularly limited, and is preferably 0.5 to 24 hours.

[0182] Compound (19-5), which is one of the compounds (1-3), can be produced, for example, by the following Production Method 19. <Manufacturing method 19>

[0183] [ka]

[0184] [In the formula, R 1 , R 2 , R 3 , R 4 , X 2 , X 3 , X 4 , Y 1 , Y 2 and Alkyl 9 The definition of is the same as above. 5 is a bromo group or an iodo group, and M 3 are boronic acids and boronic acid-related structures such as B(OH)2, B(OMe)2, B(pin), B(MIDA), and BF3K.]

[0185] (Step 19-1) In (Step 19-1), compound (19-1) can be produced by subjecting compound (12-5) to a chlorination reaction using a chlorinating agent. Examples of the chlorinating agent include N-chlorosuccinimide, N-chlorophthalimide, N-chlorosaccharin, and 1,3-dichloro-5,5-dimethylhydantoin. Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, and DMSO; and mixed solvents thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out at 0° C. to 100° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

[0186] (Step 19-2) In (step 19-2), compound (19-1) is subjected to a halogenation reaction using a halogenating agent to produce compound (19-2). Examples of halogenating agents include iodinating agents such as N-iodosuccinimide, N-iodophthalimide, N-iodosaccharin, and 1,3-diiodo-5,5-dimethylhydantoin; and brominating agents such as N-bromosuccinimide, N-bromophthalimide, N-bromosaccharin, 1,3-dibromo-5,5-dimethylhydantoin, and bromine. Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, and DMSO; and mixed solvents thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out at 0° C. to 100° C. The reaction time is not particularly limited, and is preferably 1 hour to 24 hours.

[0187] (Step 19-3) In (step 19-3), compound (19-4) can be produced by subjecting compound (19-2) and compound (19-3) to Suzuki-Miyaura coupling reaction in the same manner as in (step 1-C) of production method 1.

[0188] (Step 19-4) In (step 19-4), compound (19-4) is subjected to hydrolysis in the same manner as in (step 10-2) of production method 10, to produce compound (19-5).

[0189] Compound (20-2), which is one of compounds (1-5), can be produced, for example, by the following Production Method 20. <Manufacturing method 20>

[0190] [ka]

[0191] [In the formula, R 4 , X 2 , X 3 , X 4 , Hal 1 , Alkyl 9 and ring A are defined as above.]

[0192] (Step 20-1) In (step 20-1), compound (10-4) is subjected to hydrolysis reaction in the same manner as in (step 10-2) of production method 10, thereby compound (20-1) can be produced.

[0193] (Step 20-2) In (step 20-2), the compound (20-1) and the compound (2-4) are subjected to a condensation reaction in the same manner as in (step 2-2) of Production Method 2, thereby producing the compound (20-2).

[0194] Compound (21-4), which is one of the compounds (2-4), can be produced, for example, by the method shown in Production Method 21. <Manufacturing method 21>

[0195] [ka]

[0196] [In the formula, Ar 2 PG is an optionally substituted phenyl group or an optionally substituted 5- or 6-membered heteroaryl group. 2 is a protecting group for an amino group, for example, a carbamate protecting group such as a Boc group, a Cbz group, or an Fmoc group; an amide protecting group such as a trifluoroacetyl group; etc. 17 and R 18 are each independently a hydrogen atom, an optionally substituted C1-C6 alkyl group, an optionally substituted phenyl group, or an optionally substituted 5- to 6-membered heteroaryl group.

[0197] (Step 21-1) In (step 21-1), compound (21-3) can be produced by subjecting compound (21-1) and compound (21-2) to a condensation reaction in the same manner as in (step 2-2) of production method 2.

[0198] (Step 21-2) In step 21-2, compound (21-3) is reacted with a protecting group PG 2 Compound (21-4) can be produced by subjecting the resulting compound to a deprotection reaction to remove the following: Such a deprotection reaction may be carried out in accordance with a method well known to those skilled in the art (for example, the method described in "Protective Groups in Organic Synthesis" by Green and Wuts, 5th edition, 2014).

[0199] Compound (22-1), which is one of the compounds (I), can be further converted into functional groups by, for example, the method shown in Production Method 22. <Manufacturing method 22>

[0200] [ka]

[0201] [In the formula, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Q 1 , Q 2 , Ar 2 , R 17 and R 18 The definition of is the same as above. 10 is an optionally substituted C1-C6 alkyl group.

[0202] (Step 22-1) In (step 22-1), compound (22-2) can be produced by subjecting compound (22-1) to hydrolysis reaction in the same manner as in (step 10-2) of production method 10.

[0203] (Step 22-2) In (step 22-2), the compound (22-2) and the compound (21-2) are subjected to a condensation reaction in the same manner as in (step 2-2) of Production Method 2, thereby producing the compound (22-3).

[0204] Compound (23-1), which is one of the compounds (I), can be further converted into functional groups by, for example, the method shown in Production Method 23. <Manufacturing method 23>

[0205] [ka]

[0206] [In the formula, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Q 1 , Q 2 and Ar 2 The definition of is the same as above. 19 is an optionally substituted C1-C6 alkyl group, an optionally substituted phenyl group, or an optionally substituted 5- to 6-membered heteroaryl group.

[0207] (Step 23-1) In (Step 23-1), a compound (23-3) can be produced by a sulfonylation reaction using a compound (23-1) and a compound (23-2) in the presence of a base. Examples of the base include the bases described in Production Method 2 (Step 2-2). Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; and mixed solvents thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out at 0° C. to 100° C. The reaction time is not particularly limited, and is preferably 0.5 to 24 hours.

[0208] Compound (24-1), which is one of the compounds (I), can be further converted into functional groups by, for example, the method shown in Production Method 24. <Manufacturing method 24>

[0209] [ka]

[0210] [In the formula, R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Q 1 , Q 2 and ring A are the same as defined above. 11 is an optionally substituted C1-C6 alkyl group. 3 is an optionally substituted C1-C3 alkyl group, and Q 3 and R 2 R may be taken together with the carbon atom to which they are attached to form an optionally substituted non-aromatic heterocyclic group. 20 and R 21 are each independently a hydrogen atom or an optionally substituted C1-C6 alkyl group.

[0211] (Step 24-1) In (step 24-1), compound (24-2) can be produced by subjecting compound (24-1) to hydrolysis reaction in the same manner as in (step 10-2) of production method 10.

[0212] (Step 24-2) In (step 24-2), compound (24-2) and compound (24-3) are subjected to a condensation reaction in the same manner as in (step 2-2) of production method 2, to produce compound (24-4).

[0213] Compound (25-1), which is one of the compounds (I), can be further converted into functional groups by, for example, the method shown in Production Method 25. <Manufacturing method 25>

[0214] [ka]

[0215] [In the formula, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Q 1 , Q 2 and ring A are the same as defined above. 6 is a chloro group, a bromo group, or an iodo group. 22 , R 23 , R 24 and R 25 are each independently an optionally substituted C1-C6 alkyl group, and R 22 and R 23 may form, together with the carbon atom to which they are attached, an optionally substituted cycloalkyl group. 1 is an optionally substituted phenyl group or an optionally substituted cyclopropyl group. 4are boronic acids and boronic acid-related structures such as B(OH)2, B(OMe)2, B(pin), B(MIDA), and BF3K.

[0216] (Step 25-1) In (Step 25-1), compound (25-1) and compound (25-2) are subjected to Suzuki-Miyaura coupling reaction in the same manner as in (Step 1-C) of Production Method 1, to produce compound (25-3).

[0217] (Step 25-2) In (step 25-2), compound (25-3) is subjected to catalytic reduction in the presence of a transition metal catalyst and hydrogen to produce compound (25-4). The reaction may be carried out under the same reaction conditions as those described in Production Method 2 (Step 2-3A).

[0218] (Step 25-3) In (step 25-3), compound (25-1) and compound (25-5) are subjected to Sonogashira coupling reaction in the same manner as in (step 12-1) of production method 12, to produce compound (25-6).

[0219] (Step 25-4) In (Step 25-4), the compound (25-6) is subjected to catalytic reduction in the same manner as in (Step 25-2), to produce the compound (25-7).

[0220] (Step 25-5) In (step 25-5), compound (25-1) and trimethylsilylacetylene are subjected to Sonogashira coupling reaction in the same manner as in (step 12-1) of Production Method 12, to thereby produce compound (25-8).

[0221] (Step 25-6) In step 25-6, compound (25-8) is subjected to a detrimethylsilylation reaction to produce compound (25-9). This detrimethylsilylation reaction may be carried out according to methods well known to those skilled in the art (e.g., the method described in "Protective Groups in Organic Synthesis" by Green and Wuts, 5th edition, 2014).

[0222] (Step 25-7) In (step 25-7), compound (25-1) and compound (25-10) are subjected to Suzuki-Miyaura coupling reaction in the same manner as in (step 1-C) of production method 1 to produce compound (25-11).

[0223] Compound (26-1), which is one of the compounds (25-3), can be further converted into functional groups by, for example, the method shown in Production Method 26. <Manufacturing method 26>

[0224] [ka]

[0225] [In the formula, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Q 1 , Q 2 and ring A are defined as above. 26 is an optionally substituted C1-C6 alkyl group.

[0226] (Step 26-1) In (step 26-1), compound (26-2) can be produced by subjecting compound (26-1) to a double bond cleavage reaction in the same manner as in (step 3-2) of production method 3.

[0227] (Step 26-2) In (step 26-2), the formyl group of compound (26-2) is reduced to a hydroxymethyl group using a reducing agent to produce compound (26-3). The reducing agent includes sodium borohydride, lithium borohydride, and the like. Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and xylene; alcohols such as methanol, ethanol, 2-propanol, and tert-butanol; ethers such as diethyl ether, THF, and 1,4-dioxane; and mixed solvents thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out at 0° C. to 100° C. The reaction time is not particularly limited, and is preferably 0.5 to 24 hours.

[0228] (Step 26-3) In (step 26-3), the hydroxymethyl group of compound (26-3) is converted to a chloromethyl group by a method similar to that in (step 18-1) of Production Method 18, whereby compound (26-4) can be produced.

[0229] (Step 26-4) In (step 26-4), the chloro group of compound (26-4) is substituted with a cyano group using a cyanide to produce compound (26-5). Cyanides include sodium cyanide, potassium cyanide, and the like. Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and xylene; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, and DMSO; and mixed solvents thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out at 0° C. to 100° C. The reaction time is not particularly limited, and is preferably 0.5 to 24 hours.

[0230] (Step 26-5) In (step 26-5), the chloro group of compound (26-4) is substituted with an alkoxy group using compound (26-6), thereby producing compound (26-7). The reaction solvent is a compound of the formula (R 26 Alcohols represented by the formula (—OH) are preferred. The reaction temperature is not particularly limited, and the reaction is usually carried out at 0° C. to 100° C. The reaction time is not particularly limited, and is preferably 0.5 to 24 hours.

[0231] Compound (27-1), which is one of the compounds (I), can be further converted into functional groups by, for example, the method shown in Production Method 27. <Manufacturing method 27>

[0232] [ka]

[0233] [In the formula, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Q 1 , Q 2 and ring A are the same as defined above. 7 is a chloro group, a bromo group, or an iodo group.

[0234] (Step 27-1) In (Step 27-1), the compound (27-1) is subjected to catalytic reduction in the presence of a transition metal catalyst and hydrogen to produce the compound (27-2). The reaction may be carried out under the same reaction conditions as those described in Production Method 2 (Step 2-3A).

[0235] The compound of general formula (I) contained in the pharmaceutical composition of the present invention produced by the above-mentioned method may be a free compound, a salt thereof, or various solvates such as a hydrate or ethanolate thereof, and these compounds may be isolated and purified as an oily substance, an amorphous substance, or a substance consisting of any crystalline polymorph. Pharmaceutically acceptable salts of the compound of general formula (I) contained in the pharmaceutical composition of the present invention may be produced by a conventional salt formation reaction. Isolation and purification may be carried out by applying chemical procedures such as extraction fractionation, crystallization, and various fractional chromatography. Furthermore, optical isomers may be obtained as stereochemically pure isomers by selecting appropriate starting compounds or by optical resolution of racemic compounds.

[0236] The compound of general formula (I) or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition of the present invention exhibits excellent STAT6 inhibitory activity. Therefore, the pharmaceutical composition of the present invention is useful as a preventive or therapeutic agent for diseases associated with STAT6 in mammals, including humans. Examples of diseases associated with STAT6 include inflammatory diseases and allergic diseases. Examples of inflammatory diseases and allergic diseases include chronic obstructive pulmonary disease, atopic dermatitis, bronchial asthma, bullous pemphigoid, nasal polyps, chronic sinusitis, allergic rhinitis, eosinophilic esophagitis, prurigo, and urticaria.

[0237] The pharmaceutical of the present invention comprises Compound (I) or a pharmaceutically acceptable salt thereof alone or in combination with a pharmaceutically acceptable liquid or solid pharmaceutical carrier, such as an excipient, binder, diluent, filler, disintegrant, stabilizer, preservative, buffer, emulsifier, flavoring agent, colorant, sweetener, thickener, flavoring agent, solubilizer, or other additive, and can be prepared by a conventional method in the art. The medicament of the present invention may be in any form of a solid composition, a liquid composition, or other composition, and the most suitable one can be selected according to the need.

[0238] The pharmaceutical composition of the present invention can be administered orally or parenterally to mammals (e.g., humans, monkeys, cows, horses, pigs, dogs, cats, rabbits, guinea pigs, rats, mice, etc.) in dosage forms such as tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules, oral liquids, injections, suppositories, sustained-release preparations, lotions, liniments, ointments, patches, suspensions, emulsions, transdermal preparations, topical liquids, creams, aerosols, etc. Other drugs may also be compounded as needed.

[0239] The administration route of the medicament of the present invention is not limited. When administered orally, dosage forms such as tablets, orally disintegrating tablets, capsules, granules, powders, oral liquids, syrups, oral jellies, and oral sprays can be prepared. These can be prepared by conventional methods in the relevant technical field. The dosage of the medicament of the present invention is not limited. For example, when administered orally to an adult patient, the active ingredient, the compound of the present invention, can be administered at a single dose of approximately 0.1 to 100 mg / kg, once or more per day. Example

[0240] The features of the present invention will be explained in more detail below with reference to examples and test examples. The materials, amounts used, ratios, treatment details, treatment procedures, etc. shown in the following examples can be changed as appropriate without departing from the spirit of the present invention. Therefore, the scope of the present invention should not be construed as being limited by the specific examples shown below.

[0241] In the following examples 1 H-NMR spectra and mass spectrometry were measured under the following conditions. 1When H-NMR data is provided, it was measured using an AVANCEIII HD400 (400 MHz, Bruker BioSpin) in deuterated chloroform (CDCl), deuterated dimethyl sulfoxide (DMSO-d), or deuterated methanol (CDOD) as the solvent and tetramethylsilane as the internal standard. 1 The measurement results of chemical shifts in H-NMR spectra are shown as δ values ​​in ppm and coupling constant J values ​​in Hz. The abbreviations s, d, t, q, m, br, and s represent singlet, doublet, triplet, triplet, quartet, multiplet, and broad, respectively.

[0242] LC / MS was measured using ESI (electrospray ionization) under the following conditions, and the [M+H] + " is ESI positive ion mode, " [MH] - " means ESI negative ion mode. In each chromatography and experimental procedure, "number / number" means the volume ratio of each solvent unless otherwise specified. Apparatus: Mass spectrometer (Exactive) (manufactured by Thermo Fisher Scientific Co., Ltd.) (LC part: nanospace SI-2 / NASCA (manufactured by Shiseido Co., Ltd.)) Column: None solvent: Solution A: Distilled water Solution B: Acetonitrile The mixture ratio of A and B liquids is fixed at 50 / 50. Flow rate: 0.2mL / min. Detector (wavelength): UV detector (254 nm)

[0243] The microwave reaction device used was an Initiator sixty manufactured by Biotage Japan Co., Ltd.

[0244] In the following figures, Ref.-numbers refer to Reference Synthesis Example compounds, and Ex.-numbers refer to Example compounds. Example numbers refer to the production of the Example compounds with the same numbers.

[0245] Example 1

[0246] [ka]

[0247] Process 1 Under ice cooling, Reference Synthesis Example Compound 1 (5.00 g, 18.5 mmol) and THF (90 mL) were mixed, and then potassium carbonate (4.10 g, 29.7 mmol) and an ethylamine / THF solution (2.0 mol / L, 12 mL) were added. The mixture was heated to 50°C and stirred for 4 hours. Water and a mixture of ethyl acetate and normal hexane (3 / 1) were added to the cooled reaction mixture, and the mixture was stirred, and the aqueous layer was separated. 2 mol / L hydrochloric acid (40 mL) was added to the separated aqueous layer, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give Reference Synthesis Example Compound 2 (yield 4.22 g). Process 2 Reference Synthesis Example Compound 2 (4.22 g, 15.2 mmol) and acetonitrile (80 mL) were mixed, and then 3-amino-2-fluorobenzamide (2.69 g, 17.5 mmol) and 1-methylimidazole (2.87 mL, 36.4 mmol) were added. The mixture was cooled on ice, and TCFH (5.11 g, 18.2 mmol) was added and stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the precipitate was collected by filtration. The resulting solid was purified by silica gel column chromatography to give Reference Synthesis Example Compound 3 (yield 5.56 g). Process 3 Reference Synthesis Example Compound 3 (1.05 g, 2.53 mmol) and methanol (50 mL) were mixed, 10% palladium / carbon (250 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The reaction mixture was filtered through Celite, and the solvent was distilled off under reduced pressure. A chloroform / methanol mixture was added to the residue, and the precipitated solid was collected by filtration (A). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (B). The collected solid A and the purified fraction B by column chromatography were combined to give Reference Synthesis Example Compound 4 (yield 910 mg). Process 4 Reference Synthesis Example Compound 5 (5.00 g, 20.8 mmol) and DMF (104 mL) were mixed, and then sodium hydride (60% in oil) (1.25 g, 31.3 mmol) was added and stirred for 10 minutes. Methyl iodide (2.6 mL, 42 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 23 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the precipitate was collected by filtration to obtain Reference Synthesis Example Compound 6 (yield 4.98 g). Process 5 Reference Synthesis Example Compound 6 (4.98 g, 19.6 mmol), potassium vinyltrifluoroborate (5.25 g, 39.2 mmol), cesium carbonate (12.8 g, 39.3 mmol), and 1,4-dioxane / water (5 / 1) (98 mL) were mixed and degassed. Bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (695 mg, 0.981 mmol) was added, and the mixture was stirred at 90°C under an argon atmosphere for 4 hours. The mixture was allowed to cool and filtered through Celite®. Water was added to the filtrate, which was extracted with ethyl acetate and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 7 (yield 2.04 g). Process 6 Under ice cooling, Reference Synthesis Example Compound 7 (2.04 g, 10.1 mmol) and 1,4-dioxane (101 mL) were mixed, followed by the addition of water (34 mL), 2,6-dimethylpyridine (2.35 mL, 20.2 mmol), sodium periodate (8.66 g, 40.5 mmol), and a 2.5 w / v% osmium tetroxide / tert-butyl alcohol solution (5.15 mL, 0.51 mmol) in that order, followed by stirring at room temperature for 2 hours. The reaction mixture was ice-cooled, and saturated aqueous sodium thiosulfate and water were added in that order, followed by extraction with ethyl acetate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 8 (yield 1.88 g). Process 7 Reference Synthesis Example Compound 4 (100 mg, 0.260 mmol) and ethanol (5 mL) were mixed, and then Reference Synthesis Example Compound 8 (69 mg, 0.34 mmol) and acetic acid (149 μL, 2.60 mmol) were added, followed by stirring at 85° C. for 18 hours under an oxygen atmosphere. A saturated aqueous solution of sodium bicarbonate was added to the cooled reaction mixture, and the precipitate was collected by filtration. The resulting solid was purified by silica gel column chromatography to give Example Compound 1 (yield 106 mg).

[0248] Example 2

[0249] [ka]

[0250] Process 1-A Reference Synthesis Example Compound 9 (1.00 g, 6.20 mmol) and TFA (5.2 mL) were mixed, and then hexamethylenetetramine (957 mg, 6.83 mmol) was added and stirred at 90°C for 24 hours. The reaction solution was allowed to cool, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 10 (yield 826 mg). Process 1-B Reference Synthesis Example Compound 2 (500 mg, 1.80 mmol) and methanol (20 mL) were mixed, and then 20% palladium hydroxide / carbon (50 mg, 0.071 mmol) was added, followed by stirring at room temperature under a hydrogen atmosphere (0.3 MPa) for 4 hours. The reaction mixture was filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 11 (yield 410 mg). Process 2 Reference Synthesis Example Compound 11 (100 mg, 0.403 mmol) and ethanol (4 mL) were mixed, and then Reference Synthesis Example Compound 10 (114 mg, 0.603 mmol) and acetic acid (231 μL, 4.03 mmol) were added, followed by stirring under an oxygen atmosphere at 70° C. for 2 hours. The reaction solution was allowed to cool, and the precipitated solid was collected by filtration and washed with methanol to give Reference Synthesis Example Compound 12 (yield 86.7 mg). Process 3 Reference Synthesis Example Compound 12 (15 mg, 0.0359 mmol) and acetonitrile (500 μL) were mixed, and then 3-amino-2-fluorobenzamide (6.6 mg, 0.043 mmol), 1-methylimidazole (7.0 μL, 0.089 mmol), and TCFH (12.2 mg, 0.0435 mmol) were added, followed by stirring at room temperature for 5 hours. Water was added to the reaction solution, and the precipitated solid was collected by filtration and washed with water. The resulting solid was purified by silica gel column chromatography to give Example Compound 2 (yield 5.7 mg).

[0251] Examples 3 to 10 Example compounds 3 to 10 were produced according to the methods shown in Examples 1 and 2 above or Examples 11 to 14 below, or methods similar thereto.

[0252] Example 11

[0253] [ka]

[0254] Process 1 To a mixture of Reference Synthesis Example Compound 13 (246 mg, 1.06 mmol), 3,5-dimethylpyrrolidin-2-one (100 mg, 0.884 mmol), copper(I) iodide (8.4 mg, 0.044 mmol), and tripotassium phosphate (375 mg, 1.77 mmol), 1,4-dioxane (8 mL) and N,N'-dimethylethylenediamine (10 μL, 0.093 mmol) were added, and the mixture was stirred at 120°C for 14 hours under an argon atmosphere. The reaction mixture was allowed to cool, and water and ethyl acetate were added. The mixture was stirred, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and simultaneously the diastereomers were separated to give Reference Synthesis Example Compound 14 (the first peak diastereomer) (yield 101 mg) and Reference Synthesis Example Compound 15 (the second peak diastereomer) (yield 80.2 mg). Process 2 Reference Synthesis Example Compound 2 (1.50 g, 5.39 mmol) and acetonitrile (25 mL) were mixed, and then 3-aminobenzamide (881 mg, 6.47 mol), 1-methylimidazole (1.02 mL, 12.9 mmol), and TCFH (1.82 g, 6.49 mmol) were added and stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the precipitated solid was collected by filtration to give Reference Synthesis Example Compound 16 (yield 1.76 g). Process 3 Reference Synthesis Example Compound 16 (156 mg, 0.394 mmol) and methanol (3.9 mL) were mixed, and then 20% palladium hydroxide on carbon (15.6 mg) was added and stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 17 (yield 133 mg). Process 4 To a solution of Reference Synthesis Example Compound 17 (15 mg, 0.041 mmol) in ethanol (1 mL), Reference Synthesis Example Compound 15 (10 mg, 0.046 mmol) and acetic acid (23 μL) were added, and the mixture was stirred at 80° C. for 17 hours under an oxygen atmosphere. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the precipitate was collected by filtration. The resulting solid was purified by silica gel column chromatography to give Example Compound 11 (yield 16.8 mg).

[0255] Examples 12 and 13

[0256] [ka]

[0257] Process 1 A preparative LC system (LC-Forte / R, manufactured by YMC Co., Ltd.) was equipped with a preparative chiral column (CHIRALPAK IC, manufactured by Daicel Corporation) and equilibrated by passing an ethanol / normal hexane (1 / 1) mixture through the column at room temperature at a flow rate of 8.0 mL / min. Example compound 11 (12.0 mg, 0.0213 mmol) in ethanol (7 mL) was dissolved to give solution A. Solution A (3.5 mL) was injected, and the first peak (retention time: approximately 18 minutes) and the second peak (retention time: approximately 19 minutes) were separated while observing with a UV detector (detection wavelength: 254 nm) (this procedure was performed twice). The solvent contained in each fraction was distilled off under reduced pressure to give Example compound 12 (yield: 5.8 mg) from the fraction derived from the first peak, and Example compound 13 (yield: 5.1 mg) from the fraction derived from the second peak.

[0258] Example 14

[0259] [ka]

[0260] Process 1 Reference Synthesis Example Compound 18 (3.00 g, 10.8 mmol) and THF (54 mL) were mixed, and then potassium carbonate (2.39 g, 17.3 mmol) and 2-methoxyethylamine (1.2 mL, 14 mmol) were added, followed by stirring at room temperature for 3 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give Reference Synthesis Example Compound 19 (yield 3.65 g), partially containing impurities. Process 2 Reference Synthesis Example Compound 19 (3.65 g), which was obtained by the method described in Step 1 and contained impurities, was mixed with methanol (110 mL), and then 4 mol / L aqueous sodium hydroxide solution (21 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was ice-cooled, and 6 mol / L hydrochloric acid was added, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give Reference Synthesis Example Compound 20 (yield 3.47 g) in a partially impure state. Process 3 Reference Synthesis Example Compound 20 (3.47 g) containing impurities obtained by the method described in Step 2 was mixed with acetonitrile (54.4 mL), and then 3-aminobenzamide (1.78 g, 13.1 mmol), 1-methylimidazole (2.1 mL, 27 mmol), and TCFH (3.66 g, 13.0 mmol) were added and stirred at room temperature for 18 hours. Water was added to the reaction solution, and the precipitated solid was collected by filtration and washed with water to give Reference Synthesis Example Compound 21 (yield 4.53 g). Process 4 Reference Synthesis Example Compound 21 (4.45 g, 10.1 mmol) and ethanol (101 mL) were mixed, and then acetic acid (5.8 mL) and reduced iron (2.83 g, 50.6 mmol) were added and stirred at 50°C for 20 hours. The reaction solution was allowed to cool and then filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 22 (yield 1.68 g). Process 5 Reference Synthesis Example Compound 22 (1.15 g, 2.81 mmol) and ethanol (56 mL) were mixed, and then N-(4-formylphenyl)-N-methyl-acetamide (503 mg, 2.84 mmol) and acetic acid (1.6 mL, 28 mmol) were added, followed by stirring at 70°C for 3 hours under an oxygen atmosphere. Water and saturated aqueous sodium bicarbonate solution were added to the reaction mixture, followed by extraction with chloroform. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give Example Compound 14 (yield 1.13 g).

[0261] Example compounds 1 to 14 in the following table were produced according to the methods shown in Examples 1 and 2 and Examples 11 to 14 above, or methods similar thereto. 1 H-NMR data and / or LC / MS data are shown in the tables.

[0262] [Table 1-1] [Table 1-2] [Table 1-3]

[0263] Example 15

[0264] [ka]

[0265] Process 1 Reference Synthesis Example Compound 23 (4.02 g, 15.8 mmol) and DMF (70 mL) were mixed, and sodium hydride (60% in oil) (949 mg, 23.7 mmol) was added under ice cooling, followed by stirring for 30 minutes. Methyl iodide (2.95 mL, 47.4 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Under ice cooling, saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 24 (yield 3.83 g). Process 2 Reference Synthesis Example Compound 24 (250 mg, 0.932 mmol) was mixed with 1,4-dioxane (5 mL), and then bis(pinacolato)diboron (355 mg, 1.40 mmol), potassium acetate (183 mg, 1.87 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (68.2 mg, 0.932 mmol) were added, followed by stirring at 100°C for 3 hours. The reaction mixture was allowed to cool and filtered through Celite (registered trademark). Water and ethyl acetate were added, and the mixture was stirred, and the organic layer was separated. The separated organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 25 (yield 90 mg). Process 3 Reference Synthesis Example Compound 26 (75 mg, 0.21 mmol), Reference Synthesis Example Compound 25 (85 mg, 0.27 mmol), and 1,4-dioxane (3 mL) were mixed, followed by the addition of water (600 μL), cesium carbonate (134 mg, 0.411 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.3 mg, 0.010 mmol), and the mixture was stirred at 100°C for 3 hours. The mixture was allowed to cool, diluted with water, and then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 27 (yield 59.8 mg). Process 4 Reference Synthesis Example Compound 27 (58 mg, 0.12 mmol) and THF (2 mL) were mixed, and then methanol (3 mL) and 4 mol / L aqueous sodium hydroxide solution (3 mL, 12 mmol) were added and stirred at 60°C for 4 hours. After cooling, 2 mol / L hydrochloric acid (2.2 mL) was added to the reaction mixture, which was then diluted with water and extracted with ethyl acetate / methanol (10 / 1). The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give Reference Synthesis Example Compound 28 (yield 55 mg). Process 5 Reference Synthesis Example Compound 28 (12 mg, 0.027 mmol) and acetonitrile (300 μL) were mixed, and then 3-amino-2-fluorobenzamide (6.5 mg, 0.042 mmol), 1-methylimidazole (6.0 μL, 0.076 mmol), and TCFH (9.1 mg, 0.032 mmol) were added, followed by stirring at room temperature for 15 hours. The reaction mixture was diluted with water, and the precipitate was collected by filtration. The resulting solid was purified by silica gel column chromatography to give Example Compound 15 (yield 3.2 mg).

[0266] Example 16

[0267] [ka]

[0268] Process 1 Reference Synthesis Example Compound 29 (5.14 g, 23.5 mmol) and TFA (40 mL) were mixed, and then NIS (5.80 g, 25.8 mmol) was added and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and then saturated aqueous sodium bicarbonate and ethyl acetate were added and stirred, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 30 (yield 7.64 g). Process 2 Reference Synthesis Example Compound 30 (5.49 g, 15.9 mmol) and TEA (59 mL) were mixed, and then dichlorobis(triphenylphosphine)palladium(II) (558 mg, 0.795 mmol), copper iodide (152 mg, 0.798 mmol), and trimethylsilylacetylene (2.81 mL, 19.9 mmol) were added, followed by stirring at room temperature for 3 hours under an argon atmosphere. Chloroform and water were added to the reaction mixture, and the mixture was stirred, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 31 (yield 4.82 g). Process 3 Potassium tert-butoxide (1.35 g, 12.0 mmol) and NMP (18 mL) were mixed, and a solution of Reference Synthesis Example Compound 31 (1.80 g, 5.71 mmol) in NMP (18 mL) was added dropwise under ice cooling. The mixture was stirred for 1 hour under ice cooling and then at room temperature for 4 hours. The reaction mixture was added dropwise to an ice-cooled saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. Normal hexane was added to the extract, which was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 32 (yield 981 mg). Process 4 Reference Synthesis Example Compound 32 (410 mg, 1.69 mmol) and DMF (10 mL) were mixed, and then sodium hydride (60% in oil) (88 mg, 2.20 mmol) was added under ice-cooling and stirred for 10 minutes. 2-Bromoethyl methyl ether (475 μL, 5.06 mmol) was added, and the mixture was stirred at 60°C for 16 hours. The reaction mixture was added dropwise to an ice-cooled saturated aqueous ammonium chloride solution, diluted with water, and extracted with ethyl acetate. Normal hexane was added to the extract, and the mixture was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 33 (yield 407 mg). Process 5 Reference Synthesis Example Compound 33 (554 mg, 1.84 mmol) and THF (8 mL) were mixed and cooled to -78°C. A 1.0 mol / L solution of LDA in normal hexane / THF (approximately 1 / 7) (2.8 mL, 2.8 mmol) was added and stirred for 1 hour. A solution of carbon tetrabromide (976 mg, 2.94 mmol) in THF (368 μL) was added dropwise, and the mixture was stirred at -78°C for 3 hours. The reaction mixture was added dropwise to an ice-cooled saturated aqueous ammonium chloride solution, diluted with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 34 (yield 304 mg). Process 6 Reference Synthesis Example Compound 34 (120 mg, 0.316 mmol), Reference Synthesis Example Compound 25 (98 mg, 0.31 mmol), and 1,4-dioxane (4 mL) were mixed, followed by the addition of water (800 μL), cesium carbonate (206 mg, 0.632 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11.2 mg, 0.0158 mmol), and the mixture was stirred at 100°C for 18 hours. The mixture was allowed to cool, diluted with water, and then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 35 (yield 60.3 mg). Process 7 Reference Synthesis Example Compound 35 (60.3 mg, 0.123 mmol) and methanol (1.5 mL) were mixed, and then 4 mol / L aqueous sodium hydroxide solution (3 mL, 12 mmol) was added and stirred at 60°C for 4 hours. After cooling, 2 mol / L hydrochloric acid was added, followed by extraction with ethyl acetate / methanol (10 / 1). The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give Reference Synthesis Example Compound 36 (yield 41.0 mg). Process 8 Reference Synthesis Example Compound 36 (10 mg, 0.021 mmol) was mixed with acetonitrile (500 μL), and then 5-amino-2-fluorobenzamide (6.5 mg, 0.042 mmol), 1-methylimidazole (7 μL, 0.09 mmol), and TCFH (11.8 mg, 0.0421 mmol) were added sequentially and stirred at room temperature for 15 hours. The mixture was diluted with 2 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give Example Compound 16 (yield 8.9 mg).

[0269] Example 17

[0270] [ka]

[0271] Process 1 Reference Synthesis Example Compound 37 (5.4 g, 31 mmol) was mixed with THF (100 mL), and then sodium hydride (60% in oil) (1.59 g, 39.8 mmol) and di-tert-butyl dicarbonate (9.1 mL, 40 mmol) were added sequentially under ice cooling, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 38 (yield 7.11 g). Process 2 Diisopropylamine (10.8 mL, 77.5 mmol) and THF (103 mL) were mixed and cooled to -78°C. 2.56 mol / L n-butyllithium / n-hexane solution (20.2 mL, 51.7 mmol) was added, and the mixture was warmed to 0°C and stirred for 15 minutes. The reaction mixture was cooled to -78°C, and Reference Synthesis Example Compound 38 (7.11 g, 25.8 mmol) was added and stirred for 1 hour. A solution of carbon tetrabromide (8.7 g, 26 mmol) in THF (5.5 mL) was added dropwise, and the mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was added dropwise to an ice-cooled saturated aqueous ammonium chloride solution, followed by the addition of water and extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 39 (yield 7.7 g). Process 3 Reference Synthesis Example Compound 39 (7.7 g, 22 mmol) was mixed with dichloromethane (25 mL), and then a 4 mol / L hydrogen chloride / ethyl acetate solution (72 mL, 288 mmol) was added and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 40 (yield 2.6 g). Process 4 Reference Synthesis Example Compound 40 (1.1 g, 4.3 mmol) and DMF (8.8 mL) were mixed, and then sodium hydride (60% in oil) (0.35 g, 8.8 mmol) was added under ice-cooling and stirred for 10 minutes. Ethyl iodide (0.7 mL, 9 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was added dropwise to an ice-cooled saturated aqueous ammonium chloride solution, diluted with water, and extracted with ethyl acetate. Normal hexane was added to the extract, and the mixture was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 41 (yield 1.0 g). Process 5 Reference Synthesis Example Compound 41 (180 mg, 0.38 mmol), Reference Synthesis Example Compound 25 (300 mg, 0.952 mmol), and 1,4-dioxane (6.4 mL) were mixed, and then cesium carbonate (416 mg, 1.28 mmol) and APhos-Pd-G3 (20 mg, 0.031 mmol) were added. The mixture was stirred at 140°C for 1 hour under microwave irradiation. After cooling, water was added and the mixture was stirred, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 42 (yield 198 mg). Process 6 Reference Synthesis Example Compound 42 (198 mg, 0.507 mmol), THF (0.9 mL), and methanol (3.2 mL) were mixed, and then 4 mol / L aqueous sodium hydroxide solution (2.5 mL, 10 mmol) was added under ice cooling and stirred at room temperature for 1 hour. The reaction solution was neutralized, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 43 (yield 139 mg). Process 7 Reference Synthesis Example Compound 43 (68 mg, 0.18 mmol), 5-amino-2-fluorobenzamide (42 mg, 0.27 mmol), and acetonitrile (2 mL) were mixed, and 1-methylimidazole (0.043 mL, 0.54 mmol) and TCFH (81 mg, 0.29 mmol) were added, followed by stirring at room temperature for 4 hours. Water was added and the mixture was stirred, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Example Compound 17 (yield 71.6 mg).

[0272] Example 18

[0273] [ka]

[0274] Process 1 Reference Synthesis Example Compound 44 (10 g, 39 mmol) was mixed with DMF (196 mL), and then, under ice cooling, sodium hydride (60% in oil) (2.4 g, 60 mmol) and methyl iodide (7.4 mL, 120 mmol) were added sequentially, followed by stirring at room temperature for 3 hours. The reaction mixture was ice-cooled, and saturated aqueous ammonium chloride solution and water were added, followed by extraction with ethyl acetate. The extract was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and MTBE was added to the residue for slurry washing. The solid was collected by filtration to obtain Reference Synthesis Example Compound 45 (yield 7.78 g). Process 2 Reference Synthesis Example Compound 45 (4.47 g, 16.7 mmol), THF (0.080 L), and triethylamine (7.0 mL, 50 mmol) were mixed and degassed. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.22 g, 1.67 mmol), copper(I) iodide (0.318 g, 1.67 mmol), and trimethylsilylacetylene (3.0 mL, 21 mmol) were added, and the mixture was stirred at 75°C under an argon atmosphere for 1.5 hours. After cooling, the solvent was distilled off under reduced pressure. Chloroform and water were added to the residue, and the mixture was stirred. The mixture was then filtered through Celite®, and the organic layer of the filtrate was separated. The mixture was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 46 (yield 4.76 g). Process 3 Reference Synthesis Example Compound 46 (4.76 g, 16.7 mmol) and THF (0.067 L) were mixed, and then a 1 mol / L TBAF / THF solution (0.028 L, 28 mmol) was added and stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 47 (yield 2.83 g). Process 4 Reference Synthesis Example Compound 48 (2.00 g, 11.8 mmol) and acetic acid (40 mL) were mixed, and then NIS (2.9 g, 13 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate and chloroform were added and stirred, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 49 (yield 3.4 g). Process 5 Reference Synthesis Example Compound 49 (1.0 g, 3.4 mmol) was mixed with acetonitrile (10 mL), followed by the addition of potassium carbonate (1.4 g, 10 mmol), palladium(II) acetate (38 mg, 0.17 mmol), 1,4-bis(diphenylphosphino)butane (144 mg, 0.338 mmol), and Reference Synthesis Example Compound 47 (882 mg, 4.14 mmol). The reaction vessel was purged with argon and sealed. The reaction mixture was stirred at 140°C for 1 hour under microwave irradiation. After cooling, water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 50 (yield 284 mg). Process 6 Reference Synthesis Example Compound 50 (284 mg, 0.746 mmol) and acetonitrile (6 mL) were mixed, degassed, and the reaction vessel was purged with argon. Bis(acetonitrile)dichloropalladium(II) (212 mg, 0.817 mmol) was added and stirred at 100°C for 2 hours. After cooling, the mixture was filtered through Celite (registered trademark). Ethyl acetate, water, and a small amount of saturated aqueous sodium thiosulfate solution were added to the filtrate and stirred, and the organic layer was separated. The organic layer was washed successively with water, saturated aqueous sodium thiosulfate solution, and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 51 (yield 144 mg). Process 7 Reference Synthesis Example Compound 51 (144 mg, 0.378 mmol) and DMF (1 mL) were mixed, and then sodium hydride (60% in oil) (30 mg, 0.75 mmol) was added under ice-cooling and stirred for 10 minutes. Ethyl iodide (0.061 mL, 0.76 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was added dropwise to an ice-cooled saturated aqueous ammonium chloride solution, and then water and ethyl acetate were added and stirred, and the organic layer was separated. Normal hexane was added to the organic layer, and the mixture was washed with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 52 (yield 70.7 mg). Process 8 Reference Synthesis Example Compound 52 (70 mg, 0.17 mmol), methanol (1.6 mL), and THF (0.3 mL) were mixed, and then 4 mol / L aqueous sodium hydroxide solution (0.86 mL, 3.4 mmol) was added under ice cooling, followed by stirring at room temperature for 1 hour. Dilute hydrochloric acid was added to the reaction mixture, which was then concentrated under reduced pressure to give Reference Synthesis Example Compound 53 as a mixture with sodium chloride (yield 0.27 g). Process 9 To the sodium chloride mixture (0.13 g) of Reference Synthesis Example Compound 53 obtained by the method described in Step 8, 5-amino-2-fluorobenzamide (19 mg, 0.12 mmol), DMF (1 mL), DIPEA (0.043 mL, 0.25 mmol), and HATU (47 mg, 0.12 mmol) were added sequentially and stirred at room temperature for 4 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Example Compound 18 (yield 12.2 mg).

[0275] Example 19

[0276] [ka]

[0277] Process 1 Reference Synthesis Example Compound 54 (10.0 g, 57.8 mmol) and THF (289 mL) were mixed, and then 4-nitrophenyl chloroformate (11.7 g, 58.0 mmol) and pyridine (7.0 mL, 87 mmol) were added under ice cooling, followed by stirring at room temperature for 4 hours. The solvent was removed under reduced pressure, and the residue was added to 1,4-dioxane (289 mL) to form a suspension. Hydrazine monohydrate (8.4 mL, 170 mmol) was then added, and the mixture was stirred at 70°C for 2 hours. The reaction mixture was allowed to cool, and water was added and stirred. The precipitate was collected by filtration to give Reference Synthesis Example Compound 55 (yield 11.7 g). Process 2 Reference Synthesis Example Compound 55 (9.00 g, 39.0 mmol) and ethanol (97 mL) were mixed, and then triethyl orthoacetate (8.6 mL, 47 mmol) and p-toluenesulfonic acid monohydrate (741 mg, 3.90 mmol) were added and stirred under reflux for 16 hours. The reaction mixture was allowed to cool, and water was added and stirred. The precipitate was collected by filtration to obtain Reference Synthesis Example Compound 56 (yield 3.48 g). Process 3 Reference Synthesis Example Compound 56 (3.00 g, 11.8 mmol) was mixed with DMF (30 mL), and then potassium tert-butoxide (1.98 g, 17.7 mmol) and methyl iodide (2.2 mL, 35 mmol) were added sequentially under ice cooling, followed by stirring at room temperature for 4 hours. Water was added to the reaction mixture under ice cooling, and the mixture was stirred and then extracted with ethyl acetate. The extract was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 57 (yield 1.85 g). Process 4 Reference Synthesis Example Compound 58 (10.0 g, 41.1 mmol) and DMF (164 mL) were mixed, and then sodium hydride (60% in oil) (2.14 g, 53.5 mmol) was added under ice cooling and stirred for 20 minutes. Ethyl iodide (4.9 mL, 61 mmol) was added and stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture under ice cooling, and the mixture was stirred and extracted with ethyl acetate. The extract was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 59 (yield 7.34 g). Process 5 Reference Synthesis Example Compound 59 (3.27 g, 12.1 mmol), THF (13 mL), and isopropyl borate (3.1 mL, 13 mmol) were mixed, and then a 1.09 mol / L LDA solution in n-hexane / THF (8.6 mL, 9.4 mmol) was added under ice cooling and stirred for 30 minutes. A solution of tripotassium phosphate (2.13 g, 10.0 mmol) in water (13 mL), a solution of Reference Synthesis Example Compound 57 (1.80 g, 6.69 mmol) and chloro(crotyl)(tri-tert-butylphosphine)palladium(II) (267 mg, 0.669 mmol) in THF (13 mL) were added and stirred at 50 °C for 2 hours. The reaction mixture was allowed to cool, water was added, and the mixture was stirred. It was then extracted with ethyl acetate. The extract was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 60 (yield 2.58 g). Process 6 Reference Synthesis Example Compound 60 (500 mg, 1.09 mmol), THF (2.7 mL), and methanol (2.7 mL) were mixed, and then 4 mol / L aqueous sodium hydroxide solution (2.7 mL, 10.8 mmol) was added and stirred for 2 hours at 50° C. Under ice cooling, 1 mol / L hydrochloric acid was added to the reaction mixture, and the precipitate was collected by filtration to obtain Reference Synthesis Example Compound 61 (yield 300 mg). Process 7 Reference Synthesis Example Compound 61 (100 mg, 0.225 mmol), 3-amino-2-fluorobenzamide (51.9 mg, 0.337 mmol), and acetonitrile (1.1 mL) were mixed, and then 1-methylimidazole (71 μL, 0.90 mmol) and TCFH (126 mg, 0.449 mmol) were added and stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was stirred. The precipitate was collected by filtration to give Example Compound 19 (yield 58.9 mg).

[0278] Example 20

[0279] [ka]

[0280] Process 1 Reference Synthesis Example Compound 62 (4.00 g, 23.1 mmol) was mixed with THF (116 mL), and then 4-nitrophenyl chloroformate (4.66 g, 23.1 mmol) and pyridine (2.8 mL, 35 mmol) were added under ice-cooling, followed by stirring at room temperature for 17 hours. The solvent was removed under reduced pressure, and the residue was dissolved in 1,4-dioxane (116 mL). Hydrazine monohydrate (3.37 mL, 69.3 mmol) was added, and the mixture was stirred at 70°C for 5 hours. The cooled reaction mixture was poured into ice-cooled water (500 mL) and stirred for 30 minutes. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to give Reference Synthesis Example Compound 63 (yield 4.43 g). Process 2 Reference Synthesis Example Compound 63 (4.43 g, 19.2 mmol) was mixed with ethanol (48 mL), and then triethyl orthoacetate (5.7 mL, 39 mmol) and paratoluenesulfonic acid monohydrate (365 mg, 1.92 mmol) were added and stirred at 80°C for 6 hours. The reaction solution was allowed to cool and poured into ice-cold water (500 mL) and stirred for 30 minutes. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to give Reference Synthesis Example Compound 64 (yield 4.61 g). Process 3 Reference Synthesis Example Compound 64 (4.61 g, 18.1 mmol) and DMF (60 mL) were mixed, and then tripotassium phosphate (5.75 g, 27.1 mmol) was added under ice cooling and stirred for 10 minutes. Methyl iodide (1.69 mL, 27.1 mmol) was added and stirred at room temperature for 4 hours. The reaction solution was poured into ice-cold water (500 mL) and stirred for 30 minutes. The precipitate was collected by filtration and washed with water to obtain Reference Synthesis Example Compound 65 (yield 3.33 g). Process 4 Reference Synthesis Example Compound 59 (1.09 g, 4.02 mmol), THF (4.5 mL), and isopropyl borate (1.03 mL, 4.46 mmol) were mixed and degassed. After ice-cooling, a 1.09 mol / L LDA solution in n-hexane / THF (2.86 mL, 3.12 mmol) was added and stirred for 30 minutes. A solution of tripotassium phosphate (710 mg, 3.34 mmol) in water (4.5 mL), a solution of Reference Synthesis Example Compound 65 (600 mg, 2.23 mmol), and a solution of chloro(crotyl)(tri-tert-butylphosphine)palladium(II) (80.9 mg, 0.203 mmol) in THF (11 mL) were added sequentially, and the mixture was stirred at 40°C for 2.5 hours. The reaction mixture was allowed to cool, diluted with water, and extracted with ethyl acetate. The extract was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 66 (yield 664 mg). Process 5 Reference Synthesis Example Compound 66 (945 mg, 2.06 mmol), methanol (5.1 mL), and THF (5.1 mL) were mixed, and then 4 mol / L aqueous sodium hydroxide solution (2.57 mL, 10.3 mmol) was added and stirred at room temperature for 5 hours. Under ice cooling, the reaction mixture was acidified with 6 mol / L hydrochloric acid and then extracted with a chloroform / methanol (4 / 1) mixture. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give Reference Synthesis Example Compound 67 (yield 1.06 g) as a solvent mixture. Process 6 The solvent mixture (1.06 g) of Reference Synthesis Example Compound 67 obtained by the method described in Step 5 was mixed with acetonitrile (21 mL), and then 5-amino-2-fluorobenzamide (634 mg, 4.11 mmol), TCFH (1.15 g, 4.10 mmol), and 1-methylimidazole (649 μL, 8.22 mmol) were added sequentially and stirred at room temperature overnight. The reaction solution was diluted with water and then extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was added with 2-propanol (30 mL) for slurry washing. The solid was collected by filtration and dried under reduced pressure to obtain Example Compound 20 (yield 1.24 g).

[0281] Example 21

[0282] [ka]

[0283] Process 1 Reference Synthesis Example Compound 68 (694 mg, 3.66 mmol) and DMSO (10 mL) were mixed, and then DIPEA (1.89 mL, 11.0 mmol) and a 2.0 mol / L ethylamine / THF solution (2.2 mL, 4.4 mmol) were added. The mixture was stirred at 50°C for 3 hours and then at room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was stirred, and the organic layer was separated. The separated organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give Reference Synthesis Example Compound 69 (yield 694 mg). Process 2 Reference Synthesis Example Compound 69 (300 mg, 1.40 mmol) and acetonitrile (5 mL) were mixed, followed by the addition of potassium carbonate (580 mg, 4.20 mmol), palladium(II) acetate (15.7 mg, 0.0699 mmol), 1,4-bis(diphenylphosphino)butane (60.0 mg, 0.141 mmol), and Reference Synthesis Example Compound 47 (447 mg, 2.10 mmol). The atmosphere in the reaction vessel was replaced with argon and sealed, and the reaction mixture was stirred at 140°C under microwave irradiation for 1.5 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 70 (yield 244 mg). Process 3 Reference Synthesis Example Compound 70 (5.81 g, 14.8 mmol) and methanol (0.037 L) were mixed, degassed, and the reaction vessel was replaced with argon. Chloro(triphenylphosphine)gold(I) (1.47 g, 2.97 mmol) and silver bis(trifluoromethanesulfonyl)imide (1.15 g, 2.96 mmol) were then added and stirred at 80°C for 2 hours. After cooling, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 71 (yield 5.38 g). Process 4 Reference Synthesis Example Compound 71 (23.3 mg, 0.0595 mmol), methanol (0.5 mL), and THF (0.5 mL) were mixed, and then 4 mol / L aqueous sodium hydroxide solution (150 μL, 0.6 mmol) was added and stirred at room temperature for 18 hours. 2 mol / L hydrochloric acid (0.5 mL) was added to the reaction mixture, and the solvent was evaporated under reduced pressure to give Reference Synthesis Example Compound 72 as a sodium chloride mixture (yield 62.3 mg). Process 5 A mixture of Reference Synthesis Example Compound 72 (30 mg) with sodium chloride obtained by the method described in Step 4 and acetonitrile (1 mL) was mixed, and then 5-amino-2-fluorobenzamide (9.2 mg, 0.060 mmol), 1-methylimidazole (14 μL, 0.18 mmol), and TCFH (16.9 mg, 0.0602 mmol) were added sequentially and stirred at 40° C. for 15 hours. 1 mol / L hydrochloric acid and ethyl acetate were added to the reaction mixture and stirred, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and then slurry-washed with a normal hexane / ethyl acetate (3 / 1) mixture. The solid was collected by filtration and dried under reduced pressure to give Example Compound 21 (yield 9.2 mg).

[0284] Example 22

[0285] [ka]

[0286] Process 1 A mixture of Reference Synthesis Example Compound 72 (30 mg) with sodium chloride obtained by the method described in Step 4 of Example 21 and acetonitrile (1 mL) was mixed, and then 3-amino-2-fluorobenzamide (9.2 mg, 0.060 mmol), 1-methylimidazole (14 μL, 0.18 mmol), and TCFH (16.9 mg, 0.0602 mmol) were added sequentially and stirred at 40°C for 15 hours. 1 mol / L hydrochloric acid and ethyl acetate were added to the reaction mixture and stirred, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Example Compound 22 (yield 9.3 mg).

[0287] Example 23

[0288] [ka]

[0289] Process 1 Reference Synthesis Example Compound 73 (509 mg, 2.28 mmol) and THF (8 mL) were mixed, and then potassium carbonate (619 mg, 4.48 mmol) and a 2.0 mol / L ethylamine / THF solution (1.3 mL, 2.6 mmol) were added, followed by stirring at 70°C for 3 hours. Water and ethyl acetate were added to the cooled reaction mixture, and the mixture was stirred, and the organic layer was separated. The separated organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give Reference Synthesis Example Compound 74 (yield 610 mg), partially containing impurities. Process 2 Impurity-containing Reference Synthesis Example Compound 74 (300 mg) obtained by the method described in Step 1 was mixed with acetonitrile (10 mL), and then NBS (323 mg, 1.81 mmol) and acetic acid (69 μL, 1.21 mmol) were added, followed by stirring at 85°C for 17 hours. Ethyl acetate, saturated aqueous sodium bicarbonate, and saturated saline were added sequentially to the cooled reaction mixture, followed by stirring, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 75 (yield 118 mg). Unexpected deethylation of the amino group also occurred during this step. Process 3 Reference Synthesis Example Compound 75 (116 mg, 0.388 mmol) was mixed with THF (5 mL), and then Reference Synthesis Example Compound 47 (165 mg, 0.774 mmol), triethylamine (162 μL, 1.17 mmol), copper(I) iodide (3.7 mg, 0.019 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.2 mg, 0.0194 mmol) were added, followed by stirring at 90°C for 3 hours under an argon atmosphere. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 76 (yield 104 mg). Process 4 Reference Synthesis Example Compound 76 (103 mg, 0.238 mmol) and ethanol (1.5 mL) were mixed, degassed, and the reaction vessel was replaced with argon. Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)gold(I) (30.6 mg, 0.0476 mmol) and silver bis(trifluoromethanesulfonyl)imide (18.4 mg, 0.0474 mmol) were then added, followed by stirring at 100°C for 3 hours. The reaction mixture was allowed to cool to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 77 (yield 98 mg). Process 5 Reference Synthesis Example Compound 77 (50 mg, 0.12 mmol) and DMF (1 mL) were mixed, and then sodium hydride (60% in oil) (7.0 mg, 0.18 mmol) was added under ice-cooling and stirred for 10 minutes. Ethyl iodide (46 μL, 0.58 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was added dropwise to an ice-cooled saturated aqueous ammonium chloride solution, diluted with water, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 78 (yield 32.0 mg). Process 6 Reference Synthesis Example Compound 78 (32 mg, 0.070 mmol), methanol (1 mL), and THF (0.5 mL) were mixed, and then a 4 mol / L aqueous sodium hydroxide solution (174 μL, 0.696 mmol) was added, followed by stirring for 5 hours at 40° C. To the reaction solution, 2 mol / L hydrochloric acid (0.5 mL) and water were added successively, and the solvent was evaporated under reduced pressure to give Reference Synthesis Example Compound 79 (a sodium chloride mixture) (yield: 74.3 mg). Process 7 A mixture of Reference Synthesis Example Compound 79 (37 mg) with sodium chloride obtained by the method described in Step 6 and acetonitrile (1 mL) was mixed, followed by the addition of 5-amino-2-fluorobenzamide (8.0 mg, 0.052 mmol), 1-methylimidazole (17 μL, 0.22 mmol), and TCFH (19.5 mg, 0.0695 mmol), and the mixture was stirred at 40° C. for 15 hours. Water and ethyl acetate were added to the reaction mixture, followed by stirring, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, followed by slurry washing with a normal hexane / ethyl acetate (3 / 1) mixed solvent, and the solid was collected by filtration. The resulting solid was dried under reduced pressure to give Example Compound 23 (yield 9.7 mg).

[0290] Example 24

[0291] [ka]

[0292] Process 1 Reference Synthesis Example Compound 68 (3.00 g, 15.8 mmol) and DMSO (40 mL) were mixed, and then DIPEA (8.2 mL, 48 mmol) and cyclopropylmethylamine (1.7 mL, 20 mmol) were added, followed by stirring at 80°C for 4 hours. After cooling, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 80 (yield 2.83 g). Process 2 Palladium(II) acetate (113 mg, 0.499 mmol), XPhos (476 mg, 0.999 mmol), and acetonitrile (25 mL) were mixed and degassed, followed by stirring at room temperature for 5 minutes under an argon atmosphere. Reference Synthesis Example Compound 47 (2.66 g, 12.5 mmol), cesium carbonate (6.50 g, 19.9 mmol), and Reference Synthesis Example Compound 80 (2.40 g, 9.97 mmol) were added, followed by stirring at 90°C for 2 hours. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 81 (yield 3.05 g). Process 3 Reference Synthesis Example Compound 81 (3.00 g, 7.19 mmol) and methanol (18 mL) were mixed and degassed. The reaction vessel was then purged with argon, and chloro(triphenylphosphine)gold(I) (711 mg, 1.44 mmol) and silver bis(trifluoromethanesulfonyl)imide (558 mg, 1.44 mmol) were added, followed by stirring at 80°C for 2 hours. After cooling, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 82 (yield 2.89 g). Process 4 Reference Synthesis Example Compound 82 (2.89 g, 6.92 mmol), THF (17 mL), and methanol (17 mL) were mixed, and then 4 mol / L aqueous sodium hydroxide solution (8.7 mL, 35 mmol) was added and stirred at 50° C. for 4 hours. The reaction mixture was acidified with 10% aqueous citric acid, and the organic solvent was evaporated under reduced pressure. Ethanol (2 mL) was added to the residue, and the mixture was stirred under ice-cooling for 1 hour. The precipitate was collected by filtration to give Reference Synthesis Example Compound 83 (yield 1.37 g). Process 5 Reference Synthesis Example Compound 83 (1.00 g, 2.48 mmol), 5-amino-2-fluorobenzamide (573 mg, 3.72 mmol), and acetonitrile (12 mL) were mixed, and then 1-methylimidazole (783 μL, 9.92 mmol) and TCFH (1.39 g, 4.95 mmol) were added and stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was stirred, and the precipitate was collected by filtration. The collected solid was dried under reduced pressure and purified by silica gel column chromatography to give Example Compound 24 (yield 808 mg).

[0293] Example 25

[0294] [ka]

[0295] Process 1 Reference Synthesis Example Compound 84 (10.0 g, 41.7 mmol) was mixed with DMF (0.10 L), and then sodium hydride (60% in oil) (2.50 g, 62.5 mmol) was added and stirred at room temperature for 10 minutes. Methyl iodide (7.9 mL, 130 mmol) was added and stirred at room temperature for 2.5 hours. Sodium hydride (60% in oil) (1.50 g, 37.5 mmol) was added and stirred at room temperature for 30 minutes. Water (200 mL) was added and stirred, and the precipitated solid was collected by filtration. The collected solid was dried under reduced pressure to obtain Reference Synthesis Example Compound 85 (yield 10.6 g). Process 2 Reference Synthesis Example Compound 85 (3.00 g, 11.8 mmol), THF (0.060 L), and triethylamine (4.92 mL, 35.4 mmol) were mixed, degassed, and purged with argon. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.864 g, 1.18 mmol), copper(I) iodide (0.225 g, 1.18 mmol), and trimethylsilylacetylene (2.1 mL, 15 mmol) were added, and the mixture was stirred at 50°C for 4 hours under an argon atmosphere. After cooling, the mixture was diluted with ethyl acetate and filtered through Celite®. The solvent in the filtrate was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 86 (yield 2.71 g). Process 3 Reference Synthesis Example Compound 86 (2.71 g, 9.99 mmol) and THF (0.038 L) were mixed, and then a 1 mol / L TBAF / THF solution (0.016 L, 16 mmol) was added and stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 87 (yield 1.74 g). Process 4 XPhos (0.289 g, 0.606 mmol), palladium(II) acetate (68.6 mg, 0.303 mmol), and acetonitrile (0.015 L) were mixed, and then Reference Synthesis Example Compound 87 (1.51 g, 7.58 mmol), cesium carbonate (3.95 g, 12.1 mmol), and Reference Synthesis Example Compound 69 (1.30 g, 6.06 mmol) were added. The mixture was stirred at 95°C for 1.5 hours under an argon atmosphere. The mixture was allowed to cool, diluted with chloroform and water, and then filtered through Celite®. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography and then slurry washed with a normal hexane / ethyl acetate (1 / 1) mixture (25 mL). The solid was collected by filtration and dried under reduced pressure to give Reference Synthesis Example Compound 88 (yield 1.40 g). Process 5 Reference Synthesis Example Compound 88 (1.40 g, 3.71 mmol) and methanol (9.3 mL) were mixed, degassed, and the reaction vessel was replaced with argon. Chloro(triphenylphosphine)gold(I) (0.367 g, 0.742 mmol) and silver bis(trifluoromethanesulfonyl)imide (0.288 g, 0.742 mmol) were added, followed by stirring at 80°C for 2 hours. After cooling, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 89 (yield 1.23 g). Process 6 Reference Synthesis Example Compound 89 (1.20 g, 3.18 mmol) and THF (0.012 L) were mixed, followed by the addition of methanol (0.012 L) and 4 mol / L aqueous sodium hydroxide solution (3.2 mL, 13 mmol), and the mixture was stirred at room temperature for 3 hours. 2 mol / L hydrochloric acid (10 mL) was added dropwise to the reaction mixture, and the solvent was evaporated under reduced pressure. Approximately 10 mL of toluene was added to the residue, and the solvent was evaporated under reduced pressure. This procedure was repeated twice, and the mixture was dried under reduced pressure to obtain Reference Synthesis Example Compound 90 as a sodium chloride mixture (yield 2.01 g). Process 7 A mixture of Reference Synthesis Example Compound 90 (1.20 g) and sodium chloride obtained by the method described in Step 6 and acetonitrile (0.019 L) was mixed, and then 5-amino-2-fluorobenzamide (0.584 g, 3.79 mmol), 1-methylimidazole (0.75 mL, 9.5 mmol), and TCFH (1.06 g, 3.78 mmol) were added and stirred at room temperature for 15 hours. The solvent was removed by distillation under reduced pressure, and the mixture was diluted with water and chloroform and then filtered. The filtrate was extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography. Ethanol (15 mL) was added and the mixture was subjected to slurry washing. The solid was collected by filtration and dried under reduced pressure to obtain Example Compound 25 (yield 0.727 g).

[0296] Example 26

[0297] [ka]

[0298] Process 1 Reference Synthesis Example Compound 69 (500 mg, 2.63 mmol) and DMSO (6.6 mL) were mixed, and then DIPEA (1.36 mL, 7.91 mmol) and 2-methoxymethylamine (396 mg, 5.27 mmol) were added, followed by stirring at 80°C for 4 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was stirred, and the organic layer was separated. The separated organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give Reference Synthesis Example Compound 91 (yield 566 mg). Process 2 Reference Synthesis Example Compound 91 (197 mg, 0.805 mmol) and acetonitrile (2 mL) were mixed, and then palladium(II) acetate (9.2 mg, 0.041 mmol), XPhos (39.0 mg, 0.041 mmol), Reference Synthesis Example Compound 47 (180 mg, 0.844 mmol), and cesium carbonate (799 mg, 2.45 mmol) were added. The mixture was stirred at 100°C under an argon atmosphere for 3.5 hours. After cooling, water and ethyl acetate were added, followed by stirring and filtration. The organic layer of the filtrate was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 92 (yield 99.9 mg). Process 3 Reference Synthesis Example Compound 92 (99.9 mg, 0.237 mmol) and ethanol (3 mL) were mixed, degassed, and the reaction vessel was replaced with argon. Chloro(triphenylphosphine)gold(I) (30.5 mg, 0.0474 mmol) and silver bis(trifluoromethanesulfonyl)imide (18.4 mg, 0.0474 mmol) were then added, and the mixture was stirred at 100°C for 16 hours. After cooling, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 93 (yield 80.1 mg). Process 4 Reference Synthesis Example Compound 93 (77.7 mg, 0.184 mmol), methanol (1 mL), and THF (1 mL) were mixed, and then a 4 mol / L aqueous sodium hydroxide solution (460 μL, 1.84 mmol) was added, followed by stirring for 3 hours at 40° C. 2 mol / L hydrochloric acid (1.5 mL) was added to the reaction solution, and the solvent was evaporated under reduced pressure to obtain Reference Synthesis Example Compound 94 as a sodium chloride mixture (yield 194 mg). Process 5 Acetonitrile (1 mL), 3-amino-2-fluorobenzamide (12.0 mg, 0.0779 mmol), 1-methylimidazole (19 μL, 0.241 mmol), and TCFH (21.8 mg, 0.0777 mmol) were added sequentially to the sodium chloride mixture (40 mg) of Reference Synthesis Example Compound 94 obtained by the method described in Step 4, and the mixture was stirred at 40° C. for 15 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was stirred, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and then a normal hexane / ethyl acetate (3 / 1) mixture was added for slurry washing, and the solid was collected by filtration. The collected solid was dried under reduced pressure to give Example Compound 26 (yield 11.0 mg).

[0299] Example 27

[0300] [ka]

[0301] Acetonitrile (1 mL), 5-amino-2-fluorobenzamide (12.0 mg, 0.0779 mmol), 1-methylimidazole (19 μL, 0.241 mmol), and TCFH (21.8 mg, 0.0777 mmol) were sequentially added to the sodium chloride mixture (40 mg) of Reference Synthesis Example Compound 94 obtained by the method described in Step 4 of Example 26, and the mixture was stirred at 40°C for 15 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was stirred, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and then a mixture of normal hexane and ethyl acetate (3 / 1) was added for slurry washing, and the solid was collected by filtration. The collected solid was dried under reduced pressure to give Example Compound 27 (yield 11.2 mg).

[0302] Example 28

[0303] [ka]

[0304] Process 1 Nitromethane (20 mL) and ethyl 2,2-diethoxyacetate (2.52 g, 14.3 mmol) were added to Reference Synthesis Example Compound 95 (2.4 g, 12 mmol), followed by ice cooling. Titanium(IV) chloride (4.38 mL, 39.9 mmol) was added dropwise, and the mixture was stirred at room temperature for 20 hours. Water and ethyl acetate were added successively, followed by stirring, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 96 (yield 2.71 g). Process 2 To Reference Synthesis Example Compound 96 (1.5 g, 5.3 mmol), THF (25 mL), triethylamine (2.2 mL, 16 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.43 g, 0.53 mmol), copper(I) iodide (100 mg, 0.525 mmol), and trimethylacetylene (1.1 mL, 7.8 mmol) were added, and the mixture was stirred at 75°C under an argon atmosphere for 1.5 hours. After cooling, the reaction mixture was diluted with chloroform and then filtered through Celite®. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 97 (yield 1.64 g). Process 3 To Reference Synthesis Example Compound 97 (1.64 g, 5.42 mmol), THF (25 mL) and a 1 mol / L TBAF / THF solution (10.8 mL, 10.8 mmol) were added successively, and the mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain Reference Synthesis Example Compound 98. Process 4 Reference Synthesis Example Compound 99 (1.05 g, 5.98 mmol) and DMSO (30 mL) were mixed, and then potassium carbonate (1.24 g, 8.97 mmol) was added under ice cooling and stirred for 10 minutes. Benzyl bromide (853 μL, 7.18 mmol) was added, and the mixture was stirred at room temperature for 21 hours. Water and ethyl acetate were added, and the mixture was stirred, and the organic layer was separated. The separated organic layer was washed with saturated brine, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 100 (yield 1.01 g). Process 5 DMSO (10 mL), DIPEA (1.96 mL, 11.4 mmol), and a 2.0 mol / L ethylamine / THF solution (2.3 mL, 4.6 mmol) were added sequentially to Reference Synthesis Example Compound 100 (1.01 g, 3.80 mmol), and the mixture was stirred at 80°C for 4 hours. Under water cooling, ethyl acetate and water were added, and the mixture was stirred, and the organic layer was separated. The separated organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 101 (yield 980 mg). Process 6 Palladium(II) acetate (23.7 mg, 0.105 mmol), XPhos (99.8 mg, 0.209 mmol), and degassed acetonitrile (10 mL) were mixed, and then Reference Synthesis Example Compound 98 (0.482 g, 2.09 mmol), cesium carbonate (1.36 g, 4.17 mmol), and Reference Synthesis Example Compound 101 (0.980 g, 3.37 mmol) were added and stirred at 95°C for 1.5 hours under an argon atmosphere. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 102 (yield 0.554 g). Process 7 Reference Synthesis Example Compound 102 (554 mg, 1.14 mmol) and ethanol (10 mL) were mixed, degassed, and the reaction vessel was replaced with argon. Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)gold(I) (73.5 mg, 0.114 mmol) and silver bis(trifluoromethanesulfonyl)imide (44.3 mg, 0.114 mmol) were then added, and the mixture was stirred at 100°C for 3 hours. After cooling, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 103 (yield 272 mg). Process 8 To Reference Synthesis Example Compound 103 (270 mg, 0.557 mmol), THF (5 mL) and 10% palladium / carbon (40 mg) were added successively, and the mixture was stirred at room temperature under a hydrogen atmosphere for 17 hours. The reaction mixture was filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 104 (yield 135 mg). Process 9 Acetonitrile (1 mL), 5-amino-2-fluorobenzamide (20 mg, 0.13 mmol), 1-methylimidazole (30 μL, 0.38 mmol), and TCFH (35.6 mg, 0.127 mmol) were added sequentially to Reference Synthesis Example Compound 104 (25 mg, 0.063 mmol), and the mixture was stirred at 40° C. for 15 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was stirred, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and then a mixture of normal hexane and ethyl acetate (3 / 1) was added for slurry washing. The solid was collected by filtration to obtain Reference Synthesis Example Compound 105 (yield 43 mg) in a state containing some impurities. Step 10 Reference Synthesis Example Compound 105 (43 mg) containing an impurity obtained by the method described in Step 9 was mixed with methanol (500 μL) and THF (500 μL), and a 4 mol / L aqueous sodium hydroxide solution (203 μL) was added, followed by stirring for 2 hours at 40° C. The reaction solution was neutralized with hydrochloric acid and then concentrated to dryness under reduced pressure to obtain Reference Synthesis Example Compound 106 as a sodium chloride mixture (yield 91 mg). Step 11 To the sodium chloride mixture (91 mg) of Reference Synthesis Example Compound 106 obtained by the method described in Step 10, ammonium chloride (145 mg, 2.71 mmol), DMF (3 mL), DIPEA (467 μL, 2.72 mmol), and HATU (138 mg, 0.363 mmol) were added in that order and stirred at room temperature for 18 hours. Water and ethyl acetate were added, and the mixture was stirred, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and then slurry washed with a mixture of ethyl acetate / normal hexane (1 / 3), and the solid was collected by filtration to give Example Compound 28 (yield 19.8 mg).

[0305] Example 29

[0306] [ka]

[0307] Process 1~3 Reference Synthesis Example Compound 109 was obtained from Reference Synthesis Example Compound 1 in the same manner as in steps 1 to 3 of Example 1. Process 4 A suspension of Reference Synthesis Example Compound 96 (300 mg, 1.05 mmol), potassium vinyltrifluoroborate (281 mg, 2.10 mmol), and cesium carbonate (686 mg, 2.11 mmol) in a 1,4-dioxane / water (5 / 1) mixture (4 mL) was degassed, and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (38 mg, 0.054 mmol) was added. The mixture was stirred at 90°C for 5 hours under an argon atmosphere. The reaction mixture was allowed to cool and then filtered. Water was added to the filtrate, which was extracted with ethyl acetate and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 110 (yield 213 mg). Process 5 Reference Synthesis Example Compound 110 (212 mg, 0.913 mmol) and 1,4-dioxane (9 mL) were mixed, and then water (3 mL), 2,6-dimethylpyridine (212 μL, 1.83 mmol), sodium periodate (781 mg, 3.65 mmol), and a tert-butyl alcohol solution of osmium tetroxide (2.5 w / v%) (460 μL, 0.045 mmol) were added sequentially and stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The separated organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 111 (yield 187 mg). Process 6 To a solution of Reference Synthesis Example Compound 109 (100 mg, 0.252 mmol) in ethanol (4 mL), Reference Synthesis Example Compound 111 (71 mg, 0.30 mmol) and acetic acid (86 μL, 1.50 mmol) were added, and the mixture was stirred at 80° C. under an oxygen atmosphere for 17 hours. The reaction mixture was allowed to cool, and saturated aqueous sodium bicarbonate and ethyl acetate were added and stirred, after which the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 112 (yield 135 mg). Process 7 Reference Synthesis Example Compound 112 (122 mg, 0.200 mmol) and methanol (2 mL) were mixed, and then 4 mol / L aqueous sodium hydroxide solution (300 μL) was added and stirred at 50° C. for 3 hours. 2 mol / L hydrochloric acid (600 μL) was added to the reaction mixture, which was then diluted with water and the precipitated solid was collected by filtration. The collected solid was dried under reduced pressure to give Example Compound 29 (yield 74.5 mg).

[0308] Example 30

[0309] [ka]

[0310] Process 1 Reference Synthesis Example Compound 113 (500 mg) and DMF (3.8 mL) were mixed and then cooled on ice. Sodium hydride (60% in oil) (98.4 mg, 2.46 mmol) was added and stirred for 10 minutes. Ethyl iodide (0.21 mL, 2.6 mmol) was added to the reaction mixture and stirred at room temperature for 2 hours. The reaction mixture was added dropwise to an ice-cooled saturated aqueous ammonium chloride solution, followed by addition of water and extraction with ethyl acetate. Normal hexane was added to the extract, which was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 114 (yield 356 mg). Process 2 Reference Synthesis Example Compound 114 (356 mg, 1.22 mmol) and MTBE (4 mL) were mixed and cooled to -78°C. A 2.56 mol / L solution of n-butyllithium in n-hexane (0.72 mL) was added and stirred for 1 hour. A solution of methyl chloroformate (230 mg, 2.43 mmol) in MTBE was added dropwise, and the mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was added dropwise to an ice-cooled saturated aqueous ammonium chloride solution, followed by addition of water and extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 115 (yield 254 mg). Process 3 A solution of N,N-diisopropylamine (0.39 mL, 2.8 mmol) in THF (3.7 mL) was cooled to -78°C, and a 2.56 mol / L solution of n-butyllithium in n-hexane (0.73 mL) was added. The mixture was warmed to 0°C and stirred for 15 minutes. After cooling to -78°C, Reference Synthesis Example Compound 115 (254 mg, 0.935 mmol) was added and stirred for 1 hour. A solution of carbon tetrabromide (0.3 g, 0.9 mmol) in THF (368 μL) was added dropwise, and the mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was added dropwise to an ice-cooled saturated aqueous ammonium chloride solution, followed by addition of water and extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 116 (yield 176 mg). Process 4 Reference Synthesis Example Compound 116 (174 mg, 0.496 mmol), Reference Synthesis Example Compound 25 (234 mg, 0.742 mmol), and 1,4-dioxane (5 mL) were mixed, and then cesium carbonate (323 mg, 0.991 mmol) and APhos-Pd-G3 (15.8 mg, 0.0249 mmol) were added. The mixture was stirred at 140°C for 1 hour under microwave irradiation. Water was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The extract was neutralized with dilute hydrochloric acid, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 117 (yield 22.3 mg). Process 5 Reference Synthesis Example Compound 117 (22.3 mg, 0.0486 mmol), methanol (2.4 mL), and THF (0.6 mL) were mixed, and then 4 mol / L aqueous sodium hydroxide solution (0.24 mL) was added under ice cooling and stirred at room temperature for 1 hour. After neutralizing the reaction solution, the solvent was distilled off under reduced pressure to obtain Reference Synthesis Example Compound 118 as a sodium chloride mixture (yield 78.5 mg). Process 6 A mixture of Reference Example Compound 118 (obtained by the method described in Step 5) with sodium chloride (39 mg), 5-amino-2-fluorobenzamide (5.6 mg, 0.036 mmol), and acetonitrile (0.2 mL) was mixed, followed by the addition of 1-methylimidazole (5.9 μL, 0.074 mmol) and TCFH (10.8 mg, 0.0385 mmol), and the mixture was stirred at room temperature for 4 hours. Water was added, and the mixture was extracted with ethyl acetate. The extract was then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified sequentially by silica gel column chromatography and preparative TLC to give Example Compound 30 (yield 4.2 mg).

[0311] Example 31

[0312] [ka]

[0313] Process 1 Reference Synthesis Example Compound 58 (1.00 g, 4.11 mmol) was mixed with THF (21 mL), and then DMAP (50.3 mg, 0.412 mmol) and di-tert-butyl dicarbonate (1.17 g, 5.36 mmol) were added, followed by stirring at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 119 (yield 1.16 g). Process 2 Under ice cooling, a 1.8 mol / L LDA / normal hexane-THF solution (1.2 mL) was added to a solution of Reference Synthesis Example Compound 119 (600 mg, 1.75 mmol) and triisopropyl borate (0.64 mL, 2.8 mmol) in THF (1.2 mL), and the mixture was stirred at 0°C for 1 hour. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give Reference Synthesis Example Compound 120 (yield 317 mg). Process 3 Reference Synthesis Example Compound 120 (134 mg, 0.467 mmol), 4-(4-bromophenyl)morpholin-3-one (80.0 mg, 0.312 mmol), 1,4-dioxane (1.6 mL), and water (0.63 mL) were mixed, followed by the addition of cesium carbonate (153 mg, 0.470 mmol), XPhos (14.9 mg, 0.0313 mmol), and XPhos-palladium(crotyl)chloride (21.1 mg, 0.0313 mmol), and the mixture was stirred at 90°C for 2 hours. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 121 (yield 129 mg). Process 4 Ice-cooled Reference Synthesis Example Compound 121 (129 mg, 0.308 mmol) and DMF (3.1 mL) were mixed, and then sodium hydride (60% in oil) (16.0 mg, 0.400 mmol) was added and stirred at 0°C for 30 minutes. Ethyl iodide (74 μL, 0.93 mmol) was added, and the mixture was stirred at room temperature for 2 hours, then heated to 50°C and stirred for 3 hours. The reaction mixture was ice-cooled, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 122 (yield 108 mg) in a partially impure state. Process 5 Impurity-containing Reference Synthesis Example Compound 122 (129 mg) obtained by the method described in Step 4, methanol (1.4 mL), and THF (1.4 mL) were mixed, and then 4 mol / L aqueous sodium hydroxide solution (0.72 mL) was added and stirred at room temperature for 16 hours. 6 mol / L hydrochloric acid (0.53 mL) was added to the reaction solution, and the solvent was evaporated under reduced pressure to obtain Reference Synthesis Example Compound 123 as a sodium chloride mixture (yield 284 mg). Process 6 A mixture of Reference Synthesis Example Compound 123 (40.0 mg) with sodium chloride, 5-amino-2-fluorobenzamide (12.1 mg, 0.0785 mmol), and acetonitrile (393 μL) was mixed, followed by the addition of 1-methylimidazole (14 μL, 0.18 mmol) and TCFH (24.3 mg, 0.0866 mmol), and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Example Compound 31 (yield 9.6 mg).

[0314] Example compounds 15 to 128 in the following table were produced according to the methods shown in the above Examples 15 to 31 or methods similar thereto. 1 H-NMR data and / or LC / MS data are shown in the tables.

[0315]

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

[0316] Example 129

[0317] [ka]

[0318] Process 1 To a solution of Reference Synthesis Example Compound 124 (1.32 g, 7.7 mmol), 2-methyl-oxopentanoic acid (1.0 g, 7.7 mmol), and phenylsilane (831 mg, 7.7 mmol) in toluene (10 mL), indium(III) acetate (22.5 mg, 0.07 mmol) was added, and the mixture was stirred at 110°C under a nitrogen atmosphere for 20 hours. The reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. This reaction procedure was repeated 15 times, and the resulting crude products were combined and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 30 / 1). Simultaneous diastereomeric separation gave Reference Synthesis Example Compound 125 (the first peak diastereomer) (yield 15 g) and Reference Synthesis Example Compound 126 (the second peak diastereomer) (yield 7.0 g). Process 2 A preparative LC system (LC-Forte / R, manufactured by YMC Co., Ltd.) was equipped with a preparative chiral column (CHIRALART Cellulose-SB, manufactured by YMC Co., Ltd.) and equilibrated by passing a normal heptane / 2-propanol (9 / 1) mixture through the column at room temperature at a flow rate of 21 mL / min. Reference Synthesis Example Compound 126 (3.55 g) was dissolved in 2-propanol to prepare a 50 mg / mL solution. Normal heptane was added to this solution to prepare a 5 mg / mL solution of Reference Synthesis Example Compound 126 (Solution A). Approximately 30 mL of Solution A was injected, and the first peak (retention time: approximately 14.5 minutes) and the second peak (retention time: approximately 18.8 minutes) were separated and collected while observing with a UV detector (detection wavelength: 250 nm). (This procedure was repeated until the entire amount of Solution A was injected.) The solvent contained in each fraction was distilled off under reduced pressure to give Reference Synthesis Example Compound 127 (yield 1.72 g, optical purity >99.9% ee) from the fraction derived from the first peak, and Reference Synthesis Example Compound 128 (yield 1.69 g, optical purity 99.4% ee) from the fraction derived from the second peak. Process 3 Reference Synthesis Example Compound 127 (1.40 g, 5.22 mmol) was mixed with THF (0.026 L), followed by the addition of triethylamine (2.2 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.426 g, 0.522 mmol), copper(I) iodide (0.099 g, 0.52 mmol), and trimethylsilylacetylene (0.93 mL, 6.6 mmol), sequentially. The mixture was stirred at 75°C for 1.5 hours under an argon atmosphere. After cooling, the reaction mixture was diluted with chloroform and filtered through Celite®. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 129 (yield 1.38 g). Process 4 Reference Synthesis Example Compound 129 (1.39 g, 4.87 mmol) and THF (20.0 mL) were mixed, and then a 1 mol / L TBAF / THF solution (7.8 mL, 7.8 mmol) was added and stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 130 (yield 0.348 g). Process 5 Palladium(II) acetate (18.3 mg, 0.0808 mmol) and XPhos (77.1 mg, 0.162 mmol) were suspended in degassed acetonitrile (4.0 mL), and Reference Synthesis Example Compound 130 (0.345 g, 1.62 mmol), cesium carbonate (1.05 g, 3.22 mmol), and Reference Synthesis Example Compound 69 (0.694 g, 3.23 mmol) were added. The mixture was stirred at 95°C for 1.5 hours under an argon atmosphere. After cooling, the reaction mixture was diluted with water and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 131 (yield 0.370 g). Process 6 Reference Synthesis Example Compound 131 (0.365 g, 0.932 mmol) and methanol (2.3 mL) were mixed, degassed, and the reaction vessel was replaced with argon. Chloro(triphenylphosphine)gold(I) (92.2 mg, 0.186 mmol) and silver bis(trifluoromethanesulfonyl)imide (72.3 mg, 0.186 mmol) were then added, and the mixture was stirred at 80°C for 2 hours. After cooling, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 132 (yield 0.332 g). Process 7 Reference Synthesis Example Compound 132 (0.330 g, 0.843 mmol), THF (2.0 mL), and methanol (2.0 mL) were mixed, and then 4 mol / L aqueous sodium hydroxide solution (0.42 mL, 1.7 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 5 hours. 2 mol / L hydrochloric acid (1.5 mL) was added dropwise to the reaction mixture under ice cooling, and the solvent was evaporated under reduced pressure. Toluene was added to the residue, and the mixture was stirred. The solvent was evaporated under reduced pressure to obtain Reference Synthesis Example Compound 133 as a sodium chloride mixture (yield 0.447 g). Process 8 A mixture of Reference Example Compound 133 (30.0 mg) with sodium chloride obtained by the method described in Step 7 and acetonitrile (0.57 mL) was mixed, followed by the addition of 5-amino-2-fluorobenzamide (17.4 mg, 0.113 mmol), 1-methylimidazole (22.3 μL, 0.282 mmol), and TCFH (31.7 mg, 0.113 mmol) and stirring at room temperature for 15 hours. The mixture was diluted with water and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, and then ethanol (600 μL) was added for slurry washing. The solid was collected by filtration and dried under reduced pressure to give Example Compound 129 (yield 18.0 mg).

[0319] Example 130

[0320] [ka]

[0321] Process 1~6 Example Compound 130 (yield 11.3 mg) was obtained from Reference Synthesis Example Compound 126 in the same manner as in steps 3 to 8 of Example 129.

[0322] Example 131

[0323] [ka]

[0324] Process 1 Example Compound 131 (yield 5.0 mg) was obtained from Reference Synthesis Example Compound 138 in the same manner as in Step 8 of Example 129.

[0325] Example 132

[0326] [ka]

[0327] Process 1~5 Example Compound 132 (yield 16.6 mg) was obtained from Reference Example Compound 135 and Reference Example Compound 75 in the same manner as in steps 3 to 7 of Example 23.

[0328] Example 133

[0329] [ka]

[0330] Process 1 Example Compound 133 (yield 18.4 mg) was obtained from Reference Synthesis Example Compound 142 in the same manner as in Step 7 of Example 23.

[0331] Example 134

[0332] [ka]

[0333] Process 1~3 Example Compound 134 (yield 23.3 mg) was obtained from Reference Synthesis Example Compound 140 in the same manner as in steps 5 to 7 of Example 23.

[0334] Example 135

[0335] [ka]

[0336] Process 1 Example Compound 135 (yield 18.4 mg) was obtained from Reference Synthesis Example Compound 144 in the same manner as in Step 7 of Example 23.

[0337] Example 136

[0338] [ka]

[0339] Process 1~4 Example Compound 136 (yield 8.6 mg) was obtained from Reference Example Compound 135 and Reference Example Compound 91 in the same manner as in steps 2 to 5 of Example 26.

[0340] Example 137

[0341] [ka]

[0342] Process 1 Example Compound 137 (yield 9.5 mg) was obtained from Reference Example Compound 147 in the same manner as in Step 5 of Example 26.

[0343] Example compounds 129 to 137 in the following table were produced according to the methods shown in the above Examples 129 to 137 or methods similar thereto. 1 H-NMR data and / or LC / MS data are shown in the tables.

[0344] [Table 3-1] [Table 3-2]

[0345] Example 138

[0346] [ka]

[0347] Process 1 Reference Synthesis Example Compound 35 (500 mg, 1.02 mmol) and THF (10 mL) were mixed, and then a 4 mol / L lithium borohydride / THF solution (1 mL) was added, followed by stirring at 60°C for 4.5 hours. A saturated aqueous ammonium chloride solution and water were added to the cooled reaction solution, followed by extraction with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The mixture was then slurry-washed with a mixed solvent of ethyl acetate / normal hexane (1 / 5), and the solid was collected by filtration to give Reference Synthesis Example Compound 148 (yield 405 mg). Process 2 Reference Synthesis Example Compound 148 (20.0 mg, 0.0434 mmol) and THF (220 μL) were mixed, and then 3-hydroxybenzamide (7.2 mg, 0.053 mmol), triphenylphosphine (13.7 mg, 0.0522 mmol), and a 1.9 mol / L DIAD / toluene solution (27 μL) were added and stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The mixture was then slurry-washed with ethyl acetate / normal hexane (1 / 3), and the precipitated solid was collected by filtration to give Example Compound 138 (yield 18.3 mg).

[0348] Example 139

[0349] [ka] Process 1 Reference Synthesis Example Compound 148 (150 mg, 0.326 mmol) and dichloromethane (3.3 mL) were mixed and then cooled on ice. Triethylamine (181 μL, 1.30 mmol) and methanesulfonyl chloride (50.7 μL, 0.652 mmol) were added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 149 (yield 165 mg), which contained some impurities. Process 2 Reference Synthesis Example Compound 149 (15 mg) in a state containing some impurities obtained by the method described in Step 1 was mixed with DMF (313 μL), and then triethylamine (13.1 μL, 0.0942 mmol) and 3-aminobenzamide (8.5 mg, 0.062 mmol) were added, followed by stirring at 80° C. for 16 hours. Water was added to the cooled reaction solution, followed by extraction with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The mixture was then slurry-washed with ethyl acetate / normal hexane (1 / 3), and the solid was collected by filtration to obtain Example Compound 139 (yield 6.2 mg).

[0350] According to the methods shown in the above-mentioned Examples 138 to 139, Example Compounds 138 to 139 in the following table were prepared. 1 The H-NMR data and LC / MS data are shown in the table.

[0351] [Table 4]

[0352] Example 140

[0353] [ka]

[0354] Process 1 Reference Synthesis Example Compound 150 (300 mg, 1.20 mmol) and DMSO (5 mL) were mixed, and then DIPEA (618 μL, 3.60 mmol) and a 2.0 mol / L ethylamine-THF solution (900 μL) were added, followed by stirring at 70°C for 3 hours. Water was added to the cooled reaction mixture, which was then extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give Reference Synthesis Example Compound 151 (yield 319 mg), partially containing impurities. Process 2 Reference Synthesis Example Compound 151 (150 mg), containing impurities obtained by the method described in Step 1, was mixed with THF (2.5 mL), and then Reference Synthesis Example Compound 47 (183 mg, 0.858 mmol), triethylamine (241 μL, 1.73 mmol), copper(I) iodide (11 mg, 0.058 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21.2 mg, 0.029 mmol) were added, followed by stirring at 90°C for 18 hours under an argon atmosphere. Water was added to the cooled reaction mixture, which was then extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 152 (yield 224 mg). Process 3 Reference Synthesis Example Compound 152 (50.0 mg, 0.128 mmol) and DMF (1 mL) were mixed, and then copper(I) iodide (15 mg, 0.079 mmol) was added. The mixture was stirred at 110°C for 18 hours under an argon atmosphere. Water was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 153 (yield 38 mg). Process 4 Reference Synthesis Example Compound 153 (34.0 mg, 0.0657 mmol), methanol (0.5 mL), and THF (0.5 mL) were mixed, and then 4 mol / L aqueous sodium hydroxide solution (164 μL) was added and the mixture was stirred for 4 hours at 60° C. 2 mol / L hydrochloric acid and water were added to the cooled reaction mixture, and the solvent was then distilled off under reduced pressure to obtain Reference Synthesis Example Compound 154 as a mixture with sodium chloride (yield 72 mg). Process 5 A mixture (72 mg) of Reference Example Compound 154 obtained by the method described in Step 4 and sodium chloride was mixed with acetonitrile (1 mL), and then 5-amino-2-fluorobenzamide (14.8 mg, 0.0960 mmol), 1-methylimidazole (30.3 μL, 0.384 mmol), and TCFH (35.9 mg, 0.128 mmol) were added sequentially and stirred at 40°C for 1.5 hours. Water and 1 mol / L hydrochloric acid were added to the reaction mixture, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and then slurry washed with a normal hexane / ethyl acetate (3 / 1) mixed solvent to obtain Example Compound 140 (yield 30.1 mg).

[0355] Example 141

[0356] [ka]

[0357] Process 1 Reference Synthesis Example Compound 32 (255 mg, 1.05 mmol) and DMF (5 mL) were mixed and then cooled on ice. Sodium hydride (60% in oil) (54.5 mg, 1.36 mmol) was added and stirred for 10 minutes. Ethyl iodide (118 μL, 1.475 mmol) was added to the reaction solution and stirred at room temperature for 1 hour. The reaction solution was added dropwise to an ice-cooled saturated aqueous ammonium chloride solution, diluted with water, and extracted with ethyl acetate. Normal hexane was added to the extract, which was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 155 (yield 214 mg). Process 2 Reference Synthesis Example Compound 155 (212 mg, 0.782 mmol) and dichloromethane (5 mL) were mixed and cooled on ice. A solution of NCS (135 mg, 1.01 mmol) in dichloromethane (1 mL) was added dropwise and stirred at room temperature for 3 hours. DMF (5 mL) was added and the mixture was stirred at 60°C for 3 hours. The cooled reaction mixture was diluted with water and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 156 (yield 170 mg). Process 3 Reference Synthesis Example Compound 156 (168 mg, 0.550 mmol) and carbon tetrachloride (5 mL) were mixed, cooled on ice, and NBS (118 mg, 0.663 mmol) was added, followed by stirring at 60°C for 13 hours. Water was added to the cooled reaction mixture, which was then extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 157 (yield 117 mg). Process 4~6 Example Compound 141 (yield 10.2 mg) was obtained from Reference Synthesis Example Compound 157 (115 mg, 0.300 mmol) in a manner similar to steps 5 to 7 of Example 17.

[0358] Example compounds 140 to 143 in the following table were produced according to the methods shown in the above Examples 140 to 141 or methods similar thereto. 1 H-NMR data and / or LC / MS data are shown in the tables.

[0359] [Table 5]

[0360] Example 144

[0361] [ka]

[0362] Process 1~2 Reference Synthesis Example Compound 162 was obtained from Reference Synthesis Example Compound 160 in the same manner as in steps 1 and 2 of Example 15. Process 3 Reference Synthesis Example Compound 163 (3.00 g, 17.0 mmol) and DMF (85 mL) were mixed and then cooled on ice. Sodium hydride (60% in oil) (885 mg, 22.1 mmol) was added and stirred for 30 minutes. Paratoluenesulfonyl chloride (4.87 g, 25.5 mmol) was added to the reaction mixture and stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the ice-cooled reaction mixture, followed by extraction with ethyl acetate. The extract was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 164 (yield 2.36 g). Process 4 Reference Synthesis Example Compound 164 (2.36 g, 7.14 mmol) and THF (36 mL) were mixed and cooled to −78°C. LDA / normal hexane-THF solution (1.09 mol / L, 9.2 mL) was added and stirred at −78°C for 30 minutes. Iodine (2.72 g, 10.7 mmol) was added to the reaction mixture, which was stirred at −78°C for 30 minutes, then warmed to room temperature and stirred for 1 hour. The reaction mixture was ice-cooled, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 165 (yield 1.53 g). Process 5 Reference Synthesis Example Compound 165 (1.20 g, 2.63 mmol) and THF (13 mL) were mixed and then cooled on ice. A sodium methoxide / methanol solution (5 mol / L, 2.6 mL) was added and the mixture was stirred for 1 hour under ice cooling. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 166 (yield 429 mg). Process 6 Reference Synthesis Example Compound 166 (429 mg) and DMF (14 mL) were mixed and then cooled on ice. Sodium hydride (60% in oil) (85.2 mg, 2.13 mmol) was added and stirred for 20 minutes under ice cooling. Ethyl iodide (341 μL, 4.26 mmol) was added to the reaction mixture and stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the ice-cooled reaction mixture, followed by extraction with ethyl acetate. The extract was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 167 (yield 168 mg). Process 7 Reference Synthesis Example Compound 167 (168 mg, 0.488 mmol), methanol (1.2 mL), and THF (1.2 mL) were mixed, and then 4 mol / L aqueous sodium hydroxide solution (610 μL) was added and stirred at room temperature for 12 hours. 10% aqueous citric acid solution was added to the reaction mixture and stirred, and the solvent was then distilled off under reduced pressure. A small amount of ethanol and water were added to the residue, and the precipitate was collected by filtration to give Reference Synthesis Example Compound 168 (yield 112 mg). Process 8 Reference Synthesis Example Compound 168 (100 mg, 0.316 mmol), 5-amino-2-fluorobenzamide (73.1 mg, 0.474 mmol), and acetonitrile (1.6 mL) were mixed, and then 1-methylimidazole (100 μL, 1.27 mmol) and TCFH (178 mg, 0.634 mmol) were added, followed by stirring at room temperature for 16 hours. Water was added to the reaction mixture, and the precipitate was collected by filtration to give Reference Synthesis Example Compound 169 (yield 97.3 mg). Process 9 Reference Synthesis Example Compound 169 (20.0 mg, 0.0442 mmol), 1,4-dioxane (442 μL), and water (58 μL) were mixed, and then Reference Synthesis Example Compound 162 (20.0 mg, 0.0663 mmol), cesium carbonate (21.6 mg, 0.0663 mmol), XPhos (1.1 mg, 0.0023 mmol), and XPhos-palladium(crotyl)chloride (1.5 mg, 0.0022 mmol) were added, followed by stirring at 90°C for 2 hours. Water was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Example Compound 144 (yield 13.6 mg).

[0363] Example 145

[0364] [ka]

[0365] Process 1 Reference Synthesis Example Compound 170 (yield 110 mg) was obtained from Reference Synthesis Example Compound 65 (100 mg, 0.372 mmol) in a manner similar to that in Step 2 of Example 15. Process 2~8 Example Compound 145 (yield 15.6 mg) was obtained from Reference Synthesis Example Compound 28 in the same manner as in Steps 3 to 9 of Example 144.

[0366] Example 146

[0367] [ka]

[0368] Process 1 Reference Synthesis Example Compound 119 (10.0 g, 29.1 mmol) and THF (290 mL) were mixed and cooled to -20°C. LDA / normal hexane-THF solution (1.09 mol / L) (29 mL) was added and stirred at -20°C for 30 minutes. Iodine (8.87 g, 34.9 mmol) was added to the reaction mixture, which was stirred at -20°C for 1 hour, then warmed to room temperature and stirred for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 177 (yield 7.41 g). Process 2 Reference Synthesis Example Compound 177 (7.41 g, 15.8 mmol) and 1,1,1,3,3,3-hexafluoro-2-propanol (34 mL) were mixed and stirred under microwave irradiation at 150° C. for 30 minutes. After cooling, the solvent was distilled off under reduced pressure to obtain Reference Synthesis Example Compound 178 (yield 5.43 g). Process 3 Reference Synthesis Example Compound 178 (5.00 g, 13.5 mmol) and DMF (68 mL) were mixed and then cooled on ice. Sodium hydride (60% in oil) (813 mg, 20.3 mmol) was added and stirred for 10 minutes. Ethyl iodide (5.4 mL, 68 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the ice-cooled reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 179 (yield 4.62 g). Process 4~6 Example Compound 146 (yield 29.5 mg) was obtained from Reference Synthesis Example Compound 179 in the same manner as in Steps 7 to 9 of Example 144.

[0369] Example 147

[0370] [ka]

[0371] Process 1 In the same manner as in Step 8 of Example 144, Reference Synthesis Example Compound 183 (yield 142 mg) was obtained from Reference Synthesis Example Compound 168 and methyl 5-amino-2-fluorobenzoate. Process 2 Reference Synthesis Example Compound 183 (142 mg, 0.304 mmol), methanol (1.5 mL), and THF (1.5 mL) were mixed, and then 4 mol / L aqueous sodium hydroxide solution (380 μL) was added and stirred at room temperature for 2 hours. 2 mol / L hydrochloric acid (1.2 mL) was added to the reaction mixture, and the solvent was evaporated under reduced pressure to give Reference Synthesis Example Compound 184 as a sodium chloride mixture (yield 254 mg). Process 3 The sodium chloride mixture (254 mg) of Reference Synthesis Example Compound 184 obtained by the method of Step 2 was mixed with acetonitrile (5.0 mL), and 2-aminoacetonitrile hydrochloride (33.8 mg, 0.365 mmol), TCFH (171 mg, 0.609 mmol), and 1-methylimidazole (120 μL, 1.52 mmol) were added, followed by stirring at room temperature overnight. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 185 (yield 114 mg). Process 4 Reference Synthesis Example Compound 186 (yield 103 mg) was obtained from Reference Synthesis Example Compound 127 (100 mg, 0.373 mmol) in a manner similar to that in Step 2 of Example 144. Process 5 Reference Synthesis Example Compound 185 (15.0 mg, 0.0305 mmol), 1,4-dioxane (2.0 mL), and water (400 μL) were mixed and degassed. After that, Reference Synthesis Example Compound 186 (19.2 mg, 0.0609 mmol), cesium carbonate (19.9 mg, 0.0611 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4.5 mg, 0.0062 mmol) were added, and the mixture was stirred at 90°C for 2 hours. A saturated aqueous ammonium chloride solution was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give Example Compound 147 (yield 12.1 mg).

[0372] Example compounds 144 to 156 in the following table were produced according to the methods shown in the above Examples 144 to 147 or methods similar thereto. 1 H-NMR data and / or LC / MS data are shown in the tables.

[0373] [Table 6-1] [Table 6-2] [Table 6-3]

[0374] Example 157

[0375] [ka]

[0376] Process 1 Reference Synthesis Example Compound 187 (200 mg, 0.844 mmol) was mixed with 1,4-dioxane (2.8 mL), and then 3,5-dimethylpyrrolidin-2-one (105 mg, 0.928 mmol), tripotassium phosphate (269 mg, 1.27 mmol), and Xantphos-PD-G3 (68.0 mg, 0.0845 mmol) were added, followed by stirring at 100°C for 4 hours. Water was added to the cooled reaction mixture, which was then extracted with ethyl acetate. The extract was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography. Simultaneous diastereomeric separation gave Reference Synthesis Example Compound 188 (yield 86.3 mg) and Reference Synthesis Example Compound 189 (79.5 mg), respectively. Process 2 Reference Synthesis Example Compound 189 (50.0 mg, 0.186 mmol) was mixed with 1,4-dioxane (1.9 mL), and then bis(pinacolato)diboron (70.8 mg, 0.279 mmol), potassium acetate (36.5 mg, 0.372 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13.6 mg, 0.0186 mmol) were added, followed by stirring at 100°C for 3 hours. Water was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 190 (yield 53.6 mg). Process 3 Reference Synthesis Example Compound 181 (30.0 mg, 0.0578 mmol), 1,4-dioxane (578 μL), and water (58 μL) were mixed, and then Reference Synthesis Example Compound 190 (27.4 mg, 0.0867 mmol), cesium carbonate (28.2 mg, 0.0866 mmol), XPhos (1.4 mg, 0.0029 mmol), and XPhos-palladium(crotyl)chloride (2.0 mg, 0.0030 mmol) were added, followed by stirring at 90°C for 2 hours. Water was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Example Compound 157 (yield 22.5 mg).

[0377] Example 158

[0378] [ka]

[0379] Process 1-A Reference Synthesis Example Compound 191 (yield 1.42 g) was obtained from Reference Synthesis Example Compound 126 (1.00 g, 3.73 mmol) in the same manner as in Step 2 of Example 157. Process 1-B Reference Synthesis Example Compound 192 (yield 38.8 mg) was obtained from Reference Synthesis Example Compound 175 (50.0 mg, 0.159 mmol) in a manner similar to that in Step 7 of Example 145. Process 2 Example compound 158 (yield 18.9 mg) was obtained from Reference Example compound 191 (31.4 mg, 0.0996 mmol) and Reference Example compound 192 (30.0 mg, 0.0665 mmol) in the same manner as in Step 3 of Example 157.

[0380] Example 159

[0381] [ka]

[0382] Process 1~3 Example Compound 159 (yield 10.6 mg) was obtained from Reference Synthesis Example Compound 191 in the same manner as in steps 3 to 5 of Example 15.

[0383] Example 160

[0384] [ka]

[0385] Process 1 Example Compound 160 (yield 17.2 mg) was obtained from Reference Synthesis Example Compound 194 (22 mg, 0.050 mmol) in the same manner as in Step 5 of Example 15.

[0386] Example 161

[0387] [ka]

[0388] Process 1 Example Compound 161 (yield 5.4 mg) was obtained from Reference Synthesis Example Compound 194 (22 mg, 0.050 mmol) in a manner similar to that in Step 5 of Example 15.

[0389] According to the methods shown in the above-mentioned Examples 157 to 161, Example Compounds 157 to 161 in the following table were prepared. 1 The H-NMR data and LC / MS data are shown in the table.

[0390] [Table 7]

[0391] Example 162

[0392] [ka]

[0393] Process 1 Acetonitrile (0.032 L), methyl 3-aminobenzoate (0.717 g, 4.74 mmol), 1-methylimidazole (1.0 mL, 13 mmol), and TCFH (1.33 g, 4.74 mmol) were added sequentially to Reference Synthesis Example Compound 36 (1.50 g, 3.16 mmol) and stirred at room temperature for 16 hours. The solvent was removed by distillation under reduced pressure, and ethyl acetate and 1 mol / L hydrochloric acid were added and stirred. The organic layer was separated. The separated organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and chloroform was added to the residue, followed by filtration. The filtrate was purified by silica gel column chromatography, followed by slurry washing with a 1 / 3 ethyl acetate / normal hexane mixture (10 mL). The solid was collected by filtration to obtain Reference Synthesis Example Compound 195 (yield 1.56 g). Process 2 To Reference Synthesis Example Compound 195 (407 mg, 0.670 mmol), THF (4.1 mL), methanol (4.1 mL), and 4 mol / L aqueous sodium hydroxide solution (1.7 mL, 6.8 mmol) were added successively, and the mixture was stirred at room temperature for 5 hours. 2 mol / L hydrochloric acid (8 mL) was added dropwise to the reaction mixture, and the mixture was stirred. The mixture was then diluted with water and extracted with a chloroform / methanol (10 / 1) mixture. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give Example Compound 162 (yield 397 mg).

[0394] Example 163

[0395] [ka]

[0396] Process 1 Acetonitrile (500 μL) and TCFH (9.5 mL, 0.034 mmol) were added to Example Compound 162 (10 mg, 0.017 mmol), and the mixture was stirred for 10 minutes. Then, 1H-pyrazol-3-amine (2.8 mg, 0.034 mmol) and 1-methylimidazole (5.3 μL, 0.067 mmol) were added, and the mixture was stirred for 14 hours at 60° C. The reaction solution was concentrated under reduced pressure, and the residue was purified sequentially by preparative thin-layer chromatography (silica gel) and silica gel column chromatography to give Example Compound 163 (yield 9.1 mg).

[0397] Example 164

[0398] [ka]

[0399] Process 1 A mixture of Reference Synthesis Example Compound 72 (50.0 mg) with sodium chloride, obtained by a method similar to that of Step 4 of Example 21, was mixed with acetonitrile (0.77 mL), and then methyl 3-aminobenzoate (23.3 mg, 0.154 mmol), 1-methylimidazole (30.5 μL, 0.386 mmol), and TCFH (43.3 mg, 0.154 mmol) were added and stirred at room temperature for 15 hours. The reaction mixture was diluted with chloroform and water, and the organic layer was separated. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 196 (yield 39.4 mg). Process 2 Reference Synthesis Example Compound 196 (0.340 g, 0.666 mmol) and THF (1.7 mL) were mixed, and then methanol (1.7 mL) and 4 mol / L aqueous sodium hydroxide solution (0.666 mL, 2.66 mmol) were added, followed by stirring at room temperature for 2 hours. 2 mol / L hydrochloric acid (2.0 mL) was added dropwise to the reaction mixture, and the solvent was distilled off under reduced pressure. A small amount of toluene was added for azeotropic dehydration. The residue was purified by silica gel column chromatography to give Example Compound 164 (yield 0.298 g).

[0400] Example 165

[0401] [ka]

[0402] Process 1 Example compound 164 (13.0 mg, 0.0262 mmol) and acetonitrile (0.26 mL) were mixed, and then 3-amino-1,5-dimethyl-pyridin-2-one (3.6 mg, 0.026 mmol), 1-methylimidazole (10.3 μL, 0.130 mmol), and TCFH (14.6 mg, 0.520 mmol) were added and stirred at room temperature for 15 hours. The reaction solution was diluted with chloroform and water, and the organic layer was separated. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Example compound 165 (yield 10.2 mg).

[0403] Example 166

[0404] [ka]

[0405] Process 1 Reference Synthesis Example Compound 196 (38.0 mg, 0.0744 mmol) and THF (0.19 mL) were mixed, and then methanol (0.19 mL) and 4 mol / L aqueous sodium hydroxide solution (74.4 μL, 0.298 mmol) were added, followed by stirring at room temperature for 2 hours. 2 mol / L hydrochloric acid (0.25 mL) was added dropwise to the reaction mixture, and the solvent was then distilled off under reduced pressure. Toluene was added to the residue for azeotropic dehydration, followed by drying under reduced pressure to obtain Reference Synthesis Example Compound 197 as a sodium chloride mixture (yield 51.2 mg). Process 2 A mixture of Reference Synthesis Example Compound 197 and sodium chloride (25.0 mg) and acetonitrile (0.33 mL) was mixed, and then 5-amino-1,3-dimethyl-pyrimidine-2,4-dione (5.6 mg, 0.036 mmol), 1-methylimidazole (12.9 μL, 0.163 mmol), and TCFH (18.3 mg, 0.0652 mmol) were added and stirred at room temperature for 15 hours. The reaction mixture was diluted with chloroform and water, and the organic layer was separated. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Example Compound 166 (yield 18.8 mg).

[0406] Example 167

[0407] [ka]

[0408] Process 1 A mixture of Reference Synthesis Example Compound 197 (20.0 mg) with sodium chloride obtained by the method of Step 2 of Example 166 and acetonitrile (0.26 mL) was mixed, and then 5-amino-3-methyl-pyrimidin-4-one (3.9 mg, 0.031 mmol), 1-methylimidazole (10.3 μL, 0.130 mmol), and TCFH (14.6 mg, 0.0520 mmol) were added and stirred at room temperature for 15 hours. The reaction solution was diluted with chloroform and water, and the organic layer was separated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give Example Compound 167 (yield 9.3 mg).

[0409] Example 168

[0410] [ka]

[0411] Process 1 Acetonitrile (5 mL), methyl 5-amino-2-fluorobenzoate (78.3 mg, 0.463 mmol), 1-methylimidazole (183 μL, 2.32 mmol), and TCFH (130 mg, 0.463 mmol) were added sequentially to a mixture of Reference Synthesis Example Compound 72 and sodium chloride (150 mg) obtained by a method similar to that of Step 4 of Example 21, and the mixture was stirred at 40° C. for 15 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was stirred, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example Compound 198 (yield 127 mg) containing some impurities. Process 2 Reference Synthesis Example Compound 198 (122 mg), which was contaminated with impurities obtained by the method of Step 1, methanol (1.5 mL), and THF (1.5 mL) were mixed, and then 4 mol / L aqueous sodium hydroxide solution (346 μL) was added and stirred at room temperature for 2 hours. The reaction solution was neutralized with 2 mol / L hydrochloric acid, and the solvent was then distilled off under reduced pressure. The resulting solid was dried under reduced pressure to give Reference Synthesis Example Compound 199 (a sodium chloride mixture) (yield: 210 mg). Process 3 To the sodium chloride mixture (30 mg) of Reference Synthesis Example Compound 199 obtained by the method of Step 2, 2-aminoacetonitrile hydrochloride (39.0 mg, 0.421 mmol), DMF (1.5 mL), DIPEA (35 μL, 0.20 mmol), and HATU (25.3 mg, 0.0665 mmol) were added sequentially, and the mixture was stirred at 55° C. for 4 hours, followed by stirring at room temperature for 16 hours. Water and ethyl acetate were added, and the mixture was stirred, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and the resulting solid was slurry-washed with a normal hexane / ethyl acetate (4 / 1) mixture, and the solid was collected by filtration to give Example Compound 168 (yield 12.9 mg).

[0412] Example 169

[0413] [ka]

[0414] Process 1 Acetonitrile (500 μL), TCFH (355 mg, 1.27 mmol), and 1-methylimidazole (200 μL, 2.53 mmol) were added sequentially to Reference Synthesis Example Compound 200 (200 mg, 0.843 mmol) and stirred for 10 minutes. 3-amino-1-methyl-pyridin-2-one (157 mg, 1.26 mmol) was then added and stirred at 40° C. for 2 hours. Ethyl acetate and saturated brine were added and stirred, and the organic layer was separated. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography. The residue was then slurry-washed with an ethyl acetate / normal hexane mixture, and the solid was collected by filtration to obtain Reference Synthesis Example Compound 201 (yield 267 mg). Process 2 A 4 mol / L hydrogen chloride / 1,4-dioxane solution (5 mL) was added to Reference Synthesis Example Compound 201 (419 mg, 1.22 mmol) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure to give Reference Synthesis Example Compound 202 (yield 267 mg). Process 3 Acetonitrile (500 μL), TCFH (13 mg, 0.046 mmol), and 1-methylimidazole (18.3 μL, 0.232 mmol) were added sequentially to a mixture of Reference Synthesis Example Compound 72 and sodium chloride (15 mg) obtained by a method similar to that of Step 4 of Example 21, and the mixture was stirred for 10 minutes. Reference Synthesis Example Compound 202 (13 mg, 0.046 mmol) was added, and the mixture was stirred at 50° C. for 14 hours. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (silica gel). The resulting solid was then slurry-washed with a normal hexane / ethyl acetate mixture to give Example Compound 169 (yield 3.1 mg).

[0415] Example compounds 162 to 202 in the following table were produced according to the methods shown in the above Examples 162 to 169 or methods similar thereto. 1 H-NMR data and / or LC / MS data are shown in the tables.

[0416] [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] [Table 8-8] [Table 8-9]

[0417] Example 203

[0418] [ka]

[0419] Process 1 Example compound 14 (39.8 mg, 0.0705 mmol), Reference Synthesis Example compound 203 (54.3 mg, 0.367 mmol), 1,4-dioxane (700 μL), and water (64 μL) were mixed, and then cesium carbonate (33.2 mg, 0.102 mmol), XPhos (3.9 mg, 0.0082 mmol), and XPhos-palladium(crotyl)chloride (4.7 mg, 0.0070 mmol) were added, followed by stirring at 100°C for 2 hours. Water was added to the cooled reaction solution, and the mixture was extracted with ethyl acetate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Example compound 203 (yield 33.6 mg).

[0420] Example 204

[0421] [ka]

[0422] Process 1 Example compound 203 (23.0 mg, 0.0438 mmol) and methanol (1 mL) were mixed, and then 20% palladium hydroxide / carbon (4.8 mg) was added, followed by stirring at room temperature under a hydrogen atmosphere for 17 hours. The reaction solution was filtered through Celite (registered trademark), and the solvent was evaporated under reduced pressure to give Example compound 204 (yield 18.6 mg).

[0423] Example 205

[0424] [ka]

[0425] Process 1 Example compound 14 (50.3 mg, 0.0891 mmol) and 1,4-dioxane (886 μL) were mixed, followed by the addition of Reference Synthesis Example compound 204 (46.9 mg, 0.478 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13.1 mg, 0.0179 mmol), copper(I) iodide (4.0 mg, 0.021 mmol), and triethylamine (25 μL, 0.179 mmol). The mixture was stirred at 100°C for 3 hours under an argon atmosphere. Water was added to the cooled reaction mixture, followed by extraction with ethyl acetate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Synthesis Example compound 205 (yield 22.0 mg). Process 2 Reference Synthesis Example Compound 205 (18.0 mg, 0.0309 mmol) and methanol (1 mL) were mixed, and then 20% palladium hydroxide / carbon (3.5 mg) was added, followed by stirring at room temperature under a hydrogen atmosphere (normal pressure) for 17 hours. The reaction solution was filtered through Celite (registered trademark), and the solvent was distilled off under reduced pressure to give Example Compound 205 (yield 18.2 mg).

[0426] Example 206

[0427] [ka]

[0428] Process 1 Example compound 14 (39.7 mg, 0.0703 mmol) and 1,4-dioxane (700 μL) were mixed, and then trimethylsilylacetylene (50 μL, 0.35 mmol), dichlorobis(triphenylphosphine)palladium(II) (5.8 mg, 0.0083 mmol), copper(I) iodide (3.3 mg, 0.017 mmol), and triethylamine (19.8 μL, 0.142 mmol) were added, followed by stirring at 100°C for 3 hours under an argon atmosphere. Water was added to the cooled reaction solution, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Example Compound 206 (yield 11.3 mg). Process 2 Reference Synthesis Example Compound 206 (7.0 mg, 0.012 mmol) and THF (0.4 mL) were mixed, and then a TBAF / THF solution (1.00 mol / L) (24 μL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give Example Compound 206 (yield 6.0 mg).

[0429] Example compounds 203 to 212 in the following table were prepared according to the methods described in the above Examples 203 to 206 or methods similar thereto. 1 H-NMR data and / or LC / MS data are shown in the tables.

[0430] [Table 9-1] [Table 9-2]

[0431] Example 213

[0432] [ka]

[0433] Process 1 Example compound 207 (280 mg, 0.547 mmol) and 1,4-dioxane (5.5 mL) were mixed, and then water (1.8 mL), 2,6-dimethylpyridine (127 μL, 1.09 mmol), sodium periodate (470 mg, 2.20 mmol), and osmium tetroxide / tert-butyl alcohol (2.5 w / v%) (280 μL) were added sequentially under ice cooling, followed by stirring at room temperature for 1.5 hours. A saturated aqueous solution of sodium thiosulfate was added to the reaction mixture, which was then extracted with ethyl acetate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Reference Example Compound 207 (yield 280 mg). Process 2 Reference Synthesis Example Compound 207 (19.3 mg, 0.0376 mmol) and methanol (390 μL) were mixed, then cooled on ice, and sodium borohydride (14.7 mg, 0.389 mmol) was added and stirred at room temperature for 7 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Example Compound 213 (yield 9.6 mg).

[0434] Example 214

[0435] [ka]

[0436] Process 1 Example compound 213 (73 mg, 0.14 mmol) and dichloromethane (1.4 mL) were mixed and then cooled on ice. Triethylamine (118 μL, 0.849 mmol) and methanesulfonyl chloride (44 μL, 0.57 mmol) were added, and the mixture was stirred at room temperature for 23 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Reference Synthesis Example compound 208 (yield 38.5 mg). Process 2 Reference Synthesis Example Compound 208 (9.8 mg, 0.018 mmol) and DMSO (370 μL) were mixed, and then sodium cyanide (5.1 mg, 0.10 mmol) was added and stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and then slurry washed with a mixed solvent of ethyl acetate / normal hexane (1 / 4) to obtain Example Compound 214 (yield 4.1 mg).

[0437] Example 215

[0438] [ka] Process 1 Reference Synthesis Example Compound 208 (18.7 mg, 0.0350 mmol) and methanol (700 μL) were mixed, and then sodium methoxide (5.9 mg, 0.11 mmol) was added and the mixture was stirred at room temperature for 48 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give Example Compound 215 (yield 2.1 mg).

[0439] Example 216

[0440] [ka]

[0441] Process 1 Example compound 140 (25.4 mg, 0.0397 mmol), ethanol (1 mL), and THF (1 mL) were mixed, and then 20% palladium hydroxide on carbon (2 mg) was added and stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction solution was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give Example compound 216 (yield 17.2 mg).

[0442] Example 217

[0443] [ka]

[0444] Process 1 Example compound 95 (20 mg, 0.035 mmol) and pyridine (500 μL) were mixed, and then methanesulfonyl chloride (4 μL, 0.05 mmol) was added and stirred at room temperature for 4 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give Example compound 217 (yield 12.7 mg).

[0445] According to the methods shown in the above-mentioned Examples 213 to 217, Example Compounds 213 to 217 in the following table were prepared. 1 H-NMR data and / or LC / MS data are shown in the tables.

[0446] [Table 10]

[0447] Example 218

[0448] [ka]

[0449] Process 1~3 Example Compound 218 (yield 27.0 mg) was obtained from Reference Synthesis Example Compound 2 in the same manner as in steps 2 to 4 of Example 11.

[0450] Examples 219 and 220

[0451] [ka]

[0452] Process 1 A preparative LC system (LC-Forte / R, manufactured by YMC Co., Ltd.) was equipped with a preparative chiral column (CHIRALPAK IC, manufactured by Daicel Corporation) and equilibrated by passing an ethanol / normal hexane (1 / 1) mixture through the column at room temperature at a flow rate of 8.0 mL / min. Example compound 218 (12.8 mg, 0.0220 mmol) in ethanol (8 mL) was prepared as solution A. Solution A (4 mL) was injected, and the first peak (retention time: approximately 24 minutes) and the second peak (retention time: approximately 37 minutes) were separated and collected while observing with a UV detector (this procedure was repeated twice). The solvent contained in each fraction was distilled off under reduced pressure to obtain Example compound 219 (yield: 4.9 mg) from the fraction derived from the first peak, and Example compound 220 (yield: 4.5 mg) from the fraction derived from the second peak.

[0453] Examples 221 and 222

[0454] [ka]

[0455] Process 1~5 Reference Synthesis Example Compound 215 (yield 26.2 mg) was obtained from Reference Synthesis Example Compound 68 in the same manner as in steps 1 to 5 of Example 21. Process 6 A preparative LC system (LC-Forte / R, manufactured by YMC Co., Ltd.) was equipped with a preparative chiral column (CHIRALPAK IC, manufactured by Daicel Corporation) and equilibrated by passing an ethanol / normal-hexane (4 / 1) mixture through the column at room temperature at a flow rate of 20.0 mL / min. Reference Synthesis Example Compound 215 (26.2 mg, 0.0427 mmol) in ethanol (5.2 mL) was prepared as Solution A. Solution A (2-3 mL) was injected, and the first peak (retention time: approximately 11.5 minutes) and the second peak (retention time: approximately 14.0 minutes) were separated and collected while observing with a UV detector (this procedure was repeated twice). The solvent contained in each fraction was distilled off under reduced pressure to obtain Example Compound 221 (yield: 12.0 mg) from the fraction derived from the first peak, and Example Compound 222 (yield: 11.4 mg) from the fraction derived from the second peak.

[0456] Examples 223 and 224

[0457] [ka]

[0458] Process 1 Reference Synthesis Example Compound 216 (yield 31.2 mg) was obtained from Reference Synthesis Example Compound 214 in the same manner as in Step 5 of Example 21. Process 2 A preparative LC system (LC-Forte / R, manufactured by YMC Co., Ltd.) was equipped with a preparative chiral column (CHIRALPAK IC, manufactured by Daicel Corporation) and equilibrated by passing an ethanol / normal hexane (4 / 1) mixture through the column at room temperature at a flow rate of 20.0 mL / min. Reference Synthesis Example Compound 216 (31.2 mg, 0.0431 mmol) in ethanol (6.2 mL) was prepared as Solution A. Solution A (approximately 3 mL) was injected, and the first peak (retention time: approximately 11.0 minutes) and the second peak (retention time: approximately 13.5 minutes) were separated and collected while observing with a UV detector (this procedure was repeated twice). The solvent contained in each fraction was distilled off under reduced pressure to obtain Example Compound 223 (yield: 10.8 mg) from the fraction derived from the first peak, and Example Compound 224 (yield: 11.4 mg) from the fraction derived from the second peak.

[0459] According to the methods shown in the above-mentioned Examples 218 to 224, Example Compounds 218 to 224 in the following table were prepared. 1 H-NMR data and / or LC / MS data are shown in the tables.

[0460] [Table 11-1] [Table 11-2]

[0461] Test Example 1: Measurement of binding inhibitory activity between human STAT6 and pIL-4Rα by fluorescence polarization method 1) Construction of histidine-tagged recombinant human STAT6 (123-658 region) E. coli was transfected with a histidine-tagged recombinant human STAT6 (rhSTAT6) expression vector [plasmid DNA containing the nucleic acid sequence of human STAT6 (region 123-658) inserted into the pET28a(+) vector (Novagen)] and cultured overnight at 17°C with IPTG treatment. After disruption of the E. coli cells with a high-pressure homogenizer (EmulsiFlex-C3, AVESTIN), rhSTAT6 was purified by affinity purification using Ni-NTA agarose (Qiagen), cation exchange chromatography using HiTrap® CM-FF (GE Healthcare), and gel filtration chromatography using Superdex® 200 10 / 300GL (GE Healthcare). 2) Fluorescence polarization assay to measure the binding inhibitory activity between human STAT6 and pIL-4Rα A DMSO solution of the example compound was diluted with an assay buffer (e.g., a buffer consisting of 50 mmol / L NaCl, 10 mmol / L HEPES (pH 7.0), 1 mmol / L DTT, 1 mmol / L EDTA, and 0.01 vol% NP-40) to prepare a compound-added solution. The DMSO concentration in the compound-added solution was adjusted to 1 or 2 vol%. Ten microliters of the compound-added solution and the assay buffer containing 1 or 2 vol% DMSO were added to each well of a 384-well plate. Five microliters of an rhSTAT6-containing assay buffer solution (rhSTAT6 concentration: e.g., 1 μmol / L) or the assay buffer was added to each well of the 384-well plate. After allowing the plate to stand at room temperature for 30 minutes in the dark, 5 μL of an assay buffer solution containing FAM-labeled phosphorylated IL-4Rα peptide (sequence: FAM-Ala-pTyr-Lys-Pro-Phe-Gln-Asp-Leu-Ile-NH2) (hereinafter referred to as FAM-pIL-4Rp) (FAM-pIL-4Rp concentration: e.g., 80 nmol / L) or 2 vol% DMSO-containing assay buffer was added to each well of a 384-well plate. After allowing the plate to stand at room temperature for 30 minutes in the dark, the plate was centrifuged (200 g, 1 minute, room temperature). Fluorescence polarization values ​​were measured using an Infinite® F500 (Tecan Japan Co., Ltd.) (Excitation: 485 nm, Emission: 535 nm). The inhibition rate of each example compound was calculated using the following formula: (A) Fluorescence polarization value when rhSTAT6 and FAM-pIL-4Rp were added without adding the example compound; (B) Fluorescence polarization value when FAM-pIL-4Rp was added without adding the example compound and rhSTAT6; and (C) Fluorescence polarization value when each example compound, rhSTAT6, and FAM-pIL-4Rp were added. Inhibition rate (%) = ((A-C) / (A-B)) x 100 In the evaluation of each example compound, the 50% inhibitory concentration (IC 50 The IC of the example compounds was calculated. 50 The values ​​are shown in the table below. As a comparative example, the IC value of compound PM-301H (reference: WO2014 / 182928) in this evaluation system was 50The values ​​are also listed.

[0462] [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4]

[0463] Test Example 2: Measurement of human STAT6-dependent reporter activity 1) Construction of human STAT6-HEK293 cells HEK293 cells (ATCC) maintained in a culture medium [DMEM high glucose (Thermo Fisher Scientific) supplemented with 1 vol% Penicillin-Streptomycin (Thermo Fisher Scientific) and 10 vol% FBS] were harvested and suspended in 10 mL of 0.5% BSA / PBS. 6 The cells were harvested and centrifuged to remove the supernatant. The cells were then suspended in 100 μL of Nucleofector solution V (Lonza Japan). Two μg of STAT6 vector (plasmid DNA containing the human STAT6 sequence in pcDNA3.1 (Invitrogen)) was added, and the STAT6 vector was transfected into HEK293 cells using the Q-001 program included with Nucleofector® 2b. Resistant cells were selected in medium containing Geneticin® (Thermo Fisher Scientific) to obtain a cell line (STAT6-HEK293 cells) that constitutively expresses STAT6. 2) STAT6 reporter assay using STAT6-HEK293 cells STAT6-HEK293 cells were maintained in an assay medium (culture medium supplemented with 1 vol% Geneticin®) and collected at 3 × 10 6 100 cells were seeded onto a 10-cm dish. A transfection solution was prepared by adding 3 μg of STAT6 reporter vector (plasmid DNA containing a tandem STAT6-binding sequence and a C / EBP-binding sequence integrated into pGL4.27 (Promega)) and 9 μL of FuGENE® HD transfection reagent (Promega) to 500 μL of Opti-MEM® (Thermo Fisher Scientific). The transfection solution was vortexed and left to stand for approximately 5 minutes. The solution was then added dropwise to the STAT6-HEK293 cells, which were then cultured overnight in a CO2 incubator to produce STAT6 reporter cells. The prepared STAT6 reporter cells were seeded (3 × 10) on B&W isoplate-96 TC (PerkinElmer Japan Co., Ltd.). 4 Cells / 50 μL / well) were cultured overnight in a CO2 incubator (37°C, 5% CO2). Instead of STAT6 reporter cells, wells were provided with 50 μL of assay medium. Compound-added solutions were prepared by diluting a DMSO solution of the example compound 250-fold with assay medium. 20 μL of the compound-added solution or assay medium containing 0.4 vol% DMSO was added to the plate, and the plate was then cultured for 1 hour in a CO2 incubator. 10 μL of an 80 ng / mL human IL-4 solution (Peprotech) or assay medium was added to each well, and the plate was then cultured for 6 hours in a CO2 incubator. The viability of cells was measured using the CellTiter-Fluor® Cell Viability Assay (Promega). After adding 20 μL of diluted CellTiter reagent to each well, the cells were cultured in a CO2 incubator for 1 hour, and the fluorescence value was measured using an Infinite® F500 (Excitation: 340 nm, Emission: 495 nm). The viability of each compound was calculated using the following formula: the fluorescence value (D) obtained when cells were stimulated with IL-4 but no compound was added, the fluorescence value (E) obtained when cells were not seeded with STAT6 reporter cells, and the fluorescence value (F) obtained when cells were stimulated with IL-4 but each compound was added. Viable cell rate (%)=[(FE) / (DE)]×100 STAT6 reporter activity was measured using the Bright-Glo® Luciferase Assay System (Promega). 100 μL of Bright-Glo® reagent was added to each well, and luciferase activity was measured using an Infinite® F500. The inhibition rate for each example compound was calculated using the following formula: luciferase activity (G) under conditions where IL-4 stimulation was performed without addition of the example compound, luciferase activity (H) under conditions where IL-4 stimulation was performed without addition of the example compound, and luciferase activity (I) under conditions where IL-4 stimulation was performed after treatment with each example compound. Suppression rate (%)=[(GI) / (GH)]×100 The inhibition rates (%) for each example compound at concentrations of 1 μmol / L and 0.1 μmol / L are shown in Table 13. The cell viability under each condition was 70% or higher, and it was determined that the luciferase activity inhibitory effect of each example compound was appropriately evaluated.

[0464] [Table 13-1] [Table 13-2] [Table 13-3] [Industrial Applicability]

[0465] The medicament of the present invention has excellent STAT6 inhibitory activity and is therefore useful as a therapeutic agent and / or preventive agent for various diseases associated with STAT6. For example, the medicament of the present invention is useful as a therapeutic agent for inflammatory diseases such as atopic dermatitis and allergic diseases.

Claims

1. General formula (I): 【Chemical 1】 [In the formula, R １ represents an optionally substituted 5-membered heteroaryl group, an optionally substituted 5- or 6-membered non-aromatic heterocyclic group, an optionally substituted pyridonyl group, —C(═O)—NR ａ R ｂ or -NR ｃ -C(=O)R ｄ where R ａ , R ｂ , R ｃ and R ｄ are each independently a hydrogen atom or C １ -C ６ is an alkyl group, R ２ represents a hydrogen atom, an optionally substituted C １ -C ６ an alkyl group or an optionally substituted C １ -C ６ is a haloalkyl group, Or, R １ and R ２ may form, together with the carbon atom to which they are attached, an optionally substituted 5- or 6-membered non-aromatic heterocyclic group, R ３ represents a hydrogen atom, an optionally substituted C １ -C ６ an alkyl group or an optionally substituted C １ -C ６ is a haloalkyl group, R ４ represents a hydrogen atom, an optionally substituted C １ -C ６ alkyl group, optionally substituted C １ -C ６ Haloalkyl group, optionally substituted C １ -C ３ Alkoxy-C ２ -C ６ alkyl group, optionally substituted C １ -C ３ Haloalkoxy-C ２ -C ６ alkyl group, optionally substituted C ３ -C ６ Cycloalkyl-C １ -C ６ is an alkyl group, Q １ is C(=O) or CH ２ and Q ２ is NH or O, X １ is N or CR ５ where R ５ is a hydrogen atom or a halogen atom, X ２ , X ３ and X ４ are each independently N or CR ６ where R ６ represents a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C １ -C ６ alkyl group, optionally substituted C １ -C ６ Haloalkyl group, optionally substituted hydroxy-C １ -C ６ alkyl group, optionally substituted cyano-C １ -C ６ alkyl group, optionally substituted C ３ -C ６ cycloalkyl group, optionally substituted C １ -C ６ Alkoxy-C １ -C ６ alkyl group, optionally substituted C ２ -C ６ Alkenyl group, optionally substituted C ２ -C ６ an alkynyl group or an optionally substituted phenyl group, Y １ and Y ２ are each independently N or CR ７ where R ７ represents a hydrogen atom, an optionally substituted C １ -C ６ an alkyl group or an optionally substituted C １ -C ６ is a haloalkyl group, Ring A is an optionally substituted phenyl group or an optionally substituted 5- or 6-membered heteroaryl group, and the phenyl group or the 5- or 6-membered heteroaryl group may be further fused with another ring to form an optionally substituted 8- to 10-membered fused ring.] A pharmaceutical comprising, as an active ingredient, a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.

2. In the general formula (I), Q １ is C(=O), and Q ２ A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein is NH.

3. In the general formula (I), X １ , X ２ and X ４ are each independently CH or N, or a pharmaceutically acceptable salt thereof.

4. In the general formula (I), (i) X １ is CH and X ２ is CH, and X ４ is CH, (ii) X １ is N and X ２ is CH, and X ４ is CH, or (iii) X １ is CH and X ２ is CH, and X ４ is N, A pharmaceutical comprising the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

5. In the general formula (I), Y １ and Y ２ are each independently CH or N, or a pharmaceutically acceptable salt thereof.

6. In the general formula (I), (i) Y １ is CH and Y ２ is CH, (ii) Y １ is N and X ２ is CH, or (iii) Y １ is CH and Y ２ is N, A pharmaceutical comprising the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

7. 3. A pharmaceutical composition comprising the compound according to claim 1 or 2, wherein in the general formula (I), ring A is an optionally substituted phenyl group, an optionally substituted pyridinyl group, an optionally substituted pyrazolyl group, or an optionally substituted thiadiazolyl group, or a pharmaceutically acceptable salt thereof.

8. In the general formula (I), ring A is represented by the following formula: 【Chemistry 2】 (In the formula, R ８ represents a hydrogen atom, a cyano group, a hydroxyl group, an amino group, a methanesulfonylamino group, a sulfonamide group, C １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, hydroxy-C １ -C ６ Alkyl group, C １ -C ６ Alkoxy group, C １ -C ６ Alkoxy-C １ -C ６ Alkyl group, C １ -C ６ Alkylcarbonyl group, amino-C １ -C ６ Alkyl group, N-acetylamino-C １ -C ６ Alkyl group, C １ -C ６ Alkylcarbamoyl group, N-methyl-C １ -C ６ an alkylcarbamoyl group, an imidazolyl group, a thiazolyl group, or —C(═O)NHR ｅ where R ｅ represents a hydrogen atom, a C optionally substituted with a cyano group １ -C ６ C optionally substituted with an alkyl group or a dimethylamino group １ -C ６ an alkylcarbonyl group or an optionally substituted 5- or 6-membered heteroaryl group, R ９ is a hydrogen atom, a halogen atom or C １ -C ６ is an alkyl group.) 3. A pharmaceutical composition comprising the compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the ring is selected from the group consisting of:

9. In the general formula (I), ring A is represented by the following formula: 【Chemistry 3】 (In the formula, R ８ and R ９ is the same as the definition in claim 8.) 3. A pharmaceutical composition comprising the compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the ring is selected from the group consisting of:

10. In the general formula (I), ring A is represented by the following formula: 【Chemistry 4】 [In the formula, R ８ represents a hydrogen atom, a cyano group, C １ -C ６ an alkyl group, an imidazolyl group, a thiazolyl group, or —C(═O)—NHR ｅ and R ｅ represents a hydrogen atom, a C optionally substituted with a cyano group １ -C ６ C optionally substituted with an alkyl group or a dimethylamino group １ -C ６ Alkylcarbonyl group or the following formula 【Chemistry 5】 {In the formula, R １０ represents a hydrogen atom, a C optionally substituted with a cyano group １ -C ６ Alkyl group, C ３ -C ６ C optionally substituted with cycloalkyl １ -C ６ - alkyl group, C １ -C ６ Alkoxy-C １ -C ６ Alkylcarbonyl group or C ３ -C ６ is a cycloalkyl group, and R １１ is a hydrogen atom, a halogen atom or a cyano group, and R １２ is a hydrogen atom or C １ -C ６ is an alkyl group, and R １３ is a hydrogen atom, C １ -C ６ C optionally substituted with an alkyl group or a halogen atom １ -C ６ is an alkyl group, and R １４ is a hydrogen atom or C １ -C ６ is an alkyl group, and R １５ is a hydrogen atom, C １ -C ６ Alkyl group or C １ -C ６ Alkoxy-C １ -C ６ an alkyl group} 3. A pharmaceutical composition comprising the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:

11. In the general formula (I), R １ is expressed as follows: 【Chemistry 6】 {During the ceremony, R １６ is a hydrogen atom, C １ -C ６ Alkyl group or C １ -C ６ It is a haloalkyl group.} a ring selected from the group consisting of —C(═O)—NR ａ R ｂ or -NR ｃ -C(=O)R ｄ where R ａ , R ｂ , R ｃ and R ｄ are each independently a hydrogen atom or C １ -C ６ It is an alkyl group. Or, R １ and R ２ together with the carbon atoms to which they are attached, form the following formula: 【Chemistry 7】 {During the ceremony, * １ is R １ is the carbon atom to which * ２ is R ２ is the carbon atom to which 3. A pharmaceutical composition comprising the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which forms a ring represented by the following formula:

12. R ４ C optionally substituted with deuterium, a cyano group, a hydroxyl group, an amino group or an oxo group １ -C ６ C optionally substituted with an alkyl group, deuterium, cyano group, hydroxyl group, amino group or oxo group １ -C ６ C optionally substituted with a haloalkyl group, deuterium, cyano group, hydroxyl group, amino group or oxo group １ -C ３ Alkoxy-C ２ -C ６ C optionally substituted with an alkyl group, deuterium, cyano group, hydroxyl group, amino group or oxo group １ -C ３ Haloalkoxy-C ２ -C ６ Alkyl group, deuterium, halogen atom, cyano group, hydroxyl group, amino group, C １ -C ６ Alkyl group, C １ -C ６ C optionally substituted with a haloalkyl group or an oxo group ３ -C ６ Cycloalkyl-C １ -C ６ 3. A medicine comprising the compound according to claim 1 or 2, which is an alkyl group, or a pharmaceutically acceptable salt thereof.

13. In the general formula (I), R ４ But C １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, C １ -C ３ Alkoxy-C ２ -C ６ Alkyl group, C １ -C ３ Haloalkoxy-C ２ -C ６ C optionally substituted with an alkyl group or a cyano group ３ -C ６ Cycloalkyl-C １ -C ６ 3. A medicine comprising the compound according to claim 1 or 2, which is an alkyl group, or a pharmaceutically acceptable salt thereof.

14. In the general formula (I), X ２ is CH and X ３ is CR ６ where R ６ represents a hydrogen atom, a halogen atom, a cyano group, C １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, hydroxy-C １ -C ６ Alkyl group, cyano-C １ -C ６ Alkyl group, C ３ -C ６ Cycloalkyl group, C １ -C ６ Alkoxy-C １ -C ６ Alkyl group, C １ -C ６ Alkenyl group, C １ -C ６ 3. A medicine comprising the compound according to claim 1 or 2, wherein the compound is an alkynyl group or a phenyl group, or a pharmaceutically acceptable salt thereof.

15. The compound represented by the general formula (I) 【Chemistry 8】 【Chemistry 9】 2. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof.

16. The pharmaceutical agent according to claim 1 or 2, which is a preventive or therapeutic agent for a disease in which STAT6 is involved.

17. The pharmaceutical composition according to claim 16, wherein the disease in which STAT6 is involved is an allergic disease or an inflammatory disease.

18. 17. The pharmaceutical according to claim 16, wherein the disease involving STAT6 is one or more diseases selected from the group consisting of chronic obstructive pulmonary disease, atopic dermatitis, bronchial asthma, bullous pemphigoid, nasal polyps, chronic sinusitis, allergic rhinitis, eosinophilic esophagitis, prurigo, and urticaria.

19. Use of the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof for the manufacture of an agent for the prophylaxis or treatment of a disease in which STAT6 is involved.

20. The use according to claim 19, wherein the disease in which STAT6 is involved is an allergic disease or an inflammatory disease.

21. The use according to claim 19, wherein the disease involving STAT6 is one or more diseases selected from the group consisting of chronic obstructive pulmonary disease, atopic dermatitis, bronchial asthma, bullous pemphigoid, nasal polyps, chronic sinusitis, allergic rhinitis, eosinophilic esophagitis, prurigo, and urticaria.

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