Condensed cyclic compound and drug comprising same

Abstract

The present invention provides a novel compound which has STAT6 inhibitory activity and is effective for the treatment of inflammatory diseases such as atopic dermatitis and for allergic diseases. A compound represented by general formula (I) and having STAT6 inhibitory activity or a pharmaceutically acceptable salt thereof. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a novel polycyclic compound and a drug containing the compound as an active ingredient. More specifically, the present invention relates to a novel compound having an inhibitory effect on signal transducer and activator of transcription 6 (hereinafter referred to as STAT6). Background Art

[0002] Interleukin 4 (IL-4) and interleukin 13 (IL-13) are cytokines that transmit signals into cells by binding to receptors expressed on the cell membrane. These two cytokines are closely related to the induction of type 2 inflammatory responses, which are considered to play important roles in the pathogenesis of inflammatory diseases and allergic diseases such as bronchial asthma and atopic dermatitis, and are also important in the pathogenesis of mouse models of airway hyperresponsiveness and mouse contact dermatitis (Non-Patent Document 1). In other words, it is expected that the inhibition of intracellular signal transduction by IL-4 and IL-13 can achieve the treatment of various diseases caused by type 2 inflammatory responses. In fact, dupilumab (human IgG4 monoclonal antibody) (an antibody drug that binds to the α subunit of the IL-4 receptor (IL-4Rα) and mediates intracellular signal transduction through IL-4 and IL-13) has excellent therapeutic effects on inflammatory diseases and allergic diseases such as atopic dermatitis, bronchial asthma, and chronic paranasal sinusitis with nasal polyps.

[0003] STAT6 is a transcription factor responsible for intracellular signal transduction of IL-4 and IL-13. When IL-4 and IL-13 bind to receptors on the cell membrane, the common subunit IL-4Rα of the receptors for these two cytokines is phosphorylated. Then STAT6 binds to phosphorylated IL-4Rα, and STAT6 is phosphorylated. Phosphorylated STAT6 forms a dimer and moves into the nucleus to promote the expression of various genes as transcription factors. As described above, STAT6 plays an important role in signal transduction through IL-4 and IL-13 entering the cell, and inhibition of the activation and function of STAT6 is expected to achieve the treatment of inflammatory and allergic diseases involving IL-4 and IL-13. In fact, it has been reported that in STAT6 knockout mice, IL-4 signal cannot be transmitted and allergic reactions are inhibited (Non-Patent Documents 2, 3, 4), and pathological conditions such as contact dermatitis (Non-Patent Document 5), bronchial asthma (Non-Patent Document 6), and food allergy (Non-Patent Document 7) induced by various inflammatory and allergic substances are alleviated. In addition, in a clinical study of administering decoy oligonucleotides against STAT6 to patients with atopic dermatitis, an improvement effect on erythematous and pruritic symptoms was reported (Non-Patent Document 8). Furthermore, it has been reported that compounds that inhibit the binding between phosphorylated IL-4Rα and STAT6 alleviate the pathology of a murine allergic lung disease model (Non-Patent Documents 9 and Patent Document 1).

[0004] Based on the above, it is considered that STAT6 inhibitors that inhibit the activation and function of STAT6 are very useful as prophylactic or therapeutic agents for various pathological conditions involving IL-4 and IL-13.

[0005] The compound of general formula (I) of the present invention described below has neither been disclosed nor suggested in any conventional technical literature.

[0006] In addition, the following compounds are known 5,6-fused ring derivatives belonging to a technical field different from that of the present invention.

[0007] Patent Document 2 discloses a compound represented by the following formula, which is a sirtuin regulator:

[0008] [Chemical Drawing 1]

[0009]

[0010] (wherein each symbol is defined as in Patent Document 2).

[0011] Patent Document 3 discloses a material for imaging huntingtin, which is represented by the following formula:

[0012] [Chemical Drawing 2]

[0013]

[0014] (where each symbol is defined as in Patent Document 3).

[0015] However, Patent Documents 2 and 3 do not specifically disclose the compound of general formula (I) of the present invention, and no document describes or indicates that the compound has STAT6 inhibitory activity, nor does any document describe or indicate that the compound can be used to treat STAT6-related diseases.

[0016] Prior Art Documents

[0017] Patent Documents

[0018] Patent Document 1: International Patent Publication No. WO 2014 / 182928

[0019] Patent Document 2: International Patent Publication No. WO 2010 / 003048

[0020] Patent Document 3: International Patent Publication No. WO 2016 / 033445

[0021] Non-Patent Documents

[0022] Non-Patent Document 1: American journal of respiratory cell and molecular biology. 2013; 49: 37-46.

[0023] Non-Patent Document 2: Nature. 1996; 380: 627-630.

[0024] Non-Patent Document 3: Nature. 1996; 380: 630-633.

[0025] Non-Patent Document 4: Immunity. 1996; 4: 313-319.

[0026] Non-Patent Document 5: International Immunology. 2004; 16: 685-695.

[0027] Non-Patent Document 6: Journal of experimental medicine. 1998; 187: 1537-1542.

[0028] Non-Patent Document 7: Allergologia et al., Immunopathologia. 2019; 47: 535-543.

[0029] Non-Patent Document 8: British Journal of Dermatology. 2009:160, pp. 1124-1126.

[0030] Non-Patent Document 9: Journal of Biological Chemistry. 2018:293, pp. 10026-10040. Summary of the Invention

[0031] Problems to be Solved by the Present Invention

[0032] An object of the present invention is to provide a novel compound having STAT6 inhibitory activity and being effective for the treatment of inflammatory diseases such as atopic dermatitis and allergic diseases.

[0033] Means for Solving these Problems

[0034] As a result of intensive studies 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 based on this finding, the present invention has been achieved.

[0035] In other words, the present invention is:

[0036] (1) A compound represented by the general formula (I):

[0037] [Chemical Drawing 3]

[0038]

[0039] [wherein

[0040] R 1 is an optionally substituted 5-membered heteroaryl group, an optionally substituted 5- to 6-membered non-aromatic heterocyclic group, an optionally substituted pyridone group, -C(=O)-NR a R b or -NR c -

[0041] C(=O)R d wherein R a 、R b 、R c and R d each independently represent a hydrogen atom or a C1-C6 alkyl group;

[0042] R 2 is a hydrogen atom, an optionally substituted C1-C6 alkyl group or an optionally substituted C1-C6 haloalkyl group;

[0043] Or R 1 and R2 be capable of forming, together with the carbon atom to which they are attached, an optionally substituted 5- to 6-membered non-aromatic heterocyclic group;

[0044] R 3 be a hydrogen atom, an optionally substituted C1-C6 alkyl group or an optionally substituted C1-C6 haloalkyl group;

[0045] R 4 be 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-

[0046] C1-C6 alkyl group;

[0047] Q 1 be C(=O) or CH2;

[0048] Q 2 be NH or O;

[0049] X 1 be N or CR 5 wherein R 5 be a hydrogen atom or a halogen atom;

[0050] X 2 、X 3 and X 4 each independently be N or CR 6 wherein R 6 be 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 selected

[0051] substituted C2-C6 alkynyl group or an optionally substituted phenyl group;

[0052] Y 1 and Y 2 each independently be N or CR 7 wherein R 7 be a hydrogen atom, an optionally substituted C1-C6 alkyl group or an optionally substituted C1-C6 haloalkyl group; and

[0053] Ring A is an optionally substituted phenyl group or an optionally substituted 5- to 6-membered heteroaryl group, wherein the phenyl group or the 5- to 6-membered heteroaryl group can further be fused with another ring to form an optionally substituted 8- to 10-membered fused ring

[0054] or a pharmaceutically acceptable salt thereof.

[0055] (2) The compound according to (1) or a pharmaceutically acceptable salt thereof, wherein in the general formula (I), Q 1 is C(=O) and Q 2 is NH.

[0056] (3) The compound according to (1) or (2) or a pharmaceutically acceptable salt thereof, wherein in the general formula (I), X 1 , X 2 and X 4 are each independently CH or N.

[0057] (4) The compound according to any one of (1) to (3) or a pharmaceutically acceptable salt thereof, wherein in the general formula (I),

[0058] (i) X1 is CH, X2 is CH, and X4 is CH;

[0059] (ii) X1 is N, X2 is CH, and X4 is CH; or

[0060] (iii) X1 is CH, X2 is CH, and X4 is N.

[0061] (5) The compound according to any one of (1) to (4) or a pharmaceutically acceptable salt thereof, wherein in the general formula (I), Y 1 and Y 2 are each independently CH or N.

[0062] (6) The compound according to any one of (1) to (5) or a pharmaceutically acceptable salt thereof, wherein in the general formula (I),

[0063] (i) Y 1 is CH, and Y 2 is CH;

[0064] (ii) Y 1 is N, and X 2 is CH; or

[0065] (iii) Y 1 is CH, and Y 2 is N.

[0066] (7) The compound according to any one of (1) to (6) or a pharmaceutically acceptable salt thereof, wherein in general formula (I), ring A is an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted pyrazolyl group or an optionally substituted thiadiazolyl group.

[0067] (8) The compound according to any one of (1) to (7) or a pharmaceutically acceptable salt thereof, wherein in general formula (I), ring A is a ring selected from the group consisting of rings represented by the following formula:

[0068] [Chemical Drawing 4]

[0069]

[0070] (wherein R 8 is a hydrogen atom, a cyano group, a hydroxy group, an amino group, a methanesulfonylamino group, a sulfonamide group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a hydroxy-C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkoxy-C1-C6 alkyl group, a C1-C6 alkylcarbonyl group, an amino-C1-C6 alkyl group, an N-acetylamino-C1-C6 alkyl group, a C1-C6 alkylaminocarbonyl group, an N-methyl-C1-C6 alkylaminocarbonyl group, an imidazolyl group, a thiazolyl group or -C(=O)NHR e group, wherein R e is a C1-C6 alkyl group which can be substituted by a hydrogen atom or a cyano group, a C1-C6 alkylcarbonyl group optionally substituted by a dimethylamino group or an optionally substituted 5- to 6-membered heteroaryl group; and

[0071] R 9 is a hydrogen atom, a halogen atom or a C1-C6 alkyl group.)

[0072] (9) The compound according to any one of (1) to (7) or a pharmaceutically acceptable salt thereof, wherein in general formula (I), ring A is a ring selected from the group consisting of rings represented by the following formula:

[0073] [Chemical Drawing 5]

[0074]

[0075] wherein R 8 and R 9 are as defined above.)

[0076] (10) The compound according to any one of (1) to (7) or a pharmaceutically acceptable salt thereof, wherein in general formula (I), ring A is a ring selected from the group consisting of rings represented by the following formula:

[0077] [Chemical Drawing 6]

[0078]

[0079] [wherein

[0080] R 8 is a hydrogen atom, a cyano group, a C1-C6 alkyl group, an imidazolyl group, a thiazolyl group or -C(=O)-NHR e group; and

[0081] R e is a hydrogen atom, a C1-C6 alkyl group which can be substituted by a cyano group, a C1-C6 alkylcarbonyl group which can be substituted by a dimethylamino group or a ring selected from the rings represented by the following formula:

[0082] [Chemical Drawing 7]

[0083]

[0084] {wherein R 10 is a hydrogen atom, a C1-C6 alkyl group optionally substituted by a cyano group, a C1-C6 alkyl group optionally substituted by a C3-C6 cycloalkyl group, a C1-C6 alkoxy-C1-C6 alkylcarbonyl group or a C3-C6 cycloalkyl group; R 11 is a hydrogen atom, a halogen atom or a cyano group; R 12 is a hydrogen atom or a C1-C6 alkyl group; R 13 is a hydrogen atom,

[0085] a C1-C6 alkyl group or a C1-C6 alkyl group optionally substituted by a halogen atom; 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}}.

[0086] (11) The compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof, wherein in the general formula (I),

[0087] R 1 is a ring selected from the group consisting of the rings represented by the following formula:

[0088] [Chemical Drawing 8]

[0089]

[0090] {wherein,

[0091] R 16 is a hydrogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group}

[0092] -C(=O)-NR a R b group or -NR c -C(=O)R d group, where R a 、R b 、R c and R d are each independently a hydrogen atom or a C1-C6 alkyl group;

[0093] Or R 1 and R 2 together with the carbon atom to which they are attached form a ring represented by the following formula:

[0094] [Chemical Figure 9]

[0095]

[0096] {wherein,

[0097] * 1 is the carbon atom bonded to R 1 bonded carbon atom,

[0098] * 2 is the carbon atom bonded to R 2 bonded carbon atom}.

[0099] (12) The compound according to any one of (1) to (11) or a pharmaceutically acceptable salt thereof, wherein in the general formula (I),

[0100] 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 capable of being substituted by a cyano group.

[0101] (13) The compound according to any one of (1) to (12) or a pharmaceutically acceptable salt thereof, wherein in the general formula (I),

[0102] X 2 is a CH group, and X 3 is a CR 6 group, 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

[0103] -C1-C6 alkyl group, a C1-C6 alkenyl group, a C1-C6 alkynyl group or a phenyl group.

[0104] (14) The compound according to (1) or a pharmaceutically acceptable salt thereof, wherein the compound represented by the general formula (I) is:

[0105] [Chemical Drawing 10-1]

[0106]

[0107] [Chemical Drawing 10-2]

[0108]

[0109]

[0110] (15) A medicament, which comprises the compound according to any one of (1) to (14) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0111] (16) A medicament, which comprises the compound according to any one of (1) to (14) or a pharmaceutically acceptable salt thereof as an active ingredient, and the medicament is a prophylactic or therapeutic agent for a disease related to STAT6.

[0112] (17) The medicament according to (16), wherein the disease related to STAT6 is an allergic disease and an inflammatory disease.

[0113] (18) The medicament according to (16) or (17), wherein the disease related to 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 rhinosinusitis, allergic rhinitis, eosinophilic esophagitis, prurigo and urticaria.

[0114] (19) A method for preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease, atopic dermatitis, bronchial asthma, bullous pemphigoid, nasal polyps, chronic rhinosinusitis, allergic rhinitis, eosinophilic esophagitis, prurigo and urticaria, the method comprising: administering the compound according to any one of (1) to (14) or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0115] (20) Use of the compound according to any one of (1) to (14) or a pharmaceutically acceptable salt thereof in the manufacture of a prophylactic or therapeutic agent for a disease related to STAT6.

[0116] (21) The use according to (20), wherein the disease related to STAT6 is an allergic disease and an inflammatory disease.

[0117] (22) The use according to (20) or (21), wherein the disease related to 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 rhinosinusitis, allergic rhinitis, eosinophilic esophagitis, prurigo and urticaria.

[0118] Effects of the Present Invention

[0119] According to the present invention, novel compounds having excellent STAT6 inhibitory activity and being particularly effective for the treatment of allergic and inflammatory diseases related to STAT6 can be provided. Detailed Description

[0120] The present invention will be described below.

[0121] In the present specification, "n-" represents normal, "sec-" represents secondary, and "tert-" represents tertiary.

[0122] First, each substituent in the general formula (I) will be described, but the present invention is not limited to the substituents exemplified as specific examples.

[0123] Specific examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0124] The "C1-C6 alkyl group" means a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, a n-pentyl group, a tert-pentyl group, a 3-methylbutyl group (isopentyl group), a neopentyl group, a n-hexyl group, etc.

[0125] The "C2-C6 alkyl group" means a straight-chain or branched-chain alkyl group having 2 to 6 carbon atoms, and specific examples thereof include an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, a n-pentyl group, a tert-pentyl group, a 3-methylbutyl group (isopentyl group), a neopentyl group, a n-hexyl group, etc.

[0126] The "C1-C6 haloalkyl group" is a group obtained by substituting one or more hydrogen atoms of the above-mentioned "C1-C6 alkyl group" with halogen atoms. The halogen atoms can be bonded at any substitutable position. Specific examples thereof include trifluoromethyl group, difluoromethyl group, monofluoromethyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, 1,1-difluoroethyl group, 2,2,2-trifluoroethyl group, 1,1,2-trifluoroethyl group, 1,1,2,2,2-pentafluoroethyl group, 2-bromo-1,1-difluoroethyl group, 1,1,1-trifluoro-2-propyl group, 1,1-difluoro-2-propyl group, 3,3,3-trifluoro-2-methylpropyl group, 1,1-difluoro-2-methylpropyl group, etc.

[0127] The term "hydroxy-C1-C6 alkyl group" refers to a group obtained by substituting one of the hydrogen atoms of the above-mentioned "C1-C6 alkyl group" with a hydroxy group. The hydroxy group can be linked at any substitutable position. Specific examples thereof include hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxy-n-propyl group, 2-hydroxy-n-propyl group, 3-hydroxy-n-propyl group, 2-hydroxy-2-methyl-n-propyl group, 3-hydroxy-2,2-dimethyl-n-propyl group, 1-hydroxy-2-propyl group, 1-hydroxy-2-methyl-2-propyl group, 2-hydroxy-2-propyl group, 4-hydroxy-n-butyl group, 3-hydroxy-n-butyl group, 3-hydroxy-2-methyl-n-butyl group, 2-hydroxy-n-butyl group, 2-hydroxy-2-methyl-n-butyl group, 2-hydroxy-2-ethyl-n-butyl group, 3-hydroxy-2-butyl group, 3-hydroxy-3-methyl-2-butyl group, 3-hydroxy-2,3-dimethyl-2-butyl group, etc.

[0128] The term "cyano-C1-C6 alkyl group" refers to the above-mentioned "C1-C6 alkyl group" in which one of the hydrogen atoms is replaced by a cyano group. The hydroxyl group can be attached at any substitutable position. Specific examples thereof include cyanomethyl group, 1-cyanoethyl group, 2-cyanoethyl group, 1-cyano-n-propyl group, 2-cyano-n-propyl group, 3-cyano-n-propyl group, 2-cyano-2-methyl-n-propyl group, 3-cyano-2,2-dimethyl-n-propyl group, 1-cyano-n-prop-2-yl group, 1-cyano-2-methyl-n-prop-2-yl group, 2-cyano-n-prop-2-yl group, 4-cyano-n-butyl group, 3-cyano-n-butyl group, 3-cyano-2-methyl-n-butyl group, 2-cyano-n-butyl group, 2-cyano-2-methyl-n-butyl group, 2-cyano-2-ethyl-n-butyl group, 3-cyano-n-but-2-yl group, 3-cyano-3-methyl-n-but-2-yl group and 3-cyano-2,3-dimethyl-n-but-2-yl group.

[0129] "C3-C6 cycloalkyl group" means a monocyclic or bridged saturated carbocyclic group having 3 to 6 carbon atoms. Specific examples thereof include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, bicyclo[1.1.1]pentyl group and the like.

[0130] "5- to 6-membered non-aromatic heterocyclic group" refers to a monovalent substituent obtained by removing a hydrogen atom at any position from a 5- to 6-membered monocyclic, bridged or spiro non-aromatic heterocycle containing 1 to 2 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-forming atoms. Specific examples of such non-aromatic heterocycles include azetidine, pyrrolidine, piperidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperazine, morpholine, thiomorpholine, aze (azepine), diaze (diazepine), oxetane, tetrahydrofuran, 1,3-dioxolane, tetrahydropyran, dihydropyran, 1,4-dioxane and the like.

[0131] "C2-C6 alkenyl group" means a straight-chain or branched-chain alkenyl group having 2 to 6 carbon atoms and having one or more double bonds. Specific examples thereof include vinyl group, 1-propenyl group, isopropenyl group, 1-butenyl group, isobutenyl group, 2-methyl-1-propenyl group, 1-methyl-1-propenyl group, 1-pentenyl group, 1-hexenyl group and the like.

[0132] "C2-C6 alkynyl group" means a straight-chain or branched alkynyl group having 2 to 6 carbon atoms and having one or more triple bonds. Specific examples thereof include ethynyl group, 1-propynyl group, 1-butynyl group, 3-methyl-1-butynyl group, 1-pentynyl group, 3-methyl-1-pentynyl group, 1-hexynyl group, etc.

[0133] "5- to 6-membered heteroaryl group" means a monovalent substituent obtained by removing a hydrogen atom at any position from a 5- to 6-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-forming 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, 1,3,4-thiadiazole, etc.

[0134] "5-membered heteroaryl group" means a monovalent substituent obtained by removing a hydrogen atom at any position from a 5-membered aromatic heterocycle in the "5- to 6-membered heteroaryl group". 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, 1,3,4-thiadiazole, etc.

[0135] "C1-C6 alkoxy group" means an alkoxy group in which the alkyl part is the above-mentioned "C1-C6 alkyl group", and specific examples thereof include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, n-hexyloxy group, etc.

[0136] "C1-C3 alkoxy group" means an alkoxy group in which the alkyl part is a straight-chain or branched alkyl group having 1 to 3 carbon atoms, and specific examples thereof include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, etc.

[0137] "C1-C3 haloalkoxy group" means a group obtained by substituting one or more hydrogen atoms of the above-mentioned "C1-C3 alkoxy group" with halogen atoms. The halogen atoms can be bonded at any substitutable position. Specific examples thereof include trifluoromethoxy group, difluoromethoxy group, 2,2,2-trifluoroethoxy group, 2,2-difluoroethoxy group, 3,3,3-trifluoro-n-propoxy group, 3,3-difluoro-n-propoxy group, 2,2-difluoro-n-propoxy group, etc.

[0138] The "C1-C6 alkoxy-C1-C6 alkyl group" means the above-mentioned "C1-C6 alkyl group" substituted by a "C1-C6 alkoxy group". The alkoxy group can be bonded at any substitutable position. Specific examples thereof include methoxymethyl group, ethoxymethyl group, n-propoxymethyl group, 2-methoxyethyl group, 2-ethoxyethyl group, 2-n-propoxyethyl group, 2-isopropoxyethyl group, 3-methoxy-n-propyl group, 2-methoxy-n-propyl group, etc.

[0139] The "C1-C3 alkoxy-C2-C6 alkyl group" means the above-mentioned "C2-C6 alkyl group" substituted by a "C1-C3 alkoxy group". The alkoxy group atom can be bonded at any substitutable position. Specific examples thereof include 2-methoxyethyl group, 2-ethoxyethyl group, 2-n-propoxyethyl group, 2-isopropoxyethyl group, 3-methoxy-n-propyl group, 2-methoxy-n-propyl group, etc.

[0140] The "C1-C3 haloalkoxy-C2-C6 alkyl group" means the above-mentioned "C2-C6 alkyl group" substituted by a "C1-C3 haloalkoxy group". The haloalkoxy group can be bonded at any substitutable position. Specific examples thereof include 2-(trifluoromethoxy)ethyl group, 2-(difluoromethoxy)ethyl group, 2-(2,2,2-trifluoroethoxy)ethyl group, 2-(2,2-difluoromethoxy)ethyl group, 2-(3,3,3-trifluoro-n-propoxy)ethyl group, 2-(3,3-difluoro-n-propoxy)ethyl group, 2-(2,2-difluoro-n-propoxy)ethyl group, etc.

[0141] The "C3-C6 cycloalkyl-C1-C6 alkyl group" means the above-mentioned "C1-C6 alkyl group" substituted by a "C3-C6 cycloalkyl group". The cycloalkyl group can be bonded at any substitutable position. Specific examples thereof include cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, 2-cyclopropylethyl group, 3-cyclopropylpropyl group, etc.

[0142] The "C1-C6 alkylcarbonyl group" means the above-mentioned "C1-C6 alkyl group" substituted by a carbonyl group, and specific examples thereof include formyl group, acetyl group, 2-oxoethyl group, propionyl group, 2-oxopropyl group, 3-oxopropyl group, etc.

[0143] The "C1-C6 alkoxy-C1-C6 alkylcarbonyl group" refers to the above-mentioned "C1-C6 alkylcarbonyl group" substituted by the above-mentioned "C1-C6 alkoxy group". The alkoxy group can be bonded at any substitutable position. Specific examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a 2-methoxy-2-oxoethyl group, and the like.

[0144] In the present specification, the "8- to 10-membered fused ring" refers to any ring structure formed by a phenyl group or a "5- to 6-membered heteroaryl group", and a ring structure of a group consisting of a "C3-C6 cycloalkyl group", a "5- to 6-membered non-aromatic heterocyclic group", a "5- to 6-membered heteroaryl group", and a phenyl group, which share two atoms forming each ring. The combination of the two types of ring structures may be the same or different, and may be, for example, a fused ring containing two phenyl groups, a fused ring containing a phenyl group and a "5- to 6-membered non-aromatic heterocyclic group", or a fused ring containing a phenyl group and a "5- to 6-membered heteroaryl group". Specific examples thereof include naphthalene, tetrahydronaphthalene, quinoline, chroman, isochroman, dihydroindole, isoindoline, tetrahydroquinoline, tetrahydroisoquinoline, and the like.

[0145] In general formula (I), R 1 The substituents of the "optionally substituted 5-membered heteroaryl group", the "optionally substituted 5- to 6-membered non-aromatic heterocyclic group", and the "optionally substituted pyridone group" are substituents selected from the group consisting of deuterium, a halogen atom, a cyano group, a hydroxy group, an amino group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, and an oxo group. One or more of these substituents may be substituted at all substitutable positions.

[0146] In general formula (I), R 2 and R 3 The substituents of the "optionally substituted C1-C6 alkyl group" and the "optionally substituted C1-C6 haloalkyl group" in are substituents selected from the group consisting of deuterium, a cyano group, a hydroxy group, an amino group, and an oxo group. One or more of these substituents may be substituted at all substitutable positions.

[0147] In general formula (I), R 4The 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 atom, cyano group, hydroxy group, amino group, C1-C6 alkyl group, C1-C6 haloalkyl group and oxo group. One or more of these substituents may be substituted at all substitutable positions. However, if the substituent is "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 atom, C1-C6 alkyl group and C1-C6 haloalkyl group are excluded from the substituents.

[0148] In general formula (I), R 6 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 atom, cyano group, hydroxy group, amino group, C1-C6 alkyl group, C1-C6 haloalkyl group and oxo group. One or more of these substituents may be substituted at all substitutable positions. However, if the substituent is "optionally substituted C1-C6 alkyl group", "optionally substituted C1-C6 haloalkyl group" or "optionally substituted C1-C3 alkoxy-C2-C6 alkyl group", halogen atom, C1-C6 alkyl group and C1-C6 haloalkyl group are excluded from the substituents.

[0149] In general formula (I), R 6 The substituents of "optionally substituted phenyl group" and "optionally substituted 5- to 6-membered heteroaryl group" are substituents selected from the group consisting of deuterium, halogen atom, cyano group, hydroxy group, amino group, C1-C6 alkyl group and C1-C6 haloalkyl group. One or more of these substituents may be substituted at all substitutable positions.

[0150] In general formula (I), R 7The 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, a cyano group, a hydroxyl group, and an amino group. One or more of these substituents may be substituted at all substitutable positions.

[0151] In general formula (I), the substituents of the "optionally substituted phenyl group" and the "optionally substituted 5- to 6-membered heteroaryl group" in ring A are selected from the group consisting of deuterium, a halogen atom, a cyano group, a hydroxyl group, an amino group, a methanesulfonylamino group, a sulfonamide group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a hydroxy-C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkoxy-C1-C6 alkyl group, a C1-C6 alkylcarbonyl group, an amino-C1-C6 alkyl group, an N-acetylamino-C1-C6 alkyl group, a C1-C6 alkylcarbamoyl group, an N-methyl-C1-C6 alkylcarbamoyl group, an imidazolyl group, a thiazolyl group, and -C(=O)NHR e (R e represents a hydrogen atom, deuterium, a cyano-C1-C6 alkyl group, a dimethylamino-C1-C6 alkylcarbonyl group, or an optionally substituted 5- to 6-membered heteroaryl group) consisting of substituents. One or more of these substituents may be substituted at all substitutable positions.

[0152] In general formula (I), the substituents of the "optionally substituted fused ring" are substituents 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. One or more of these substituents may be substituted at all substitutable positions.

[0153] R e The substituents of the "optionally substituted 5- to 6-membered heteroaryl group" are substituents selected from the group consisting of deuterium, a halogen atom, a cyano group, a hydroxyl 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 C3-C6 cycloalkyl-C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkoxy-C1-C6 alkyl group, and a C1-C6 alkoxy-C1-C6 alkylcarbonyl group. One or more of these substituents may be substituted at all substitutable positions.

[0154] When there is an asymmetric carbon in the compound represented by general formula (I), all racemates, diastereomers, and individual optically active forms are included in the present invention.

[0155] In addition, the compound represented by the general formula I or a pharmaceutically acceptable salt thereof may form a hydrate or a solvate, which is also included within the scope of the present invention.

[0156] Preferred atoms or substituents of the compound of general formula I of the present invention or a pharmaceutically acceptable salt thereof are described below.

[0157] Q 1 A preferred example of is C(=O).

[0158] Q 2 A preferred example of is NH.

[0159] More preferred examples are those in which Q 1 is C(=O) and Q 2 is NH.

[0160] X 1 Preferred examples of are CH and N.

[0161] X 2 Preferred examples of are CH and N.

[0162] X 3 Preferred examples of are CR 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 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.

[0163] X 4 Preferred examples of are CH and N.

[0164] 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.

[0165] Y 2 Preferred examples of are N and CR 7 where R 7 is a hydrogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group.

[0166] More preferred examples are the following cases:

[0167] (i) Y 1 is CH, and Y 2 is CH;

[0168] (ii) Y 1 is N, and X2 is CH; or

[0169] (iii) Y 1 is CH, and Y 2 is N.

[0170] An even more preferred example is when Y 1 is CH and Y 2 is CH. Preferred examples of ring A include rings selected from the rings represented by the following formulas:

[0171] [Chemical Drawing 11]

[0172]

[0173] (wherein

[0174] R 8 is a hydrogen atom, a cyano group, a hydroxy group, an amino group, a methanesulfonylamino group, a sulfonamide group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a hydroxy-C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkoxy-C1-C6 alkyl group, a C1-C6 alkylcarbonyl group, an amino-C1-C6 alkyl group, an N-acetylamino-C1-C6 alkyl group, C 1- C6 alkylaminocarbonyl group, an N-methyl-C1-C6 alkylaminocarbonyl group, an imidazolyl group, a thiazolyl group or -C(=O)NHR e group, wherein R e is a C1-C6 alkyl group which can be substituted by a hydrogen atom or a cyano group, a C1-C6 alkylcarbonyl group optionally substituted by a dimethylamino group; or

[0175] [Chemical Drawing 12]

[0176]

[0177] {wherein R 10 is a hydrogen atom, a C1-C6 alkyl group optionally substituted by a cyano group, a C1-C6 alkyl group optionally substituted by a C3-C6 cycloalkyl group, a C1-C6 alkoxy-C1-C6 alkylcarbonyl group or a C3-C6 cycloalkyl group; R 11 is a hydrogen atom, a halogen atom or a cyano group; R 12 is a hydrogen atom or a C1-C6 alkyl group; R 13 is a hydrogen atom, a C1-C6 alkyl group or a C1-C6 alkyl group optionally substituted by a halogen atom; R 14 is a hydrogen atom or a C1-C6 alkyl group; and R 15is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 alkoxy-C1-C6 alkyl group;

[0178] R 9 is a hydrogen atom, a halogen atom, or a C1-C6 alkyl group).

[0179] More preferably, it is a ring selected from the group consisting of rings represented by the following formula:

[0180] [Chemical Figure 13]

[0181]

[0182] (wherein

[0183] R 8 is an imidazolyl group, a thiazolyl group, or a -C(=O)NHR e group, where R e is a hydrogen atom, a C1-C6 alkyl group optionally substituted by a cyano group, a C1-C6 alkylcarbonyl group optionally substituted by a dimethylamino group, or a group represented by the following formula:

[0184] [Chemical Figure 14]

[0185]

[0186] {where R 10 is a hydrogen atom, a C1-C6 alkyl group optionally substituted by a cyano group, a C1-C6 alkyl group optionally substituted by a C3-C6 cycloalkyl group, a C1-C6 alkoxy-C1-C6 alkylcarbonyl group, or a C3-C6 cycloalkyl group; R 11 is a hydrogen atom, a halogen atom, or a cyano group; R 12 is a hydrogen atom or a C1-C6 alkyl group; R 13 is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 alkyl group optionally substituted by a halogen atom; 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};

[0187] R 9 is a hydrogen atom or a halogen atom.).

[0188] In addition, in another embodiment of the present invention, a preferred example of ring A is a ring selected from the group consisting of rings represented by the following formula:

[0189] [Chemical Figure 15]

[0190]

[0191] (wherein

[0192] R 8 is a hydrogen atom, a cyano group, a hydroxyl group, an amino group, a mesylamino group, a sulfonamide group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a hydroxy-C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkoxy-C1-C6 alkyl group, a C1-C6 alkylcarbonyl group, an amino-C1-C6 alkyl group, an N-acetylamino-C1-C6 alkyl group, a C1-C6 alkylaminocarbonyl group, an N-methyl-C1-C6 alkylaminocarbonyl group, an imidazolyl group, a thiazolyl group or -C(=O)NHR e group, wherein R e is a C1-C6 alkyl group which may be substituted by a hydrogen atom or a cyano group, a C1-C6 alkylcarbonyl group optionally substituted by a dimethylamino group; or

[0193] [Chemical Drawing 16]

[0194]

[0195] {wherein R 10 is a hydrogen atom, a C1-C6 alkyl group optionally substituted by a cyano group, a C1-C6 alkyl group optionally substituted by a C3 - C6 cycloalkyl group, a C1-C6 alkoxy-C1-C6 alkylcarbonyl group or a C3-C6 cycloalkyl group; R 11 is a hydrogen atom, a halogen atom or a cyano group; R 12 is a hydrogen atom or a C1-C6 alkyl group; R 13 is a hydrogen atom, a C1-C6 alkyl group or a C1-C6 alkyl group optionally substituted by a halogen atom; 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};

[0196] R 9 is a hydrogen atom, a halogen atom or a C1-C6 alkyl group).

[0197] More preferably, it is a ring selected from the rings represented by the following formula:

[0198] [Chemical Drawing 17]

[0199]

[0200] (wherein

[0201] R 8 is an imidazolyl group, a thiazolyl group or -C(=O)NHRe a group, wherein R e is 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:

[0202] [Chemical Figure 18]

[0203]

[0204] {wherein 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; R 11 is a hydrogen atom, a halogen atom, or a cyano group; R 12 is a hydrogen atom or a C1-C6 alkyl group; R 13 is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 alkyl group optionally substituted with a halogen atom; 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};

[0205] R 9 is a hydrogen atom or a halogen atom.)

[0206] In addition, in another embodiment of the present invention, a preferred example of ring A is a ring selected from the group consisting of rings represented by the following formula:

[0207] [Chemical Figure 19]

[0208]

[0209] (wherein

[0210] R 8 is an imidazolyl group, a thiazolyl group, or a -C(=O)-NHR e group, wherein R e is 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:

[0211] [Chemical Figure 20]

[0212]

[0213] {wherein 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 group, a C1-C6 alkoxy-C1-C6 alkylcarbonyl group or a C3-C6 cycloalkyl group; R 11 is a hydrogen atom, a halogen atom or a cyano group; R 12 is a hydrogen atom or a C1-C6 alkyl group; R 13 is a hydrogen atom, a C1-C6 alkyl group or a C1-C6 alkyl group optionally substituted with a halogen atom; 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};

[0214] R 9 is a hydrogen atom or a halogen atom.)

[0215] R 1 The preferred examples of R are rings selected from the group consisting of the rings represented by the following formula:

[0216] [Chemical Figure 21]

[0217]

[0218] {wherein

[0219] R 16 is a hydrogen atom, a C1-C6 alkyl group or a C1-C6 haloalkyl group}

[0220] and -C(=O)-NR a R b group or -NR c -C(=O)R d group, wherein R a 、R b 、R c and R d are each independently a hydrogen atom or a C1-C6 alkyl group.

[0221] R 2 The preferred example of R is a hydrogen atom.

[0222] Alternatively, the preferred examples are those in which R 1 and R 2 together with the carbon atom to which they are attached form a ring represented by the following formula:

[0223] [Chemical Figure 22]

[0224]

[0225] {wherein

[0226] * 1 is a carbon atom bonded to R 1 bonded carbon atom,

[0227] * 2 is a carbon atom bonded to R 2 bonded carbon atom}.

[0228] R 3 A preferred example of R is a hydrogen atom.

[0229] R 4 Preferred examples of R are C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C3 alkoxy-C2-C6 alkyl groups, C1-C3 haloalkoxy-C2-C6 alkyl groups, and C3-C6 cycloalkyl-C1-C6 alkyl groups optionally substituted with a cyano group. More preferred examples are C1-C6 alkyl groups, C1-C3 alkoxy-C2-C6 alkyl groups, and C3-C6 cycloalkyl-C1-C6 alkyl groups capable of being substituted with a cyano group.

[0230] In particular, compounds selected from the following are particularly preferred.

[0231] [Chemical Drawing 23-1]

[0232]

[0233] [Chemical Drawing 23-2]

[0234]

[0235]

[0236] [Chemical Drawing 23-3]

[0237]

[0238] There is no particular limitation on the "salt" of compound (I) as long as the salt is a pharmaceutically acceptable salt, and examples thereof include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, and phosphate; organic carboxylates such as acetate, oxalate, fumarate, maleate, malonate, citrate, succinate, and malate; organic sulfonates such as methanesulfonate, benzenesulfonate, and p-toluenesulfonate; alkali metal salts such as lithium salt, sodium salt, and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and the like.

[0239] The compound (I) of the present invention or a pharmaceutically acceptable salt thereof can be prepared by various methods. For example, the general synthetic methods described in Preparation Methods 1 to 27 below, methods similar to the following preparation methods, or synthetic methods well-known to those skilled in the art can be appropriately combined. For example, other compounds of general formula I or pharmaceutically acceptable salts thereof can be obtained by performing known reactions such as condensation reactions, addition reactions, oxidation reactions, reduction reactions, substitution reactions, halogenation reactions, dehydration reactions, or hydrolysis reactions, or by appropriately combining these reactions. Additionally, unless otherwise specified, the salts of compound (I) can be appropriately selected from the above-mentioned "salts" for each of the following preparation methods, and the salts can be prepared by methods well-known to those skilled in the art.

[0240] If compound (I) has one or more asymmetric carbon atoms, the operation of resolving stereoisomers can be included in any of the steps described in Preparation Methods 1 to 27. The method for separating stereoisomers can be any method commonly used by those skilled in the art, and for example, separation by column chromatography can be recommended. All starting materials and reagents for synthesis are commercially available or can be prepared using commercially available compounds by methods well-known to those skilled in the art.

[0241] The treatment of the compounds of the present invention such as extraction and purification can be carried out by conventional organic chemistry procedures. In each step of preparing the intermediates for preparing compound (I), the product can be transferred to the next step as a crude product containing impurities without purification, or multiple steps can be continuously carried out as in a one-pot reaction. In addition, compound (I) or the products of each step in preparing compound (I) can be obtained in the form of salts, solvates, etc. Additionally, in all the steps described below, the order of the steps to be performed can be appropriately changed. It should be noted that the preparation method of the compound (I) of the present invention is not limited to the following examples.

[0242] The abbreviations in the corresponding preparation methods and examples in this specification are as follows.

[0243] Pin: Pinacol

[0244] MIDA: N-Methyliminodiacetic acid

[0245] THF: Tetrahydrofuran

[0246] DMF: N,N-Dimethylformamide

[0247] DMAc: N,N-Dimethylacetamide

[0248] DMSO: Dimethyl sulfoxide

[0249] tert: tertiary

[0250] DABCO: 1,4-Diazabicyclo[2.2.2]octane

[0251] DBU: 1,8-Diazabicyclo[5.4.0]-7-undecene

[0252] DCC: N,N'-Dicyclohexylcarbodiimide

[0253] DIC: N,N'-Diisopropylcarbodiimide

[0254] EDC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0255] HBTU: 1-[Bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate

[0256] HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0257] COMU: (1-Cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate

[0258] TCFH: Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate

[0259] BOP: Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate

[0260] PyBOP: (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate

[0261] PyBrop: Bromotripyrrolidonium phosphonium hexafluorophosphate

[0262] DMT-MM: 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride

[0263] T3P: 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide

[0264] HOBt: 1-Hydroxybenzotriazole

[0265] HOAt: 1-Hydroxy-7-azabenzotriazole

[0266] Oxyma: Ethyl cyano(isonitroso)acetate

[0267] DIPEA: N,N-Diisopropylethylamine

[0268] DMAP: 4-Dimethylaminopyridine

[0269] DEAD: Diethyl azodicarboxylate

[0270] DIAD: Diisopropyl azodicarboxylate

[0271] TMAD: 1,1'-Azobis(N,N-dimethylformamide)

[0272] ADDP: 1,1'-(Azodicarbonyl)dipiperidine

[0273] XPhos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0274] Aphos-PD-G3: [4-(Di-tert-butylphosphino)-N,N-dimethylaniline-2-(2'-aminobiphenyl)]palladium(II) methanesulfonate

[0275] Xantphos-PD-G3: Methanesulfonic acid [(4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0276] SPhos-PD-G3: (2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0277] BINAP: 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl

[0278] SPhos: 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl

[0279] tBuXPhos: 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl

[0280] DavePhos: 2-Dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl

[0281] XantPhos: 4,5-Bis(diphenylphosphino)-9,9-dimethyloxanthene

[0282] BrettPhos: 2-(Dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl

[0283] QPhos: 1,2,3,4,5-Pentaphenyl-1'-(di-tert-butylphosphino)ferrocene

[0284] LDA: Lithium diisopropylamide

[0285] MTBE: Methyl tert-butyl ether

[0286] Boc: tert-Butyloxycarbonyl

[0287] Cbz: Benzyloxycarbonyl

[0288] Fmoc: 9-Fluorenylmethoxycarbonyl

[0289] TMS: Trimethylsilyl

[0290] LC: Liquid chromatography

[0291] MS: Mass spectrometry

[0292] ESI: Electrospray ionization

[0293] UV: Ultraviolet light

[0294] NMR: Nuclear magnetic resonance

[0295] TEA: Triethylamine

[0296] TFA: Trifluoroacetic acid

[0297] NIS: N-Iodosuccinimide

[0298] NMP: N-Methylpyrrolidone

[0299] TBAF: Tetrabutylammonium fluoride

[0300] NBS: N-Bromosuccinimide

[0301] NCS: N-Chlorosuccinimide

[0302] DTT: Dithiothreitol

[0303] EDTA: Ethylenediaminetetraacetic acid

[0304] Compound (I) can be prepared, for example, by Preparation Method 1 below.

[0305] <Preparation Method 1>

[0306] [Chemical Figure 24]

[0307]

[0308] [wherein R 1 、R 2 、R 3 、R 4 、X 1 、X 2 、X 3 、X 4 、Y 1 、Y 2 、Q 1 、Q 2Ring A is as defined above. In addition, LG 1 is a hydroxyl group or a chloro group, M 1 is boric acid or a boric acid-related structure such as B(OH)2, B(OMe)2, B(pin), B(MIDA) or BF3K, and Hal 1 is a chloro group, a bromo group or an iodo group.]

[0309] (Step 1-A)

[0310] (Step 1-A) Compound (I) can be prepared by subjecting compound (1-1) and compound (1-2) to a cyclization reaction in air or in an oxygen atmosphere.

[0311] An acid can be present to facilitate the reaction. Examples of the acid include, but are not limited to, acetic acid, trifluoroacetic acid, ammonium acetate, p-toluenesulfonic acid, hydrochloric acid, phosphoric acid, etc.

[0312] Examples of the reaction solvent include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc.; nitriles such as acetonitrile, propionitrile, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, DMSO, etc.; alcohols such as methanol, ethanol, etc.; water; and their mixed solvents, and the reaction can be carried out under solvent-free conditions.

[0313] 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 defined and is preferably 1 hour to 24 hours.

[0314] (Step 1-B)

[0315] In (Step 1-B), compound (I) can be synthesized by subjecting compound (1-3) and compound (1-4) to an addition-elimination reaction or a substitution reaction in the presence or absence of a base.

[0316] Examples of the reaction solvent include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc.; nitriles such as acetonitrile, propionitrile, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, DMSO, etc.; and their mixed solvents.

[0317] Examples of bases include, but are not limited to: alkali 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, sodium hydride, etc.; and 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, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), etc.

[0318] If Q 1 is a carbonyl group and LG 1 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 or T3P. In addition, additives can be added to promote the reaction, and examples of additives include HOBt, HOAt, Oxyma, DMAP, etc.

[0319] If Q 1 is a methylene group (-CH2-) and LG 1 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 and tri-n-butylphosphine.

[0320] The reaction temperature is not particularly limited and is generally 0°C to 150°C. The reaction time is not particularly limited and is preferably 0.5 hours to 24 hours.

[0321] (Step 1-C)

[0322] In (Step 1-C), compound (I) can be prepared by subjecting compound (1-5) and compound (1-6) to a Suzuki-Miyaura coupling reaction in the presence of a palladium catalyst and a base.

[0323] Examples of palladium catalysts include, but are not limited to, metal palladium, such as palladium-carbon, palladium black, etc.; palladium salts, such as palladium chloride, palladium acetate, etc.; organic palladium complexes, such as tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1'-bis (diphenylphosphino) ferrocene, tris (dibenzylideneacetone) dipalladium, bis [di-tert-butyl (4-dimethylaminophenyl) phosphine] dichloro palladium bis (acetonitrile) dichloro palladium, chloro (crotyl) (tri-tert-butylphosphine) palladium, XPhos-palladium chloride (crotyl), etc.; palladium cyclic complexes, such as APhos-Pd-G3, Xantphos-PD-G3, SPhos-PD-G3, etc.; and polymer-fixed organic palladium complexes, such as polymer-supported bis (acetate) triphenylphosphine palladium, polymer-supported di (acetic acid) dicyclohexylphenylphosphine palladium, etc. These can be used in combination.

[0324] Examples of the base include, but are not limited to, alkali 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, sodium hydride, and the like; and organic bases such as trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, tributylamine, N-methylmorpholine, pyridine, 4- (N,N-dimethylamino)pyridine, 2,6-lutidine, 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, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), etc.

[0325] Additives may be present to facilitate the reaction and include, but are not limited to, trialkylphosphines such as trimethylphosphine, tri-tert-butylphosphine, and the like; tricycloalkylphosphines such as tricyclohexylphosphine, and the like; triarylphosphines such as triphenylphosphine, tritolylphosphine, and the like; trialkylphosphites such as trimethylphosphite, triethylphosphite, tributylphosphite, and the like; tricycloalkylphosphites such as tricyclohexylphosphite, and the like; triarylphosphites such as triphenylphosphite, and the like; imidazolium salts such as 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride, and the like; diketones such as acetylacetone, octafluoroacetylacetone, and the like; amines such as trimethylamine, triethylamine, tripropylamine, triisopropylamine, tributylamine, and the like; 1,1'-bis(diphenylphosphino)ferrocene; 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 (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.

[0326] Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; aliphatic hydrocarbons such as hexane, heptane, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc.; nitriles such as acetonitrile, propionitrile, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, DMSO, etc.; alcohols such as methanol, ethanol, etc.; water; and mixed solvents thereof.

[0327] The reaction temperature is not particularly limited, and is usually room temperature to 150° C. The reaction time is not particularly limited, and is preferably 0.1 hour to 24 hours.

[0328] Compound (2-6) which is one of the above compounds (1-1) can be produced by, for example, the following Production Method 2.

[0329] <Preparation Method 2>

[0330] [Chemical Figure 25]

[0331]

[0332] [Wherein R 4 , X 2 , X 3 , X 4 and ring A are as defined above. In addition, Hal 2 is a fluorine group or a chlorine group.]

[0333] (Step 2-1)

[0334] In (Step 2-1), compound (2-3) can be prepared by subjecting compound (2-1) and compound (2-2) to an aromatic nucleophilic substitution reaction in the presence of a base.

[0335] Examples of the base include, but are not limited to: alkali metals 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, sodium hydride, etc.; and organic bases such as trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, 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, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), etc.

[0336] Examples of the reaction solvent include, but are not limited to: aromatic hydrocarbons such as benzene, toluene, chlorobenzene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc.; nitriles such as acetonitrile, propionitrile, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, DMSO, etc.; water; and their mixed solvents, and the reaction can be carried out under solvent-free conditions.

[0337] The reaction temperature is not particularly limited and is usually from room temperature to 200 °C. The reaction time is not particularly limited and is preferably from 0.5 hour to 24 hours.

[0338] (Step 2-2)

[0339] In (Step 2-2), compound (2-5) can be prepared 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.

[0340] Examples of condensing agents include, but are not limited to, DCC, DIC, EDC, HBTU, HATU, COMU, TCFH, BOP, PyBOP, PyBrOP, DMT-MM, T3P, etc.

[0341] Additives can be added to facilitate the reaction, and examples of additives include HOBt, HOAt, Oxyma, DMAP, etc.

[0342] Examples of bases 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, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), etc.

[0343] Examples of reaction solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc.; nitriles such as acetonitrile, propionitrile, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, DMSO, etc.; and their mixed solvents.

[0344] The reaction temperature is not particularly limited and is usually from room temperature to 100 °C. The reaction time is not particularly limited and is preferably from 0.5 hour to 24 hours.

[0345] (Step 2-3A)

[0346] In (Step 2-3A), compound (2-6) can be prepared by subjecting compound (2-5) to a catalytic reduction reaction in the presence of a transition metal catalyst and hydrogen.

[0347] Examples of transition metal catalysts include, but are not limited to, palladium / carbon, palladium hydroxide / carbon, palladium / silk fibroin, Raney nickel, platinum oxide, etc.

[0348] Examples of reaction solvents include, but are not limited to, alcohols such as methanol, ethanol, 2-propanol, tert-butanol, etc.; esters such as methyl acetate, ethyl acetate, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, DMSO, etc.; protic polar solvents such as acetic acid, etc.; water; and their mixed solvents.

[0349] The reaction temperature is not particularly limited and is generally from room temperature to 100 °C, and the reaction is carried out under normal pressure or under pressure. The reaction time is not particularly limited and is preferably from 0.5 hour to 24 hours.

[0350] (Step 2-3B)

[0351] In (Step 2-3B), compound (2-6) can be prepared by subjecting compound (2-5) to a reduction reaction in the presence of reduced iron or zinc.

[0352] To promote the reaction, additives can be present, and examples of the additives include but are not limited to acetic acid, hydrochloric acid, ammonium chloride, etc.

[0353] Examples of the reaction solvent include but are not limited to alcohols such as methanol, ethanol, 2-propanol, tert-butyl alcohol, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; protic polar solvents such as acetic acid, etc.; water; and mixed solvents thereof.

[0354] The reaction temperature is not particularly limited and is generally from 0 °C to 100 °C. The reaction time is not particularly limited and is preferably from 0.5 hour to 24 hours.

[0355] Compound (1-2) can be prepared, for example, by Preparation Method 3 below.

[0356] <Preparation Method 3>

[0357] [Chemical Drawing 26]

[0358]

[0359] [wherein R 1 , R 2 , R 3 , Y 1 and Y 2 are as defined above. Further, Hal 3 is a chloro group, a bromo group or an iodo group.]

[0360] (Step 3-1)

[0361] In (Step 3-1), compound (3-2) can be prepared by subjecting compound (3-1) and vinylboronic acid or a vinylboronic acid derivative to a Suzuki-Miyaura coupling reaction in the presence of a palladium catalyst and a base.

[0362] Examples of the vinylboronic acid derivative include vinylboronic acid pinacol ester, vinylboronic acid dibutyl ester, MIDA vinylboronic acid MIDA, potassium vinyltetrafluoroborate, etc.

[0363] Examples of the palladium catalyst and the base include those described in Preparation Method 1 (Step 1-C).

[0364] Additives may be present to promote the reaction, and examples of the additives include those described in Preparation Method 1 (Step 1-C).

[0365] Examples of the reaction solvent include those described in Preparation Method 1 (Step 1-C).

[0366] The reaction temperature is not particularly limited and is generally from room temperature to 150 °C. The reaction time is not particularly limited and is preferably from 0.1 hour to 24 hours.

[0367] (Step 3-2)

[0368] In (Step 3-2), Compound (1-2) can be prepared by subjecting Compound (3-2) to a double bond cleavage reaction using osmium tetroxide and sodium periodate.

[0369] To promote the reaction, additives may be present, and examples of the additives include 2,6-dimethylpyridine and the like.

[0370] Examples of the reaction solvent include, but are not limited to, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc.; nitriles such as acetonitrile, propionitrile, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; acetone; water; and mixed solvents thereof.

[0371] The reaction temperature is not particularly limited and is generally from 0 °C to 100 °C. The reaction time is not particularly limited and is preferably from 1 hour to 24 hours.

[0372] Compound (4-3) as one of the above Compounds (3-1) can be prepared, for example, by the following Preparation Method 4.

[0373] <Preparation Method 4>

[0374] [Chemical Drawing 27]

[0375]

[0376] [wherein R 2 、R 3 、R 4 、Y 1 、Y 2 and Hal 3 are as defined above. Additionally, Y 3 and Y 4 are each independently CH, C-alkyl 2or 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.]

[0377] (Step 4-1)

[0378] In (Step 4-1), compound (4-3) can be prepared by subjecting compound (4-1) and compound (4-2) to a substitution reaction in the presence of a base.

[0379] Examples of the base include the bases described in (Step 2-1), and preferably include sodium hydride, tripotassium phosphate and potassium tert-butoxide.

[0380] Examples of the reaction solvent include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, xylene, etc.; nitriles such as acetonitrile, propionitrile, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, DMSO, etc.; and mixed solvents thereof.

[0381] The reaction temperature is not particularly limited and is generally from 0°C to 100°C. The reaction time is not particularly limited and is preferably from 0.5 hour to 24 hours.

[0382] Compound (5-5), which is one of the above compounds (4-1), can be prepared, for example, by Preparation Method 5 below.

[0383] <Preparation Method 5>

[0384] [Chemical Figure 28]

[0385]

[0386] [wherein R 2 , R 3 , Y 1 , Y 2 , Hal 3 and alkyl 2 are as defined above. Further, alkyl 3 is an optionally substituted C1-C3 alkyl group.]

[0387] (Step 5-1)

[0388] In (Step 5-1), compound (5-2) can be prepared by subjecting compound (5-1) to a carbamate esterification reaction with 4-nitrophenyl chloroformate in the presence of a base.

[0389] Examples of the base include the base described in (Step 2-2).

[0390] Examples of the reaction solvent include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc.; nitriles such as acetonitrile, propionitrile, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; and mixed solvents thereof.

[0391] The reaction temperature is not particularly limited and is generally 0°C to 100°C. The reaction time is not particularly limited and is preferably 0.5 hours to 24 hours.

[0392] (Step 5-2)

[0393] In (Step 5-2), compound (5-3) can be prepared by subjecting compound (5-2) to an addition-elimination reaction with hydrazine or hydrazine monohydrate in the presence or absence of a base.

[0394] Examples of the base include the base described in (Step 2-2).

[0395] Examples of the reaction solvent include the solvents described in (Step 5-1).

[0396] The reaction temperature is not particularly limited and is generally 0°C to 100°C. The reaction time is not particularly limited and is preferably 0.5 hours to 24 hours.

[0397] (Step 5-3)

[0398] In (Step 5-3), compound (5-5) can be prepared by subjecting compound (5-3) and compound (5-4) to a triazolone cyclization reaction in the presence of an acid.

[0399] Examples of the acid include, but are not limited to, p-toluenesulfonic acid.

[0400] Examples of the reaction solvent include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; aliphatic hydrocarbons such as hexane, heptane, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; alcohols such as methanol, ethanol, n-butanol, tert-butyl alcohol, etc.; and mixed solvents thereof.

[0401] The reaction temperature is not particularly limited and is generally 0°C to 100°C. The reaction time is not particularly limited and is preferably 0.5 hours to 24 hours.

[0402] Compound (6-3), which is one of the above compounds (3-1), can be prepared, for example, by Preparation Method 6 below.

[0403] <Preparation Method 6>

[0404] [Chemical Figure 29]

[0405]

[0406] [Wherein R 3 , Y 1 , Y 2 and Hal 3 are as defined above. In addition, the alkyl 4 is an optionally substituted C1-C6 alkyl group.]

[0407] (Step 6-1)

[0408] In (Step 6-1), the compound (6-3) can be prepared by subjecting the compounds (6-1) and (6-2) to an oxa-Pictet-Spengler reaction in the presence of an acid.

[0409] The acid includes but is not limited to hydrochloric acid, sulfuric acid, trifluoroacetic acid, titanium(IV) chloride, boron trifluoride, etc.

[0410] Examples of the reaction solvent include but are not limited to aromatic hydrocarbons such as benzene, toluene, xylene, etc.; aliphatic hydrocarbons such as hexane, heptane, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; alcohols such as methanol, ethanol, tert-butyl alcohol, etc.; nitromethane; water; and mixed solvents thereof, and the reaction can also be carried out under solvent-free conditions.

[0411] The reaction temperature is not particularly limited and is generally 0°C to 100°C. The reaction time is not particularly limited and is preferably 1 hour to 100 hours.

[0412] The compound (7-3), which is one of the above compounds (3-1), can be prepared, for example, by the following Preparation Method 7.

[0413] <Preparation Method 7>

[0414] [Chemical Figure 30]

[0415]

[0416] [Wherein R 2 , R 3 , Y 1 , Y 2 and Hal 3 are as defined above. In addition, the alkyl 5 and the alkyl6 Each independently is a hydrogen atom or an optionally substituted C1-C6 alkyl group.

[0417] (Step 7-1)

[0418] In (Step 7-1), compound (7-3) can be prepared by subjecting compound (7-1) and compound (7-2) to an intramolecular lactam cyclization reaction in the presence of phenylsilane and indium acetate.

[0419] The intramolecular lactam cyclization can be carried out, for example, according to the method described in Angewandte Chemie - International Edition 2016, 55, pages 1864 to 1867.

[0420] Compound (8-2), which is one of the above compounds (1-2), can be prepared, for example, by the following Preparation Method 8.

[0421] <Preparation Method 8>

[0422] [Chemical Diagram 31]

[0423]

[0424] [wherein R 2 , R 3 , Y 1 and Y 2 are as defined above. Further, Het 1 is an optionally substituted amino group or an optionally substituted alkoxy group. R 2 and Het 1 can together with the carbon atoms to which they are respectively bonded form an optionally substituted ring.

[0425] (Step 8-1)

[0426] In (Step 8-1), compound (8-2) can be prepared by subjecting compound (8-1) to a Duff reaction using an acid and hexamethylenetetramine.

[0427] Examples of the acid include, but are not limited to, acetic acid; trifluoroacetic acid; methanesulfonic acid; trifluoromethanesulfonic acid; etc.

[0428] Examples of the reaction solvent include halogenated hydrocarbons such as dichloromethane, etc.; alcohols such as ethanol, etc.; water; and their mixed solvents, but the reaction can be carried out under solvent-free conditions.

[0429] The reaction temperature is not particularly limited and is generally 0°C to 100°C. The reaction time is not particularly limited and is preferably 0.5 hours to 24 hours.

[0430] The compound (9-3), which is one of the above compounds (1-2), can be prepared, for example, by the following preparation method 9.

[0431] <Preparation Method 9>

[0432] [Chemical Drawing 32]

[0433]

[0434] [wherein R 2 , R 3 , Y 1 and Y 2 are as defined above. Hal 4 is a chlorine group, a bromine group or an iodine group. ] Additionally, alkyl 7 is an optionally substituted C1-C6 alkyl group; alkyl 8 is a hydrogen atom or an optionally substituted C1-C6 alkyl group; and alkyl 7 and alkyl 8 can together with the carbon atoms to which they are bonded form an optionally substituted ring. ]

[0435] (Step 9-1)

[0436] In (Step 9-1), the compound (9-3) can be prepared by subjecting the compound (9-1) and the compound (9-2) to a Goldberg amination reaction in the presence of a copper catalyst and a base.

[0437] Examples of the copper catalyst 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, etc.

[0438] 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, sodium tert-butoxide, etc.

[0439] To promote the reaction, an additive can coexist, and examples of the additive include N,N'-dimethylethylenediamine, etc.

[0440] Examples of the reaction solvent include, but are not limited to, aromatic hydrocarbons such as toluene, etc.; ethers such as THF, 1,4-dioxane, etc.; aprotic polar solvents such as DMF, N-methylpyrrolidone, etc.; and their mixed solvents.

[0441] The reaction temperature is not particularly limited and is generally from room temperature to 150 °C. The reaction time is not particularly limited and is preferably from 0.5 hour to 24 hours.

[0442] Compound (10-3), which is one of the above compounds (1-6), and compound (10-6), which is one of the above compounds (1-3), can be prepared, for example, by the following Preparation Method 10.

[0443] <Preparation Method 10>

[0444] [Chemical Drawing 33]

[0445]

[0446] [wherein R 1 , R 2 , R 3 , R 4 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Hal 1 and Hal 3 are as defined above. Further, M 2 is boric acid or a borate ester, and alkyl 9 is a methyl group, an ethyl group or a benzyl group.]

[0447] (Step 10-1A-1)

[0448] In (Step 10-1A-1), compound (10-2) can be prepared by subjecting compound (10-1) to a borylation reaction using a borate ester in the presence of LDA.

[0449] Examples of the borate ester include, but are not limited to, trimethyl borate, triethyl borate, triisopropyl borate, etc.

[0450] Examples of the reaction solvent include, but are not limited to, aromatic hydrocarbons such as toluene, etc.; ethers such as THF, 1,4-dioxane, etc.; and mixed solvents thereof.

[0451] The reaction temperature is not particularly limited and is usually from -78 °C to room temperature. The reaction time is not particularly limited and is preferably from 0.5 hour to 24 hours.

[0452] (Step 10-1A-2)

[0453] In (Step 10-1A-2), compound (10-5) can be prepared by subjecting compound (10-2) and compound (3-1) to a Suzuki-Miyaura coupling reaction by the same method as in Step (1-C).

[0454] (Step 10-1B-1)

[0455] In (Step 10-1B-1), compound (10-3) can be prepared by subjecting compound (3-1) and bis(pinacolato)diboron to a Miyaura borylation reaction in the presence of a palladium catalyst and potassium acetate.

[0456] Examples of the palladium catalyst include the palladium catalysts described in (Step 1-C) of Preparation Method 1.

[0457] An additive may be present to promote the reaction, and examples of the additive include the additives described in (Step 1-C) of Preparation Method 1.

[0458] Examples of the reaction solvent include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, xylene, etc.; aliphatic hydrocarbons such as hexane, heptane, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc.; nitriles such as acetonitrile, propionitrile, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, DMSO, etc.; and mixed solvents thereof.

[0459] The reaction temperature is not particularly limited and is generally 80°C to 150°C. The reaction time is not particularly limited and is preferably 0.1 hour to 24 hours.

[0460] (Step 10-1B-2)

[0461] In Step 10-1B-2, compound (10-5) can be prepared by subjecting compound (10-3) and compound (10-4) to a Suzuki-Miyaura coupling reaction by the same method as in (Step 1-C) of Preparation Method 1.

[0462] (Step 10-2)

[0463] In Step (10-2), compound (10-6) can be prepared by subjecting compound (10-5) to a hydrolysis reaction in the presence of a base.

[0464] Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.

[0465] Examples of the reaction solvent include, but are not limited to, ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; alcohols such as methanol, ethanol, 2-propanol, tert-butyl alcohol, etc.; water; and mixed solvents thereof.

[0466] The reaction temperature is not particularly limited and is generally 0°C to 100°C. The reaction time is not particularly limited and is preferably 0.5 hour to 24 hours.

[0467] Compound (10-6) can be prepared, for example, by the following Preparation Method 11.

[0468] <Preparation Method 11>

[0469] [Chemical Drawing 34]

[0470]

[0471] [wherein R 1 、R 2 、R 3 、R 4 、X 2 、X 3 、X 4 、Y 1 and Y 2 are as defined above. In addition, Ar 1 is an optionally substituted phenyl group.]

[0472] (Step 11-1)

[0473] In (Step 11-1), compound (10-6) can be prepared by subjecting compound (11-1) to a catalytic reduction reaction in the presence of a transition metal catalyst and in the presence of hydrogen.

[0474] The reaction can be carried out under the same conditions as those described in (Step 2-3A) of Preparation Method 2.

[0475] Compound (10-4) can be prepared, for example, by the following Preparation Method 12.

[0476] <Preparation Method 12>

[0477] [Chemical Drawing 35]

[0478]

[0479] [wherein R 1 、R 2 、R 3 、R 4 、X 2 、X 3 、X 4 、Y 1 、Y 2 、Hal 1 and alkyl 9 are as defined above. Hal 5 is a chloro group, a bromo group or an iodo group. ] In addition, LG 3 is a leaving group such as a chloro group, a bromo group, an iodo group, a trifluoromethanesulfonyloxy group, etc.; and PG 1is a protecting group selected from the following: carbamate-based protecting groups such as Boc group, etc.; amide-based protecting groups such as acetyl group, etc.; sulfonamide-based protecting groups such as p-toluenesulfonyl group, etc.; and the like.

[0480] (Step 12-1)

[0481] In (Step 12-1), compound (12-2) can be prepared by subjecting compound (12-1) and trimethylsilylacetylene to a Sonogashira coupling reaction in the presence of a palladium catalyst and a base.

[0482] Examples of the palladium catalyst include the palladium catalysts described in (Step 1-C).

[0483] Examples of the base include the bases described in (Step 1-C).

[0484] To promote the reaction, an additive can be added, and examples of the additive include the additives described in (Step 1-C) and copper salts such as copper(I) iodide, and these additives can be used alone or in combination.

[0485] Examples of the reaction solvent include but are not limited to aromatic hydrocarbons such as benzene, toluene, xylene, etc.; aliphatic hydrocarbons such as hexane, heptane, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc.; nitriles such as acetonitrile, propionitrile, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, DMSO, etc.; alcohols such as methanol, ethanol, etc.; and their mixed solvents.

[0486] (Step 12-2)

[0487] In (Step 12-2), compound (12-3) can be prepared by subjecting compound (12-2) to an indole cyclization reaction in the presence of a base or in the presence of a transition metal catalyst.

[0488] Examples of the base include but are not limited to sodium tert-butoxide, sodium hydride, etc.

[0489] Examples of the transition metal catalyst include but are not limited to copper salts such as copper(I) iodide, etc.; silver complexes such as silver bis(trifluoromethanesulfonyl)imide, etc.; and gold salts such as chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)gold(I), chloro(triphenylphosphine)gold(I), etc. In addition, these catalysts can be used in combination.

[0490] Examples of the reaction solvent include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; aliphatic hydrocarbons such as hexane, heptane, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, DMSO, etc.; alcohols such as methanol, ethanol, etc.; acetonitrile; and mixed solvents thereof.

[0491] The reaction temperature is not particularly limited and is usually from room temperature to 150 °C. The reaction time is not particularly limited and is preferably from 1 hour to 24 hours.

[0492] (Step 12-3)

[0493] In (Step 12-3), compound (12-5) can be prepared by subjecting compound (12-3) and compound (12-4) to a substitution reaction in the presence of a base.

[0494] Examples of the base include the bases described in (Step 1-B).

[0495] Examples of the reaction solvent include the reaction solvents described in (Step 1-B).

[0496] The reaction temperature is not particularly limited and is usually from 0 °C to 150 °C. The reaction time is not particularly limited and is preferably from 1 hour to 24 hours.

[0497] (Step 12-4)

[0498] In (Step 12-4), compound (10-4) can be prepared by subjecting compound (12-5) to a halogenation reaction using LDA and a halogenating agent.

[0499] Examples of the halogenating agent include iodinating agents such as N-iodosuccinimide, N-iodophthalimide, N-iodosaccharin, 1,3-diiodo-5,5-dimethylhydantoin, iodine, etc.; brominating agents such as N-bromosuccinimide, N-bromophthalimide, N-bromosaccharin, 1,3-dibromo-5,5-dimethylhydantoin, carbon tetrabromide, bromine, etc.; and chlorinating agents such as N-chlorosuccinimide, N-chlorophthalimide, N-chlorosaccharin, 1,3-dichloro-5,5-dimethylhydantoin, etc.

[0500] Examples of the reaction solvent include, but are not limited to, ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.

[0501] The reaction temperature is not particularly limited and is usually from -78 °C to room temperature. The reaction time is not particularly limited and is preferably from 1 hour to 24 hours.

[0502] (Step 12-5)

[0503] In (Step 12-5), compound (12-7) can be prepared by subjecting compound (12-6) and compound (12-4) to a substitution reaction by the same method as in (Step 12-3).

[0504] (Step 12-6)

[0505] In (Step 12-6), compound (12-5) can be prepared by subjecting compound (12-7) to an esterification reaction using n-butyllithium and compound (12-8).

[0506] Examples of the reaction solvent include, but are not limited to, ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, MTBE, etc.

[0507] The reaction temperature is not particularly limited and is generally from -78 °C to room temperature. The reaction time is not particularly limited and is preferably from 1 hour to 24 hours.

[0508] (Step 12-7)

[0509] In (Step 12-7), compound (12-9) can be prepared by protecting the nitrogen of the azole ring forming compound (12-3) with a protecting group PG 1 The reaction can be carried out by methods known to those skilled in the art (for example, the methods described in "Protective Groups in Organic Synthesis (5th Edition, 2014)" by Green and Wuts, etc.).

[0510] (Step 12-8)

[0511] In (Step 12-8), compound (12-10) can be prepared by subjecting compound (12-9) to a hydrogenation reaction by the same method as in (Step 12-4).

[0512] (Step 12-9)

[0513] In (Step 12-9), compound (12-11) can be prepared by subjecting compound (12-10) to a deprotection reaction to remove the protecting group PG 1 The deprotection reaction can be carried out according to methods known to those skilled in the art (for example, the methods described in "Protective Groups in Organic Synthesis (5th Edition, 2014)" by Green and Wuts, etc.).

[0514] (Step 12-10)

[0515] In (Step 12-10), compound (10-4) can be prepared by subjecting compound (12-11) and compound (12-4) to a substitution reaction by the same method as in (Step 12-3).

[0516] Compound (10-5) can be prepared, for example, by Preparation Method 13 below.

[0517] <Preparation Method 13>

[0518] [Chemical Drawing 36]

[0519]

[0520] [wherein R 1 , R 2 , R 3 , R 4 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Hal 1 , Hal 5 , LG 3 and alkyl 9 are as defined above.]

[0521] (Step 13-1)

[0522] In (Step 13-1), compound (13-1) can be prepared by subjecting compound (3-1) and trimethylsilylacetylene to a Sonogashira coupling reaction by the same method as in (Step 12-1).

[0523] (Step 13-2)

[0524] In (Step 13-2), compound (13-2) can be prepared by subjecting compound (13-1) to a desilylation reaction. The desilylation reaction can be carried out according to methods well known to those skilled in the art (for example, the methods described in Green and Wuts' "Protective Groups in Organic Synthesis (5th Edition, 2014)", etc.).

[0525] (Step 13-3)

[0526] In (Step 13-3), compound (13-3) can be prepared by subjecting compound (13-2) and compound (12-1) to a substitution reaction by the same method as in (Step 12-1).

[0527] (Step 13-4)

[0528] In (Step 13-4), compound (13-4) can be prepared by subjecting compound (13-3) to an indole cyclization reaction in the presence of a transition metal catalyst.

[0529] Examples of the transition metal catalyst 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'-dimethoxybiphenyl)gold(I), chloro(triphenylphosphine)gold(I), etc.

[0530] Examples of the reaction solvent include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; aliphatic hydrocarbons such as hexane, heptane, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; alcohols such as methanol, ethanol, etc.; and mixed solvents thereof.

[0531] The reaction temperature is not particularly limited and is generally from room temperature to 150 °C. The reaction time is not particularly limited and is preferably from 1 hour to 24 hours.

[0532] (Step 13-5)

[0533] In (Step 13-5), compound (10-5) can be prepared by subjecting compound (13-4) and compound (12-4) to a substitution reaction by the same method as in (Step 12-3).

[0534] (Step 13-6)

[0535] In (Step 13-6), compound (13-6) can be prepared by subjecting compound (13-5) and compound (2-2) to an aromatic nucleophilic substitution reaction by the same method as in (Step 2-1).

[0536] (Step 13-7)

[0537] In (Step 13-7), compound (13-7) can be prepared by subjecting compound (13-6) and compound (13-2) to a substitution reaction by the same method as in (Step 12-1).

[0538] (Step 13-8)

[0539] In (Step 13-8), compound (10-5) can be prepared by subjecting compound (13-7) to an indole cyclization reaction by the same method as in (Step 13-4).

[0540] Compound (13-4) can be prepared, for example, by Preparation Method 14 below.

[0541] <Preparation Method 14>

[0542] [Chemical Drawing 37]

[0543]

[0544] [wherein R 1 , R 2 , R 3 , R 4 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Hal 1 , PG 1 , M 2 and alkyl 9 are as defined above.]

[0545] (Step 14-1)

[0546] In (Step 14-1), Compound (14-1) can be prepared by subjecting Compound (12-9) to a boration reaction by the same method as in (Step 10-1A-1).

[0547] (Step 14-2)

[0548] In (Step 14-2), Compound (14-2) can be prepared by subjecting Compound (14-1) to a deprotection reaction to remove the protecting group PG 1 by the same method as in (Step 12-9).

[0549] (Step 14-3)

[0550] In (Step 14-3), Compound (13-4) can be prepared by subjecting Compound (14-2) and Compound (3-1) to a Suzuki-Miyaura coupling reaction by the same method as in (Step 1-C).

[0551] Compound (15-2), which is one of the above Compounds (1-3), can be prepared, for example, by the method of Preparation Method 15 shown below.

[0552] <Preparation Method 15>

[0553] [Chemical Drawing 38]

[0554]

[0555] [wherein R 1 、R 2 、R 3 、R 4 、X 2 、X 3 、X 4 、Y 1 、Y 2 and alkyl 9 are as defined above.]

[0556] (Step 15-1)

[0557] In (Step 15-1), compound (15-1) can be prepared by subjecting compound (13-7) to an indole cyclization reaction in the presence of copper(I) iodide.

[0558] Examples of the reaction solvent include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; aliphatic hydrocarbons such as hexane, heptane, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; alcohols such as methanol, ethanol, etc.; and mixed solvents thereof.

[0559] The reaction temperature is not particularly limited and is generally from room temperature to 150 °C. The reaction time is not particularly limited and is preferably from 1 hour to 24 hours.

[0560] (Step 15-2)

[0561] In (Step 15-2), compound (15-2) can be prepared by subjecting compound (15-1) to a hydrolysis reaction by the same method as in (Step 10-2).

[0562] Compound (16-2) as one of the above compounds (1-3) can be prepared, for example, by the method of Preparation Method 16 shown below.

[0563] <Preparation Method 16>

[0564] [Chemical Drawing 39]

[0565]

[0566] [wherein R 1 、R 2 、R 3 、R 4 、X 2 、X 3 、X 4 、Y 1 and Y 2 are as defined above.]

[0567] (Step 16-1)

[0568] In (Step 16-1), Compound (16-1) can be prepared by subjecting Compound (2-3) to a nitro reduction reaction in the same manner as in (Step 2-3A) or (Step 2-3B) of Preparation Method 2.

[0569] (Step 16-2)

[0570] In (Step 16-2), Compound (16-2) can be prepared by subjecting Compound (16-1) and Compound (1-2) to a cyclization reaction in the same manner as in (Step 1-A) of Preparation Method 1.

[0571] Compound (17-1), which is one of the above Compounds (1-3), can be prepared, for example, by the following Preparation Method 17.

[0572] <Preparation Method 17>

[0573] [Chemical Drawing 40]

[0574]

[0575] [wherein R 1 , R 2 , R 3 , R 4 , X 2 , X 3 , X 4 , Y 1 , Y 2 and alkyl 9 are as defined above.]

[0576] (Step 17-1)

[0577] In (Step 17-1), Compound (17-1) can be prepared by reducing the alkoxycarbonyl group (-CO2alkyl 9 ) of Compound (10-5) to a hydroxymethyl group using a reducing agent.

[0578] Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, isobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, etc.

[0579] Examples of the reaction solvent include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, xylene, etc.; alcohols such as methanol, ethanol, 2-propanol, tert-butanol, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, etc.; and mixed solvents thereof.

[0580] The reaction temperature is not particularly limited and is usually from 0°C to 100°C. The reaction time is not particularly limited and is preferably from 1 hour to 24 hours.

[0581] Compound (18-1), which is one of the above compounds (1-3), can be prepared, for example, by the following Preparation Method 18.

[0582] <Preparation Method 18>

[0583] [Chemical Figure 41]

[0584]

[0585] [wherein R 1 , R 2 , R 3 , R 4 , X 2 , X 3 , X 4 , Y 1 and Y 2 are as defined above.]

[0586] (Step 18-1)

[0587] In (Step 18-1), compound (18-1) can be prepared by converting the hydroxymethyl group of compound (17-1) into a chloromethyl group using methanesulfonyl chloride in the presence of a base.

[0588] Examples of the base include organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-(N,N-dimethylamino)pyridine, etc.

[0589] Examples of the reaction solvent include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc.; nitriles such as acetonitrile, propionitrile, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; and mixed solvents thereof.

[0590] The reaction temperature is not particularly limited and is generally 0°C to 50°C. The reaction time is not particularly limited and is preferably 0.5 hours to 24 hours.

[0591] Compound (19-5), which is one of the above compounds (1-3), can be prepared, for example, by the method of Preparation Method 19 shown below.

[0592] <Preparation Method 19>

[0593] [Chemical Figure 42]

[0594]

[0595] [wherein R 1 , R 2, R 3 , R 4 , X 2 , X 3 , X 4 , Y 1 , Y 2 and alkyl 9 as defined above. Additionally, Hal 5 is a bromo group or an iodo group, and M 3 is boric acid or a boron acid-related structure such as B(OH)2, B(OMe)2, B(pin), B(MIDA), or BF3K.]

[0596] (Step 19-1)

[0597] In (Step 19-1), compound (19-1) can be prepared by subjecting compound (12-5) to a chlorination reaction using a chlorinating agent.

[0598] Examples of the chlorinating agent include N-chlorosuccinimide, N-chlorophthalimide, N-chlorosaccharin, and 1,3-dichloro-5,5-dimethylhydantoin.

[0599] Examples of the reaction solvent include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc.; nitriles such as acetonitrile, propionitrile, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, DMSO, etc.; and mixed solvents thereof.

[0600] The reaction temperature is not particularly limited and is generally from 0 °C to 100 °C. The reaction time is not particularly limited and is preferably from 1 hour to 24 hours.

[0601] (Step 19-2)

[0602] In (Step 19-2), compound (19-2) can be prepared by subjecting compound (19-1) to a halogenation reaction using a halogenating agent.

[0603] Examples of the halogenating agent include iodinating agents such as N-iodosuccinimide, N-iodophthalimide, N-iodosaccharin, 1,3-diiodo-5,5-dimethylhydantoin, etc.; and brominating agents such as N-bromosuccinimide, N-bromophthalimide, N-bromosaccharin, 1,3-dibromo-5,5-dimethylhydantoin, bromine, etc.

[0604] Examples of the reaction solvent include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc.; nitriles such as acetonitrile, propionitrile, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, DMSO, etc.; and mixed solvents thereof.

[0605] The reaction temperature is not particularly limited and is usually from 0 °C to 100 °C. The reaction time is not particularly limited and is preferably from 1 hour to 24 hours.

[0606] (Step 19-3)

[0607] In (Step 19-3), compound (19-4) can be prepared by subjecting compound (19-2) and compound (19-3) to a Suzuki-Miyaura coupling reaction in the same manner as in (Step 1-C) of Preparation Method 1.

[0608] (Step 19-4)

[0609] In (Step 19-4), compound (19-5) can be prepared by subjecting compound (19-4) to a hydrolysis reaction in the same manner as in (Step 10-2) of Preparation Method 10.

[0610] Compound (20-2), which is one of compounds (1-5), can be prepared, for example, by the method of Preparation Method 20 shown below.

[0611] <Preparation Method 20>

[0612] [Chemical Figure 43]

[0613]

[0614] [wherein R 4 , X 2 , X 3 , X 4 , Hal 1 , alkyl 9 and ring A are as defined above.]

[0615] (Step 20-1)

[0616] In (Step 20-1), compound (20-1) can be prepared by subjecting compound (10-4) to a hydrolysis reaction in the same manner as in (Step 10-2) of Preparation Method 10.

[0617] (Step 20-2)

[0618] In (Step 20-2), compound (20-2) can be prepared by subjecting compound (20-1) and compound (2-4) to a condensation reaction in the same manner as in (Step 2-2) of Preparation Method 2.

[0619] Compound (21-4), which is one of the above-mentioned compounds (2-4), can be prepared, for example, by the method shown in Preparation Method 21.

[0620] <Preparation Method 21>

[0621] [Chemical Drawing 44]

[0622]

[0623] [where Ar 2 is an optionally substituted phenyl group or an optionally substituted 5- to 6-membered heteroaryl group. PG 2 is a protecting group for an amino group, and examples thereof include carbamate-based protecting groups such as Boc group, Cbz group, Fmoc group, etc.; and amide-based protecting groups such as trifluoroacetyl group, etc. R 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.]

[0624] (Step 21-1)

[0625] In (Step 21-1), compound (21-3) can be prepared by subjecting compound (21-1) and compound (21-2) to a condensation reaction in the same manner as in (Step 2-2) of Preparation Method 2.

[0626] (Step 21-2)

[0627] In (Step 21-2), compound (21-4) can be prepared by subjecting compound (21-3) to a deprotection reaction to remove the protecting group PG 2 The deprotection reaction can be carried out according to methods well-known to those skilled in the art (for example, the methods described in "Protective Groups in Organic Synthesis (5th Edition, 2014)" by Green and Wuts, etc.).

[0628] Compound (22-1), which is one of the above-mentioned compounds (I), can be prepared, for example, by the method shown in Preparation Method 22, and then the functional group can be transformed.

[0629] <Preparation Method 22>

[0630] [Chemical Figure 45]

[0631]

[0632] [wherein 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 are as defined above. Further, alkyl 10 is an optionally substituted C1-C6 alkyl group.]

[0633] (Step 22-1)

[0634] In (Step 22-1), compound (22-2) can be prepared by subjecting compound (22-1) to a hydrolysis reaction by the same method as in (Step 10-2) of Preparation Method 10.

[0635] (Step 22-2)

[0636] In (Step 22-2), compound (22-3) can be prepared by subjecting compound (22-2) and compound (21-2) to a condensation reaction by the same method as in (Step 2-2) of Preparation Method 2.

[0637] Compound (23-1), which is one of the above compounds (I), can be prepared, for example, by the method shown in Preparation Method 23, and then the functional groups can be transformed.

[0638] <Preparation Method 23>

[0639] [Chemical Figure 46]

[0640]

[0641] [wherein R 1 、R 2 、R 3 、R 4 、X 1 、X 2 、X 3 、X 4 、Y 1 、Y2 , Q 1 , Q 2 and Ar 2 are as defined above. Further, R 19 is an optionally substituted C1-C6 alkyl group, an optionally substituted phenyl group, or an optionally substituted 5- to 6-membered heteroaryl group.]

[0642] (Step 23-1)

[0643] In (Step 23-1), compound (23-3) can be prepared by subjecting compound (23-1) and compound (23-2) to a sulfonylation reaction in the presence of a base.

[0644] Examples of the base include the bases described in (Step 2-2) of Preparation Method 2.

[0645] Examples of the reaction solvent include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc.; nitriles such as acetonitrile, propionitrile, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; and mixed solvents thereof.

[0646] The reaction temperature is not particularly limited and is generally 0°C to 100°C. The reaction time is not particularly limited and is preferably 0.5 hour to 24 hours.

[0647] Compound (24-1), which is one of the above compounds (I), can be prepared, for example, by the method shown in Preparation Method 24, and then the functional group can be transformed.

[0648] <Preparation Method 24>

[0649] [Chemical Figure 47]

[0650]

[0651] [wherein 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 as defined above. Alkyl 11 is an optionally substituted C1-C6 alkyl group. Q 3 is absent or is an optionally substituted C 1 -C 3 alkyl group, or Q3 and R 2 together with the carbon atom to which they are attached may form an optionally substituted non-aromatic heterocyclic group. R 20 and R 21 are each independently a hydrogen atom or an optionally substituted C1-C6 alkyl group.]

[0652] (Step 24-1)

[0653] In (Step 24-1), the compound (24-2) can be prepared by subjecting the compound (24-1) to a hydrolysis reaction in the same manner as in (Step 10-2) of Preparation Method 10.

[0654] (Step 24-2)

[0655] In (Step 24-2), the compound (24-4) can be prepared by subjecting the compound (24-2) and the compound (24-3) to a condensation reaction in the same manner as in (Step 2-2) of Preparation Method 2.

[0656] The compound (25-1), which is one of the above compounds (I), can be prepared, for example, by the method shown in Preparation Method 25, and then the functional group can be transformed.

[0657] <Preparation Method 25>

[0658] [Chemical Figure 48]

[0659]

[0660] [wherein 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 as defined above. Hal 6 is a chloro group, a bromo group or an iodo group. ]R 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 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl group. Cyc 1 is an optionally substituted phenyl group or an optionally substituted cyclopropyl group. M4 is boric acid or a boric acid-related structure, such as B(OH)2, B(OMe)2, B(pin), B(MIDA), BF3K, etc.

[0661] (Step 25-1)

[0662] In (Step 25-1), compound (25-3) can be prepared by subjecting compound (25-1) and compound (25-2) to a Suzuki-Miyaura coupling reaction in the same manner as in (Step 1-C) of Preparation Method 1.

[0663] (Step 25-2)

[0664] In (Step 25-2), compound (25-4) can be prepared by subjecting compound (25-3) to a catalytic reduction reaction in the presence of a transition metal catalyst and in the presence of hydrogen.

[0665] The reaction can be carried out under the same conditions as those described in (Step 2-3A) of Preparation Method 2.

[0666] (Step 25-3)

[0667] In (Step 25-3), compound (25-6) can be prepared by subjecting compound (25-1) and compound (25-5) to a Sonogashira coupling reaction in the same manner as in (Step 12-1) of Preparation Method 12.

[0668] (Step 25-4)

[0669] In (Step 25-4), compound (25-7) can be prepared by subjecting compound (25-6) to a catalytic reduction reaction in the same manner as in (Step 25-2).

[0670] (Step 25-5)

[0671] In (Step 25-5), compound (25-8) can be prepared by subjecting compound (25-1) and trimethylsilylacetylene to a Sonogashira coupling reaction in the same manner as in (Step 12-1) of Preparation Method 12.

[0672] (Step 25-6)

[0673] In (Step 25-6), compound (25-9) can be prepared by subjecting compound (25-8) to a desilylation reaction. The desilylation reaction can be carried out according to methods well-known to those skilled in the art (for example, the methods described in "Protective Groups in Organic Synthesis (5th Edition, 2014)" by Green and Wuts, etc.).

[0674] (Step 25-7)

[0675] In (Step 25-7), compound (25-11) can be prepared by subjecting compound (25-1) and compound (25-10) to a Suzuki-Miyaura coupling reaction by the same method as in (Step 1-C) of Preparation Method 1.

[0676] Compound (26-1), which is one of the above-mentioned compounds (25-3), can be prepared, for example, by the method shown in Preparation Method 26, and then the functional group can be transformed.

[0677] <Preparation Method 26>

[0678] [Chemical Drawing 49]

[0679]

[0680] [wherein 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 as defined above. R 26 is an optionally substituted C1-C6 alkyl group.]

[0681] (Step 26-1)

[0682] In (Step 26-1), compound (26-2) can be prepared by subjecting compound (26-1) to a double bond cleavage reaction by the same method as in (Step 3-2) of Preparation Method 3.

[0683] (Step 26-2)

[0684] In (Step 26-2), compound (26-3) can be prepared by reducing the formyl group of compound (26-2) using a reducing agent.

[0685] Examples of the reducing agent include sodium borohydride, lithium borohydride, etc.

[0686] Examples of the reaction solvent include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, xylene, etc.; alcohols such as methanol, ethanol, 2-propanol, tert-butanol, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, etc.; and mixed solvents thereof.

[0687] The reaction temperature is not particularly limited and is usually from 0°C to 100°C. The reaction time is not particularly limited and is preferably from 0.5 hour to 24 hours.

[0688] (Step 26-3)

[0689] In (Step 26-3), Compound (26-4) can be prepared by converting the hydroxymethyl group of Compound (26-3) into a chloromethyl group by the same method as in (Step 18-1) of Preparation Method 18.

[0690] (Step 26-4)

[0691] In (Step 26-4), Compound (26-5) can be prepared by substituting the chloro group of Compound (26-4) with a cyano group using a cyanide.

[0692] Examples of the cyanide include sodium cyanide, potassium cyanide, etc.

[0693] Examples of the reaction solvent include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, xylene, etc.; ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, etc.; aprotic polar solvents such as DMF, DMAc, N-methylpyrrolidone, DMSO, etc.; and mixed solvents thereof.

[0694] The reaction temperature is not particularly limited and is usually from 0°C to 100°C. The reaction time is not particularly limited and is preferably from 0.5 hour to 24 hours.

[0695] (Step 26-5)

[0696] In (Step 26-5), Compound (26-7) can be prepared by substituting the chloro group of Compound (26-4) with an alkoxy group using Compound (26-6).

[0697] The reaction solvent is preferably an alcohol represented by the formula (R 26 -OH).

[0698] The reaction temperature is not particularly limited and is usually from 0°C to 100°C. The reaction time is not particularly limited and is preferably from 0.5 hour to 24 hours.

[0699] The compound (27-1), which is one of the above-mentioned compounds (I), can be prepared, for example, by the method shown in Preparation Method 27, and then the functional groups can be transformed.

[0700] <Preparation Method 27>

[0701] [Chemical Drawing 50]

[0702]

[0703] [wherein 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 as defined above. Hal 7 is a chlorine group, a bromine group or an iodine group.]

[0704] (Step 27-1)

[0705] In (Step 27-1), the compound (27-2) can be prepared by subjecting the compound (27-1) to a catalytic reduction reaction in the presence of a transition metal catalyst and in the presence of hydrogen.

[0706] The reaction can be carried out under the same conditions as those described in (Step 2-3A) of Preparation Method 2.

[0707] The compounds of the present invention prepared by the above methods can be free compounds, their salts, their hydrates or various solvates such as ethanolates, and the compounds of the present invention can be isolated and purified as oily substances, amorphous substances or substances composed of any crystalline polymorphs. The pharmaceutically acceptable salts of the compounds of the present invention can be prepared by conventional salt-forming reactions. The isolation and purification can be carried out by applying chemical operations such as extraction fractionation, crystallization and various types of preparative chromatography. In addition, by selecting suitable starting compounds or by optical resolution of racemic compounds, optical isomers can be obtained as stereochemically pure isomers.

[0708] The compounds (I) of the present invention and their pharmaceutically acceptable salts exhibit excellent STAT6 inhibitory activity. Therefore, drugs containing these compounds as active ingredients can be used as prophylactic or therapeutic agents for diseases associated with mammalian STAT6, including humans. Diseases associated with STAT6 include, for example, inflammatory diseases and allergic diseases. Inflammatory diseases and allergic diseases include, for example, chronic obstructive pulmonary disease, atopic dermatitis, bronchial asthma, bullous pemphigoid, nasal polyps, chronic rhinosinusitis, allergic rhinitis, eosinophilic esophagitis, prurigo, and urticaria.

[0709] Drugs containing the compound I of the present invention or its pharmaceutically acceptable salt as an active ingredient can be prepared by conventional methods known in the art, either by using the compound alone or in combination with pharmaceutically acceptable liquid or solid carriers (such as excipients, binders, diluents, extenders, disintegrants, stabilizers, preservatives, buffers, emulsifiers, fragrances, colorants, sweeteners, thickeners, flavoring agents, solubilizers, etc.).

[0710] The drugs according to the present invention can be in any form, including solid compositions, liquid compositions, and other compositions, and the optimal form is selected as needed.

[0711] The drugs of the present invention can be administered orally or parenterally to mammals (such as humans, monkeys, cows, horses, pigs, dogs, cats, rabbits, rodents, rats, mice, etc.) in the form of tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules, oral solutions, injections, suppositories, sustained-release preparations, lotions, liniments, ointments, patches, suspensions, emulsions, transdermal absorption preparations, topical solutions, creams, aerosols, etc. Additionally, other drugs can be added as needed.

[0712] The administration route of the drugs of the present invention is not limited. In the case of oral administration, dosage forms such as tablets, orally disintegrating tablets, capsules, granules, powders, oral liquids, syrups, oral gels, and oral sprays can be prepared. Each of these compounds can be prepared by conventional methods known in the art. The dosage of the drugs of the present invention is not limited. For example, in the case of oral administration to adult patients, the compounds of the present invention can be administered once or multiple times a day as an active ingredient at a dose of about 0.1 mg / kg to 100 mg / kg.

[0713] Examples

[0714] Hereinafter, the features of the present invention will be described in more detail with reference to the examples and test examples.

[0715] The materials, amounts used, ratios, treatment details, treatment procedures, etc. shown in the following examples can be appropriately changed without departing from the gist of the present invention. Therefore, the scope of the present invention should not be construed as being limited to the specific examples shown below.

[0716] The following examples were measured under the following conditions 1 1H-NMR spectra and mass spectra.

[0717] When describing 1 1H-NMR, deuterated chloroform (CDCl3), deuterated dimethyl sulfoxide (DMSO-d6), or deuterated methanol (CD3OD) was used as the solvent, and tetramethylsilane measured as an internal standard was measured using an AVANCEIII HD400 type (400 MHz, manufactured by Bruker BioSpin K.K.).

[0718] In 1 the measurement results of the chemical shifts of the 1H-NMR spectra, the δ values are expressed in ppm, and the J values of the coupling constants are expressed in Hz. The meanings of the abbreviations are: d: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, and br: broad peak.

[0719] LC / MS was measured using the ESI (electrospray ionization) method under the following conditions, where "[M+H] + " refers to the ESI positive ion mode, and "[M-H] - " refers to the ESI negative ion mode. In each chromatographic and experimental procedure, unless otherwise specified, "number / number" refers to the volume ratio of each solvent.

[0720] Apparatus: Mass spectrometer (Exactive) (manufactured by Thermo Fisher Scientific Inc.) (LC part: nanospace SI-2 / NASCA (manufactured by Shiseido Company, Limited.))

[0721] Column: None

[0722] Solvent:

[0723] Liquid A: Distilled water

[0724] Liquid B: Acetonitrile

[0725] The mixing ratio of Liquid A and Liquid B was fixed at 50 / 50.

[0726] Flow rate: 0.2 mL / min

[0727] Detector (wavelength): UV detector (254 nm)

[0728] The microwave reaction apparatus used was an Initiator sixty manufactured by Biotage Japan.

[0729] In addition, in the following drawings, the reference numbers refer to the reference synthetic example compounds, and the example numbers refer to the example compounds. Further, the example numbers refer to the preparation of the example compounds having the same numbers.

[0731] Example 1

[0732] [Chemical Drawing 51]

[0733]

[0734] Step 1

[0735] Under ice cooling, the reference synthetic example compound 1 (5.00 g, 18.5 mmol) and THF (90 mL) were mixed, potassium carbonate (4.10 g, 29.7 mmol) and an ethylamine / THF solution (2.0 mol / L, 12 mL) were added, the temperature was raised to 50 °C, and the mixture was stirred for 4 hours. Water and a mixed solution of ethyl acetate / n-hexane (3 / 1) were added to the cooled reaction solution and stirred, and the aqueous layer was separated. 2 mol / L hydrochloric acid (40 mL) was added to the separated aqueous layer, and then extraction was carried out using ethyl acetate. The extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the reference synthetic example compound 2 (yield 4.22 g).

[0736] Step 2

[0737] The reference synthetic example compound 2 (4.22 g, 15.2 mmol) and acetonitrile (80 mL) were mixed, 3-amino-2-fluorobenzamide (2.69 g, 17.5 mmol) and 1-methylimidazole (2.87 mL, 36.4 mmol) were added, ice-cold TCFH (5.11 g, 18.2 mmol) was added, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, and the precipitate was collected by filtration. The obtained solid was purified by silica gel column chromatography to obtain the reference synthetic example compound 3 (yield 5.56 g).

[0738] Step 3

[0739] The reference synthetic 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 at room temperature for 1 hour under a hydrogen atmosphere. By Filter the reaction solution and distill off the solvent under reduced pressure. Add a chloroform / methanol mixed solution to the residue and collect the precipitated solid (A) by filtration. Concentrate the filtrate under reduced pressure and purify the residue by silica gel column chromatography (B). Combine the solid A collected by filtration and the fraction B purified by column chromatography to obtain Reference Synthesis Example Compound 4 (yield 910 mg).

[0740] Step 4

[0741] Mix Reference Synthesis Example Compound 5 (5.00 g, 20.8 mmol) and DMF (104 mL), add sodium hydride (60% in oil) (1.25 g, 31.3 mmol), and stir the mixture for 10 minutes. Add methyl iodide (2.6 mL, 42 mmol) to the reaction solution and stir the mixture at room temperature for 23 hours. Add saturated aqueous ammonium chloride solution and water to the reaction solution, collect the precipitate by filtration to obtain Reference Synthesis Example Compound 6 (yield 4.98 g).

[0742] Step 5

[0743] Mix 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), degas the mixture, add bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II) dichloride (695 mg, 0.981 mmol), and stir the mixture at 90 °C for 4 hours under an argon atmosphere. Cool the solution and then filter it. Add water to the filtrate, extract the mixture with ethyl acetate, and wash it with saturated brine. Dry the filtrate over anhydrous sodium sulfate and distill off the solvent under reduced pressure. Purify the residue by silica gel column chromatography to obtain Reference Synthesis Example Compound 7 (yield 2.04 g).

[0744] Step 6

[0745] ​Compound 7 of the reference synthesis example (2.04 g, 10.1 mmol) and 1,4-dioxane (101 mL) were mixed under ice cooling, and then water (34 mL), 2,6-dimethylpyridine (2.35 mL, 20.2 mmol), sodium periodate (8.66 g, 40.5 mmol), and osmium tetroxide / tert-butyl alcohol solution (2.5 w / v%) (5.15 mL, 0.51 mmol) were added in sequence, followed by stirring at room temperature for 2 hours. The reaction solution was cooled on ice, saturated aqueous sodium thiosulfate solution and water were added in sequence, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain Compound 8 of the reference synthesis example (yield 1.88 g).

[0746] Step 7

[0747] Compound 4 of the reference synthesis example (100 mg, 0.260 mmol) and ethanol (5 mL) were mixed, and then Compound 8 of the reference synthesis example (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. Saturated aqueous sodium bicarbonate solution was added to the cooled reaction solution, and the precipitate was collected by filtration. The obtained solid was purified by silica gel column chromatography to obtain Example Compound 1 (yield 106 mg).

[0749] Example 2

[0750] [Chemical Figure 52]

[0751]

[0752] Step 1-A

[0753] Compound 9 of the reference synthesis example (1.00 g, 6.20 mmol) and TFA (5.2 mL) were mixed, and then hexamethylenetetramine (957 mg, 6.83 mmol) was added, followed by stirring at 90 °C for 24 hours. The cooled reaction solution was 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 then the residue was purified by silica gel column chromatography to obtain Compound 10 of the reference synthesis example (yield 826 mg).

[0754] Step 1-B

[0755] Reference synthetic example compound 2 (500 mg, 1.80 mmol) and methanol (20 mL) were mixed, 20% palladium hydroxide / carbon (50 mg, 0.071 mmol) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere (0.3 MPa). The reaction solution was filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain reference synthetic example compound 11 (yield 410 mg).

[0756] Step 2

[0757] Reference synthetic example compound 11 (100 mg, 0.403 mmol) and ethanol (4 mL) were mixed, then reference synthetic example compound 10 (114 mg, 0.603 mmol) and acetic acid (231 μL, 4.03 mmol) were added, and the mixture was then stirred at 70 °C for 2 hours under an oxygen atmosphere. The reaction solution was cooled, the precipitated solid was collected by filtration and washed with methanol to obtain reference synthetic example compound 12 (yield 86.7 mg).

[0758] Step 3

[0759] Reference synthetic example compound 12 (15 mg, 0.0359 mmol) and acetonitrile (500 μL) were mixed, 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, and the mixture was then stirred 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 obtained solid was purified by silica gel column chromatography to obtain example compound 2 (yield 5.7 mg).

[0760] Examples 3 to 10

[0761] Example compounds 3 to 10 were prepared according to the methods shown in Example 1 and Example 2 above or Example 11 to Example 14 below or similar methods.

[0763] Example 11

[0764] [Chemical Drawing 53]

[0765]

[0766] Step 1

[0767] To a solution 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) in 1,4-dioxane (8 mL) and N,N'-dimethylethylenediamine (10 μL, 0.093 mmol) was added, and the mixture was stirred at 120 °C for 14 hours under an argon atmosphere. The reaction solution was cooled, water and ethyl acetate were added and stirred, and then 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 while separating diastereomers to obtain Reference Synthesis Example Compound 14 (diastereomer of the first peak) (yield 101 mg) and Reference Synthesis Example Compound 15 (diastereomer of the second peak) (yield 80.2 mg).

[0768] Step 2

[0769] Reference Synthesis Example Compound 2 (1.50 g, 5.39 mmol) and acetonitrile (25 mL) were mixed, then 3-aminobenzamide (881 mg, 6.47 mmol), 1-methylimidazole (1.02 mL, 12.9 mmol), and TCFH (1.82 g, 6.49 mmol) were added, and the mixture was then stirred at room temperature for 5 hours. Water was added to the reaction solution, and the precipitated solid was collected by filtration to obtain Reference Synthesis Example Compound 16 (yield 1.76 g).

[0770] Step 3

[0771] Reference Synthesis Example Compound 16 (156 mg, 0.394 mmol) and methanol (3.9 mL) were mixed, 20% palladium hydroxide on carbon (15.6 mg) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain Reference Synthesis Example Compound 17 (yield 133 mg).

[0772] Step 4

[0773] To a solution of Reference Synthesis Example Compound 17 (15 mg, 0.041 mmol) in ethanol (1 mL) was added Reference Synthesis Example Compound 15 (10 mg, 0.046 mmol) and acetic acid (23 μL), and the solution was stirred at 80 °C for 17 hours under an oxygen atmosphere. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the precipitate was collected by filtration. The obtained solid was purified by silica gel column chromatography to obtain Example Compound 11 (yield 16.8 mg).

[0775] Examples 12 and 13

[0776] [Chemical Figure 54]

[0777]

[0778] Step 1

[0779] A preparative chiral column (CHIRALPAK IC, manufactured by Daicel Corporation) was connected to a preparative LC system (LC-Forte / R, manufactured by YMC Co., Ltd.), and a mixed solution of ethanol / n-hexane (1 / 1) was passed through the column at room temperature and a flow rate of 8.0 mL / min for equilibration. Example Compound 11 (12.0 mg, 0.0213 mmol) was dissolved in ethanol (7 mL) to obtain Solution A. Solution A (3.5 mL) was injected, and the first peak (retention time: about 18 minutes) and the second peak (retention time: about 19 minutes) were collected while observing with a UV detector (detection wavelength: 254 nm) (this operation was performed twice). The solvent contained in each fraction was removed by distillation under reduced pressure. Example Compound 12 (yield 5.8 mg) was obtained from the fraction derived from the first peak, and Example Compound 13 (yield 5.1 mg) was obtained from the fraction derived from the second peak.

[0781] Example 14

[0782] [Chemical Figure 55]

[0783]

[0784] Step 1

[0785] Reference Synthetic Example Compound 18 (3.00 g, 10.8 mmol) and THF (54 mL) were mixed, then potassium carbonate (2.39 g, 17.3 mmol) and 2-methoxyethylamine (1.2 mL, 14 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and then extraction was performed using chloroform. The extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain Reference Synthetic Example Compound 19 in a partially impure state (yield 3.65 g).

[0786] Step 2

[0787] The reference synthetic example compound 19 (3.65 g) containing impurities obtained by the method described in Step 1 was mixed with methanol (110 mL), and then 4 mol / L aqueous sodium hydroxide solution (21 mL) was added, followed by stirring at room temperature for 2 hours. The reaction solution was cooled in ice, 6 mol / L hydrochloric acid was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the reference synthetic example compound 20 in a partially impure state (yield 3.47 g).

[0788] Step 3

[0789] The reference synthetic 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, followed by stirring 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 obtain the reference synthetic example compound 21 (yield 4.53 g).

[0790] Step 4

[0791] The reference synthetic 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, followed by stirring at 50 °C for 20 hours. The reaction solution was cooled and then filtered by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the reference synthetic example compound 22 (yield 1.68 g).

[0792] Step 5

[0793] The reference synthetic 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 acetate (1.6 mL, 28 mmol) were added, and the mixture was stirred in an oxygen atmosphere at 70 °C for 3 hours. Water and saturated aqueous sodium bicarbonate solution were added to the reaction solution, and the mixture was extracted with chloroform. The extracted solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain Example Compound 14 (yield 1.13 g).

[0794] Prepare Example Compounds 1 to 14 in the table according to the methods shown in the above-mentioned Example 1, Example 2, and Examples 11 to 14 or similar methods. In addition, the 1 1H-NMR data and / or LC / MS data of these example compounds are shown in the table.

[0796] [Table 1-1]

[0797]

[0798]

[0799] [Table 1-2]

[0800]

[0801]

[0802] [Table 1-3]

[0803]

[0805] Example 15

[0806] [Chemical Figure 56]

[0807]

[0808] Step 1

[0809] Mix Reference Synthetic Example Compound 23 (4.02 g, 15.8 mmol) and DMF (70 mL), add sodium hydride (60% in oil) (949 mg, 23.7 mmol) under ice cooling, and stir the mixture for 30 minutes. Add methyl iodide (2.95 mL, 47.4 mmol) and stir at room temperature for 18 hours. Add saturated aqueous ammonium chloride solution to the reaction solution under ice cooling, and then extract with ethyl acetate. Wash the extract with saturated brine and dry over anhydrous sodium sulfate. Distill the solvent under reduced pressure, and purify the residue by silica gel column chromatography to obtain Reference Synthetic Example Compound 24 (yield 3.83 g).

[0810] Step 2

[0811] Reference synthetic example compound 24 (250 mg, 0.932 mmol) was mixed with 1,4-dioxane (5 mL), 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 and the mixture was stirred at 100 °C for 3 hours. The reaction solution was cooled and filtered through filter paper. Water and ethyl acetate were added, 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 obtain reference synthetic example compound 25 (yield 90 mg).

[0812] Step 3

[0813] Reference synthetic example compound 26 (75 mg, 0.21 mmol), reference synthetic example compound 25 (85 mg, 0.27 mmol) and 1,4-dioxane (3 mL) were mixed, then water (600 μL), cesium carbonate (134 mg, 0.411 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.3 mg, 0.010 mmol) were added, and the mixture was subsequently stirred at 100 °C for 3 hours. The mixture was cooled, diluted with water and 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 obtain reference synthetic example compound 27 (yield 59.8 mg).

[0814] Step 4

[0815] Reference synthetic example compound 27 (58 mg, 0.12 mmol) was mixed with THF (2 mL), methanol (3 mL) and 4 mol / L aqueous sodium hydroxide solution (3 mL, 12 mmol) were added, and the mixture was stirred at 60 °C for 4 hours. The reaction solution was cooled, and 2 mol / L hydrochloric acid (2.2 mL) was added to the mixture, which was subsequently 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 obtain reference synthetic example compound 28 (yield 55 mg).

[0816] Step 5

[0817] The reference synthetic example compound 28 (12 mg, 0.027 mmol) and acetonitrile (300 μL) were mixed, 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, and then the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with water, and the precipitate was collected by filtration. The obtained solid was purified by silica gel column chromatography to obtain Example compound 15 (yield 3.2 mg).

[0819] Example 16

[0820] [Chemical Figure 57]

[0821]

[0822] Step 1

[0823] The reference synthetic example compound 29 (5.14 g, 23.5 mmol) and TFA (40 mL) were mixed, then NIS (5.80 g, 25.8 mmol) was added, and then the mixture was stirred at room temperature for 5 hours. After the reaction solution was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution and ethyl acetate were added and stirred, and then 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 obtain the reference synthetic example compound 30 (yield 7.64 g).

[0824] Step 2

[0825] The reference synthetic example compound 30 (5.49 g, 15.9 mmol) and TEA (59 mL) were mixed, then dichlorobis(triphenylphosphine)palladium(II) (558 mg, 0.795 mmol), copper(I) iodide (152 mg, 0.798 mmol) and trimethylsilylacetylene (2.81 mL, 19.9 mmol) were added, and the mixture was stirred at room temperature for 3 hours under an argon atmosphere. Chloroform and water were added to the reaction solution 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 obtain the reference synthetic example compound 31 (yield 4.82 g).

[0826] Step 3

[0827] 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. Then the mixture was stirred for 1 hour under ice cooling and then for 4 hours at room temperature. The reaction solution was added dropwise to ice-cold saturated aqueous ammonium chloride solution, and then extracted with ethyl acetate. n-Hexane was added to the extract, and the mixture was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain Reference Synthesis Example Compound 32 (yield 981 mg).

[0828] Step 4

[0829] Reference Synthesis Example Compound 32 (410 mg, 1.69 mmol) and DMF (10 mL) were mixed, sodium hydride (60% in oil) (88 mg, 2.20 mmol) was added under ice cooling, and the mixture was 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 solution was added dropwise to ice-cold saturated aqueous ammonium chloride solution, diluted with water, and extracted with ethyl acetate. n-Hexane was added to the extract, and the mixture was washed successively with water and saturated brine. The filtrate 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 obtain Reference Synthesis Example Compound 33 (yield 407 mg).

[0830] Step 5

[0831] Reference Synthesis Example Compound 33 (554 mg, 1.84 mmol) and THF (8 mL) were mixed and cooled to -78 °C, n-hexane / THF (ca. 1 / 7) containing 1.0 mol / L LDA (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 solution was added dropwise to ice-cold 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 obtain Reference Synthesis Example Compound 34 (yield 304 mg).

[0832] Step 6

[0833] Compound 34 of the reference synthesis example (120 mg, 0.316 mmol), compound 25 of the reference synthesis example (98 mg, 0.31 mmol) and 1,4-dioxane (4 mL) were mixed, then water (800 μL), cesium carbonate (206 mg, 0.632 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (11.2 mg, 0.0158 mmol) were added, and then the mixture was stirred at 100 °C for 18 hours. The mixture was cooled, diluted with water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain compound 35 of the reference synthesis example (yield 60.3 mg).

[0834] Step 7

[0835] Compound 35 of the reference synthesis example (60.3 mg, 0.123 mmol) and methanol (1.5 mL) were mixed, then 4 mol / L aqueous sodium hydroxide solution (3 mL, 12 mmol) was added, and then the mixture was stirred at 60 °C for 4 hours. After cooling, 2 mol / L hydrochloric acid was added, and the mixture was extracted with ethyl acetate / methanol (10 / 1). The extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain compound 36 of the reference synthesis example (yield 41.0 mg).

[0836] Step 8

[0837] Compound 36 of the reference synthesis example (10 mg, 0.021 mmol) and acetonitrile (500 μL) were mixed, 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 in sequence, and then the mixture was stirred at room temperature for 15 hours. The mixture was diluted with 2 mol / L HCl and extracted with EtOAc. 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 obtain Example Compound 16 (yield 8.9 mg).

[0839] Example 17

[0840] [Chemical Diagram 58]

[0841]

[0842] Step 1

[0843] Compound 37 (5.4 g, 31 mmol) of the reference synthesis example and THF (100 mL) were mixed, and sodium hydride (60% in oil) (1.59 g, 39.8 mmol) and di-tert-butyl dicarbonate (9.1 mL, 40 mmol) were sequentially added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and then extraction was performed with ethyl acetate. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain Compound 38 of the reference synthesis example (yield 7.11 g).

[0844] Step 2

[0845] 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, the temperature was raised to 0 °C, and the mixture was stirred for 15 minutes. The reaction solution was cooled to -78 °C, and Compound 38 of the reference synthesis example (7.11 g, 25.8 mmol) was added, followed by stirring 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 solution was added dropwise to an ice-cold saturated aqueous ammonium chloride solution, water was added, 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 obtain Compound 39 of the reference synthesis example (yield 7.7 g).

[0846] Step 3

[0847] Compound 39 (7.7 g, 22 mmol) of the reference synthesis example and dichloromethane (25 mL) were mixed, then 4 mol / L hydrochloric acid-ethyl acetate (72 mL, 288 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain Compound 40 of the reference synthesis example (yield 2.6 g).

[0848] Step 4

[0849] Reference synthetic example compound 40 (1.1 g, 4.3 mmol) and DMF (8.8 mL) were mixed, and sodium hydride (60% in oil) (0.35 g, 8.8 mmol) was added under ice cooling, followed by stirring for 10 minutes. Ethyl iodide (0.7 mL, 9 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 12 hours. The reaction solution was added dropwise to ice-cold saturated aqueous ammonium chloride solution, diluted with water, and extracted with ethyl acetate. n-Hexane was added to the extract, and the mixture was washed successively with water and saturated brine. The filtrate 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 obtain reference synthetic example compound 41 (yield 1.0 g).

[0850] Step 5

[0851] Reference synthetic example compound 41 (180 mg, 0.38 mmol), reference synthetic example compound 25 (300 mg, 0.952 mmol) and 1,4-dioxane (6.4 mL) were mixed, then cesium carbonate (416 mg, 1.28 mmol) and APhos-Pd-G3 (20 mg, 0.031 mmol) were added, and 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 obtain reference synthetic example compound 42 (yield 198 mg).

[0852] Step 6

[0853] Reference synthetic example compound 42 (198 mg, 0.507 mmol), THF (0.9 mL) and methanol (3.2 mL) were mixed, then 4 mol / L aqueous sodium hydroxide solution (2.5 mL, 10 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. After neutralizing the reaction solution, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain reference synthetic example compound 43 (yield 139 mg).

[0854] Step 7

[0855] Compound 43 of the reference synthesis example (68 mg, 0.18 mmol), 5-amino-2-fluorobenzamide (42 mg, 0.27 mmol) and acetonitrile (2 mL) were mixed, 1-methylimidazole (0.043 mL, 0.54 mmol) and TCFH (81 mg, 0.29 mmol) were added, and the mixture was stirred at room temperature for 4 hours. Water was added, then the mixture was stirred and 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 obtain Compound 17 of the example (yield 71.6 mg).

[0857] Example 18

[0858] [Chemical Figure 59]

[0859]

[0860] Step 1

[0861] Compound 44 of the reference synthesis example (10 g, 39 mmol) and DMF (196 mL) were mixed, sodium hydride (60% in oil) (2.4 g, 60 mmol) and methyl iodide (7.4 mL, 120 mmol) were added sequentially under ice-cooling, and then the mixture was stirred at room temperature for 3 hours. The reaction solution was ice-cooled, saturated aqueous ammonium chloride solution and water were added, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, then MTBE was added to the residue for slurry washing, and the solid was collected by filtration to obtain Compound 45 of the reference synthesis example (yield 7.78 g).

[0862] Step 2

[0863] Compound 45 of the reference synthesis example (4.47 g, 16.7 mmol), THF (0.080 L) and triethylamine (7.0 mL, 50 mmol) were mixed, and then 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 for 1.5 hours under an argon atmosphere. After cooling, the solvent was distilled off under reduced pressure. Chloroform and water were added to the residue, the mixture was stirred, and then by Filter and separate the organic layer of the filtrate. Dry the filtrate over anhydrous sodium sulfate and distill off the solvent under reduced pressure. Purify the residue by silica gel column chromatography to obtain Reference Synthetic Example Compound 46 (yield: 4.76 g).

[0864] Step 3

[0865] Mix Reference Synthetic Example Compound 46 (4.76 g, 16.7 mmol) and THF (0.067 L), then add 1 mol / L TBAF / THF solution (0.028 L, 28 mmol), and subsequently stir at room temperature for 30 minutes. Distill off the solvent under reduced pressure, then purify the residue by silica gel column chromatography to obtain Reference Synthetic Example Compound 47 (yield: 2.83 g).

[0866] Step 4

[0867] Mix Reference Synthetic Example Compound 48 (2.00 g, 11.8 mmol) and acetic acid (40 mL), add NIS (2.9 g, 13 mmol), and then stir the mixture at room temperature for 2 hours. Concentrate the reaction solution under reduced pressure, add saturated aqueous sodium bicarbonate solution and chloroform and stir, and separate the organic layer. Dry the organic layer over anhydrous sodium sulfate and distill off the solvent under reduced pressure. Purify the residue by silica gel column chromatography to obtain Reference Synthetic Example Compound 49 (yield: 3.4 g).

[0868] Step 5

[0869] Mix Reference Synthetic Example Compound 49 (1.0 g, 3.4 mmol) and acetonitrile (10 mL), add 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 Synthetic Example Compound 47 (882 mg, 4.14 mmol), purge the reactor with argon and seal it, then stir the reaction mixture under microwave irradiation at 140 °C for 1 hour. After cooling, add water to the reaction solution and extract the mixture with chloroform. Dry the organic layer over anhydrous sodium sulfate and distill off the solvent under reduced pressure. Purify the residue by silica gel column chromatography to obtain Reference Synthetic Example Compound 50 (yield: 284 mg).

[0870] Step 6

[0871] Reference synthetic example compound 50 (284 mg, 0.746 mmol) and acetonitrile (6 mL) were mixed, then degassed, the reactor was purged with argon, bis(acetonitrile)palladium(II) dichloride (212 mg, 0.817 mmol) was added, and the mixture was stirred at 100 °C for 2 hours. After cooling it, by the mixture was filtered. Ethyl acetate, water, and a small amount of 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 then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain reference synthetic example compound 51 (yield 144 mg).

[0872] Step 7

[0873] Reference synthetic example compound 51 (144 mg, 0.378 mmol) and DMF (1 mL) were mixed, and sodium hydride (60% in oil) (30 mg, 0.75 mmol) was added under ice-cooling, followed by stirring 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 solution was added dropwise to ice-cold saturated aqueous ammonium chloride solution, then water and ethyl acetate were added, the mixture was stirred, and the organic layer was separated. n-Hexane was added to the organic layer, and the mixture was washed successively with water and saturated brine. The filtrate 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 obtain reference synthetic example compound 52 (yield 70.7 mg).

[0874] Step 8

[0875] Reference synthetic example compound 52 (70 mg, 0.17 mmol), methanol (1.6 mL), and THF (0.3 mL) were mixed, 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. The reaction solution was concentrated under reduced pressure to obtain reference synthetic example compound 53 as a mixture with sodium chloride (yield 0.27 g).

[0876] Step 9

[0877] To the sodium chloride mixture (0.13 g) of Reference Synthetic 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 sequentially added, and then the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, and then extraction was performed using 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 obtain Example Compound 18 (yield 12.2 mg).

[0879] Example 19

[0880] [Chemical Figure 60]

[0881]

[0882] Step 1

[0883] Reference Synthetic Example Compound 54 (10.0 g, 57.8 mmol) and THF (289 mL) were mixed, cooled with ice, then phenyl 4-nitrophenyl carbonate (11.7 g, 58.0 mmol) and pyridine (7.0 mL, 87 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, then 1,4-dioxane (289 mL) and hydrazine hydrate (8.4 mL, 170 mmol) were added to the residue to form a suspension, which was stirred at 70 °C for 2 hours. The reaction solution was cooled, water was added and stirred, and then the precipitate was collected by filtration to obtain Reference Synthetic Example Compound 55 (yield 11.7 g).

[0884] Step 2

[0885] Reference Synthetic Example Compound 55 (9.00 g, 39.0 mmol) and ethanol (97 mL) were mixed, then triethyl orthoacetate (8.6 mL, 47 mmol) and p-toluenesulfonic acid monohydrate (741 mg, 3.90 mmol) were added, and then the mixture was stirred under reflux for 16 hours. The reaction solution was cooled, water was added, and the mixture was stirred. The precipitate was collected by filtration to obtain Reference Synthetic Example Compound 56 (yield 3.48 g).

[0886] Step 3

[0887] Reference synthesis example compound 56 (3.00g, 11.8mmol) and DMF (30mL) are mixed, and then potassium tert-butoxide (1.98g, 17.7mmol) and methyl iodide (2.2mL, 35mmol) are sequentially added under ice cooling, and then the mixture is stirred at room temperature for 4 hours. Water is added to the reaction solution under ice cooling, and the mixture is stirred and extracted with ethyl acetate. The extract is washed with water and saturated brine in sequence, and then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is then purified by silica gel column chromatography to obtain reference synthesis example compound 57 (output 1.85g).

[0888] Step 4

[0889] Reference synthesis example compound 58 (10.0g, 41.1mmol) and DMF (164mL) are mixed, sodium hydride (60% in oil) (2.14g, 53.5mmol) is added under ice cooling, and the mixture is stirred for 20 minutes. Ethyl iodide (4.9mL, 61mmol) is added and stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution is added to the reaction solution under ice cooling and stirred, and then extracted with ethyl acetate. The extract is washed with water and saturated brine in sequence, and then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is then purified by silica gel column chromatography to obtain reference synthesis example compound 59 (yield 7.34g).

[0890] Step 5

[0891] Reference synthesis example compound 59 (3.27g, 12.1mmol), THF (13mL) and isopropyl borate (3.1mL, 13mmol) are mixed, and n-hexane / THF (8.6mL, 9.4mmol) containing 1.09mol / L LDA is added under ice cooling, and the mixture is subsequently stirred for 30 minutes. Add the aqueous solution (13mL) of tripotassium phosphate (2.13g, 10.0mmol), reference synthesis example compound 57 (1.80g, 6.69mmol) and THF (13mL) solution of chloro (crotyl) (tri-tert-butyl phosphine) palladium (II) (267mg, 0.669mmol), and the mixture is stirred at 50 DEG C for 2 hours. The reaction solution is cooled, water is added, and the mixture is stirred, and then extracted with ethyl acetate. The extract is washed with water and saturated brine in sequence, then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel column chromatography to obtain Reference Synthesis Example Compound 60 (yield 2.58 g).

[0892] Step 6

[0893] Compound 60 of the reference synthesis example (500 mg, 1.09 mmol), THF (2.7 mL), and methanol (2.7 mL) were mixed, and then an aqueous sodium hydroxide solution (2.7 mL, 10.8 mmol) at 4 mol / L was added, followed by stirring at 50 °C for 2 hours. 1 mol / L hydrochloric acid was added to the reaction solution under ice cooling, and the precipitate was collected by filtration to obtain Compound 61 of the reference synthesis example (yield 300 mg).

[0894] Step 7

[0895] Compound 61 of the reference synthesis example (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, followed by stirring at room temperature for 16 hours. Water was added to the reaction solution and stirred, and then the precipitate was collected by filtration to obtain Example Compound 19 (yield 58.9 mg).

[0897] Example 20

[0898] [Chemical Diagram 61]

[0899]

[0900] Step 1

[0901] Compound 62 of the reference synthesis example (4.00 g, 23.1 mmol) and THF (116 mL) were mixed, and phenyl 4-nitrophenyl carbonate (4.66 g, 23.1 mmol) and pyridine (2.8 mL, 35 mmol) were added under ice cooling, and then the mixture was stirred at room temperature for 17 hours. The solvent was distilled off under reduced pressure, and then the residue was dissolved in 1,4-dioxane (116 mL), hydrazine hydrate (3.37 mL, 69.3 mmol) was added, and the mixture was stirred at 70 °C for 5 hours. The cooled reaction solution was poured into ice-cold water (500 mL) and stirred for 30 minutes. The precipitate was filtered, washed with water, and dried under reduced pressure to obtain Compound 63 of the reference synthesis example (yield 4.43 g).

[0902] Step 2

[0903] Reference synthesis example compound 63 (4.43g, 19.2mmol) and ethanol (48mL) were mixed, then triethyl orthoacetate (5.7mL, 39mmol) and p-toluenesulfonic acid monohydrate (365mg, 1.92mmol) were added, and the mixture was stirred for 6 hours at 80°C. The reaction solution was poured into ice-cold water (500mL) and stirred for 30 minutes. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to obtain reference synthesis example compound 64 (output 4.61g).

[0904] Step 3

[0905] Reference synthesis example compound 64 (4.61g, 18.1mmol) and DMF (60mL) are mixed, then tripotassium phosphate (5.75g, 27.1mmol) is added under ice cooling, and the mixture is stirred for 10 minutes.Iodomethane (1.69mL, 27.1mmol) is added, then stirred at room temperature for 4 hours.Reaction solution is poured in ice-cold water (500mL) and stirred for 30 minutes.Precipitation is collected by filtration and washed with water, obtain reference synthesis example compound 65 (output 3.33g).

[0906] Step 4

[0907] 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, and then n-hexane / THF (2.86 mL, 3.12 mmol) containing 1.09 mol / L LDA was added under ice cooling and stirred for 30 minutes. Water (4.5 mL) containing tripotassium phosphate (710 mg, 3.34 mmol), Reference Synthesis Example Compound 65 (600 mg, 2.23 mmol) and THF (11 mL) containing chloro(crotyl)(tri-tert-butylphosphine)palladium (II) (80.9 mg, 0.203 mmol) were added in sequence and stirred at 40° C. for 2.5 hours. The reaction solution was cooled, diluted with water and extracted with ethyl acetate. The extract was washed with water and saturated brine in sequence, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel column chromatography to obtain Reference Synthesis Example Compound 66 (yield 664 mg).

[0908] Step 5

[0909] Reference synthetic 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, followed by stirring at room temperature for 5 hours. The reaction solution was acidified with 6 mol / L hydrochloric acid under ice cooling and extracted with a mixture of chloroform / methanol (4 / 1). The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain reference synthetic example compound 67 (yield 1.06 g) as a solvent mixture.

[0910] Step 6

[0911] The solvent mixture (1.06 g) of reference synthetic example compound 67 obtained by the method described in Step 5 and acetonitrile (21 mL) were mixed, 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 in sequence, followed by stirring at room temperature overnight. The reaction solution was diluted with water and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, then 2-propanol (30 mL) was added to the residue for slurry washing, and then the solid was collected by filtration and dried under reduced pressure to obtain Example compound 20 (yield 1.24 g).

[0913] Example 21

[0914] [Chemical Figure 62]

[0915]

[0916] Step 1

[0917] Reference synthetic example compound 68 (694 mg, 3.66 mmol) and DMSO (10 mL) were mixed, and then DIPEA (1.89 mL, 11.0 mmol) and 2.0 mol / L ethylamine / THF (2.2 mL, 4.4 mmol) were added, followed by stirring at 50 °C for 3 hours and then at room temperature for 16 hours. Water and ethyl acetate were added to the reaction solution, stirred, and then the organic layer was separated. The separated organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain reference synthetic example compound 69 (yield 694 mg).

[0918] Step 2

[0919] Reference Synthetic Example Compound 69 (300 mg, 1.40 mmol) and acetonitrile (5 mL) were mixed, and then 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 Synthetic Example Compound 47 (447 mg, 2.10 mmol) were added. The reactor was purged with argon and sealed, and then the reaction mixture was stirred at 140 °C for 1.5 hours under microwave irradiation. After cooling, water was added to the reaction solution, 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 obtain Reference Synthetic Example Compound 70 (yield 244 mg).

[0920] Step 3

[0921] Reference Synthetic Example Compound 70 (5.81 g, 14.8 mmol) and methanol (0.037 L) were mixed and degassed, and the reactor was purged with argon. Then, chloro(triphenylphosphine)gold(I) (1.47 g, 2.97 mmol) and silver bis(trifluoromethanesulfonyl)imide (1.15 g, 2.96 mmol) were 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 obtain Reference Synthetic Example Compound 71 (yield 5.38 g).

[0922] Step 4

[0923] Reference Synthetic 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 the mixture was stirred at room temperature for 18 hours. 2 mol / L hydrochloric acid (0.5 mL) was added to the reaction solution, and the solvent was distilled off under reduced pressure to obtain Reference Synthetic Example Compound 72 as a sodium chloride mixture (yield 62.3 mg).

[0924] Step 5

[0925] The sodium chloride mixture (30 mg) of reference synthetic example compound 72 obtained by the method described in Step 4 was mixed with acetonitrile (1 mL), 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, followed by stirring at 40 °C for 15 hours. 1 mol / L HCl and EtOAc were added to the reaction solution and stirred, and then 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, then slurried with a mixed solution of n-hexane / ethyl acetate (3 / 1), and then the solid was collected by filtration and dried under reduced pressure to obtain Example Compound 21 (yield 9.2 mg).

[0927] Example 22

[0928] [Chemical Figure 63]

[0929]

[0930] Step 1

[0931] The sodium chloride mixture (30 mg) of reference synthetic example compound 72 obtained by the method described in Step 4 of Example 21 was mixed with acetonitrile (1 mL), 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, followed by stirring at 40 °C for 15 hours. 1 mol / L HCl and EtOAc were added to the reaction solution and stirred, and then 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 obtain Example Compound 22 (yield 9.3 mg).

[0933] Example 23

[0934] [Chemical Figure 64]

[0935]

[0936] Step 1

[0937] Reference synthetic example compound 73 (509 mg, 2.28 mmol) was mixed with THF (8 mL), and potassium carbonate (619 mg, 4.48 mmol) and 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 solution and stirred, and the organic layer was separated. The separated organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain reference synthetic example compound 74 containing impurities in part (yield 610 mg).

[0938] Step 2

[0939] The reference synthetic example compound 74 containing impurities (300 mg) obtained by the method described in Step 1 was mixed with acetonitrile (10 mL), 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 solution and saturated brine were sequentially added to the cooled reaction solution and stirred, and then 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 obtain reference synthetic example compound 75 (yield 118 mg). In this step, unexpected deethylation of the amino group also occurred simultaneously.

[0940] Step 3

[0941] Reference synthetic example compound 75 (116 mg, 0.388 mmol) was mixed with THF (5 mL), then reference synthetic 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] palladium(II) dichloride (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 solution 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 obtain reference synthetic example compound 76 (yield 104 mg).

[0942] Step 4

[0943] Reference Synthetic Example Compound 76 (103 mg, 0.238 mmol) and ethanol (1.5 mL) were mixed, degassed, the reactor was purged 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 added, and the mixture was stirred at 100 °C for 3 hours. The reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain Reference Synthetic Example Compound 77 (yield 98 mg).

[0944] Step 5

[0945] Reference Synthetic Example Compound 77 (50 mg, 0.12 mmol) and DMF (1 mL) were mixed, sodium hydride (60% in oil) (7.0 mg, 0.18 mmol) was added under ice-cooling, and the mixture was stirred for 10 minutes. Ethyl iodide (46 μL, 0.58 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. The reaction solution was added dropwise to ice-cold saturated aqueous ammonium chloride, 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 obtain Reference Synthetic Example Compound 78 (yield 32.0 mg).

[0946] Step 6

[0947] Reference Synthetic Example Compound 78 (32 mg, 0.070 mmol), methanol (1 mL) and THF (0.5 mL) were mixed, then 4 mol / L aqueous sodium hydroxide solution (174 μL, 0.696 mmol) was added, and the mixture was stirred at 40 °C for 5 hours. 2 mol / L HCl (0.5 mL) and water were sequentially added to the reaction solution, and then the solvent was distilled off under reduced pressure to obtain a mixture of Reference Synthetic Example Compound 79 and NaCl (yield 74.3 mg).

[0948] Step 7

[0949] The sodium chloride mixture (37 mg) of reference synthetic example compound 79 obtained by the method described in Step 6 was mixed with acetonitrile (1 mL), then 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) were added, and then stirred at 40 °C for 15 hours. Water and ethyl acetate were added to the reaction solution, stirred, and then 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, then slurried with a mixed solvent of n-hexane / ethyl acetate (3 / 1), and the solid was collected by filtration. The obtained solid was dried under reduced pressure to obtain Example Compound 23 (yield 9.7 mg).

[0951] Example 24

[0952] [Chemical Figure 65]

[0953]

[0954] Step 1

[0955] Reference synthetic example compound 68 (3.00 g, 15.8 mmol) and DMSO (40 mL) were mixed, then DIPEA (8.2 mL, 48 mmol) and cyclopropylmethylamine (1.7 mL, 20 mmol) were added, and then stirred at 80 °C for 4 hours. After cooling, water was added to the reaction solution, and the mixture was 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 then the residue was purified by silica gel column chromatography to obtain reference synthetic example compound 80 (yield 2.83 g).

[0956] Step 2

[0957] Palladium(II) acetate (113 mg, 0.499 mmol), XPhos (476 mg, 0.999 mmol), and acetonitrile (25 mL) were mixed, degassed, and then stirred at room temperature for 5 minutes under an argon atmosphere. Compound 47 of Reference Synthesis Example (2.66 g, 12.5 mmol), cesium carbonate (6.50 g, 19.9 mmol), and Compound 80 of Reference Synthesis Example (2.40 g, 9.97 mmol) were added and the mixture was stirred at 90 °C for 2 hours. The reaction solution was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain Compound 81 of Reference Synthesis Example (yield 3.05 g).

[0958] Step 3

[0959] Compound 81 of Reference Synthesis Example (3.00 g, 7.19 mmol) and methanol (18 mL) were mixed, degassed, and the reactor was purged with argon. Then, chloro(triphenylphosphine)gold(I) (711 mg, 1.44 mmol) and silver bis(trifluoromethanesulfonyl)imide (558 mg, 1.44 mmol) were 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 obtain Compound 82 of Reference Synthesis Example (yield 2.89 g).

[0960] Step 4

[0961] Compound 82 of Reference Synthesis Example (2.89 g, 6.92 mmol), THF (17 mL), and methanol (17 mL) were mixed, then 4 mol / L aqueous sodium hydroxide solution (8.7 mL, 35 mmol) was added, and the mixture was stirred at 50 °C for 4 hours. The reaction solution was acidified with 10% aqueous citric acid solution, and the organic solvent was distilled off under reduced pressure. Ethanol (2 mL) was added to the residue, and the mixture was stirred for 1 hour under ice-cooling. The precipitate was collected by filtration to obtain Compound 83 of Reference Synthesis Example (yield 1.37 g).

[0962] Step 5

[0963] Compound 83 of the reference synthesis example (1.00 g, 2.48 mmol), 5-amino-2-fluorobenzamide (573 mg, 3.72 mmol) and acetonitrile (12 mL) were mixed, 1-methylimidazole (783 μL, 9.92 mmol) and TCFH (1.39 g, 4.95 mmol) were added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution and stirred, and the precipitate was filtered out. The solid collected by filtration was dried under reduced pressure and then purified by silica gel column chromatography to obtain Example Compound 24 (yield 808 mg).

[0965] Example 25

[0966] [Chemical Figure 66]

[0967]

[0968] Step 1

[0969] Compound 84 of the reference synthesis example (10.0 g, 41.7 mmol) and DMF (0.10 L) were mixed, sodium hydride (60% in oil) (2.50 g, 62.5 mmol) was added, and the mixture was 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, followed by stirring at room temperature for 30 minutes. Water (200 mL) was added and stirred, and then the precipitated solid was collected by filtration. The solid collected by filtration was dried under reduced pressure to obtain Compound 85 of the reference synthesis example (yield 10.6 g).

[0970] Step 2

[0971] Compound 85 of the reference synthesis example (3.00 g, 11.8 mmol), THF (0.060 L) and triethylamine (4.92 mL, 35.4 mmol) were mixed, and the mixture was 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 then filtered through filtration. The solvent in the filtrate was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain Compound 86 of the reference synthesis example (yield 2.71 g).

[0972] Step 3

[0973] Compound 86 (2.71 g, 9.99 mmol) of the reference synthesis example was mixed with THF (0.038 L), then a 1 mol / L TBAF / THF solution (0.016 L, 16 mmol) was added, and then the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain Compound 87 of the reference synthesis example (yield 1.74 g).

[0974] Step 4

[0975] XPhos (0.289 g, 0.606 mmol), palladium(II) acetate (68.6 mg, 0.303 mmol) and acetonitrile (0.015 L) were mixed, then Compound 87 of the reference synthesis example (1.51 g, 7.58 mmol), cesium carbonate (3.95 g, 12.1 mmol) and Compound 69 of the reference synthesis example (1.30 g, 6.06 mmol) were added, and then the mixture was stirred at 95 °C for 1.5 hours under an argon atmosphere. The mixture was cooled, diluted with chloroform and water, and then filtered through filtration. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography, and then slurried with a mixed solution of n-hexane / ethyl acetate (1 / 1) (25 mL). The solid was collected by filtration and then dried under reduced pressure to obtain Compound 88 of the reference synthesis example (yield 1.40 g).

[0976] Step 5

[0977] Compound 88 (1.40 g, 3.71 mmol) of the reference synthesis example was mixed with methanol (9.3 mL), then degassed, the reactor was purged 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, 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 obtain Compound 89 of the reference synthesis example (yield 1.23 g).

[0978] Step 6

[0979] The reference synthetic example compound 89 (1.20 g, 3.18 mmol) was mixed with THF (0.012 L), methanol (0.012 L) and 4 mol / L aqueous sodium hydroxide solution (3.2 mL, 13 mmol) were added, and the mixture was stirred at room temperature for 3 hours. 2 mol / L hydrochloric acid (10 mL) was added dropwise to the reaction solution, and the mixture was distilled under reduced pressure. Approximately 10 mL of toluene was added to the residue, and the mixture was distilled under reduced pressure. This operation was repeated twice, and then dried under reduced pressure to obtain the reference synthetic example compound 90 (yield 2.01 g) as a sodium chloride mixture.

[0980] Step 7

[0981] The sodium chloride mixture (1.20 g) of the reference synthetic example compound 90 obtained by the method described in Step 6 was mixed with acetonitrile (0.019 L), 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 the mixture was then stirred at room temperature for 15 hours. The solvent was removed by distillation under reduced pressure, the residue was diluted with water and chloroform, and 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, the residue was purified by silica gel column chromatography, ethanol (15 mL) was added for slurry washing, and then the solid was collected by filtration and dried under reduced pressure to obtain Example Compound 25 (yield 0.727 g).

[0983] Example 26

[0984] [Chemical Figure 67]

[0985]

[0986] Step 1

[0987] The reference synthetic example compound 69 (500 mg, 2.63 mmol) was mixed with DMSO (6.6 mL), DIPEA (1.36 mL, 7.91 mmol) and 2-methoxymethylamine (396 mg, 5.27 mmol) were added, and the mixture was stirred at 80 °C for 4 hours. Water and ethyl acetate were added to the reaction solution, stirred, and then the organic layer was separated. The separated organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to obtain the reference synthetic example compound 91 (yield 566 mg).

[0988] Step 2

[0989] Reference synthetic 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 synthetic example compound 47 (180 mg, 0.844 mmol), and cesium carbonate (799 mg, 2.45 mmol) were added, followed by stirring at 100 °C for 3.5 hours under an argon atmosphere. After cooling, water and ethyl acetate were added, stirred, and filtered. The organic layer of the filtrate was separated and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain reference synthetic example compound 92 (yield 99.9 mg).

[0990] Step 3

[0991] Reference synthetic example compound 92 (99.9 mg, 0.237 mmol) and ethanol (3 mL) were mixed, degassed, and the reactor was purged with argon. Then, chloro(triphenylphosphine)gold(I) (30.5 mg, 0.0474 mmol) and silver bis(trifluoromethanesulfonyl)imide (18.4 mg, 0.0474 mmol) were 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 obtain reference synthetic example compound 93 (yield 80.1 mg).

[0992] Step 4

[0993] Reference synthetic example compound 93 (77.7 mg, 0.184 mmol), methanol (1 mL), and THF (1 mL) were mixed, and then 4 mol / L aqueous sodium hydroxide solution (460 μL, 1.84 mmol) was added, followed by stirring at 40 °C for 3 hours. 2 mol / L hydrochloric acid (1.5 mL) was added to the reaction solution, and the solvent was distilled off under reduced pressure to obtain reference synthetic example compound 94 (yield 194 mg) as a sodium chloride mixture.

[0994] Step 5

[0995] To a sodium chloride mixture (40 mg) of reference synthetic example compound 94 obtained by the method described in Step 4, 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 sequentially added, and the mixture was stirred at 40 °C for 15 hours. Water and ethyl acetate were added to the reaction solution, stirred, and then 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, washed with a mixed solution of n-hexane / ethyl acetate (3 / 1) for slurrying, and then the solid was collected by filtration. The solid collected by filtration was dried under reduced pressure to obtain Example Compound 26 (yield 11.0 mg).

[0997] Example 27

[0998] [Chemical Figure 68]

[0999]

[1000] To a sodium chloride mixture (40 mg) of reference synthetic example compound 94 obtained by the method described in Step 4 of Example 26, 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, followed by stirring at 40 °C for 15 hours. Water and ethyl acetate were added to the reaction solution, stirred, and then 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, washed with a mixed solution of n-hexane / ethyl acetate (3 / 1) for slurrying, and then the solid was collected by filtration. The solid collected by filtration was dried under reduced pressure to obtain Example Compound 27 (yield 11.2 mg).

[1002] Example 28

[1003] [Chemical Figure 69]

[1004]

[1005] Step 1

[1006] To Reference Synthesis Example Compound 95 (2.4 g, 12 mmol), nitromethane (20 mL) and ethyl 2,2 - diethoxyacetate (2.52 g, 14.3 mmol) were added. The mixture was cooled with ice, and titanium(IV) chloride (4.38 mL, 39.9 mmol) was added dropwise. Then the mixture was stirred at room temperature for 20 hours. Water and ethyl acetate were added in sequence 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 obtain Reference Synthesis Example Compound 96 (yield 2.71 g).

[1007] Step 2

[1008] 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 for 1.5 hours under an argon atmosphere. After cooling, the reaction solution was diluted with chloroform and filtered through filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain Reference Synthesis Example Compound 97 (yield 1.64 g).

[1009] Step 3

[1010] To Reference Synthesis Example Compound 97 (1.64 g, 5.42 mmol), THF (25 mL) and 1 mol / L TBAF / THF solution (10.8 mL, 10.8 mmol) were added in sequence, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain Reference Synthesis Example Compound 98.

[1011] Step 4

[1012] Compound 99 of the reference synthesis example (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, followed by stirring 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, 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 obtain Compound 100 of the reference synthesis example (yield 1.01 g).

[1013] Step 5

[1014] DMSO (10 mL), DIPEA (1.96 mL, 11.4 mmol), and 2.0 mol / L ethylamine / THF (2.3 mL, 4.6 mmol) were sequentially added to Compound 100 of the reference synthesis example (1.01 g, 3.80 mmol), and the mixture was stirred at 80 °C for 4 hours. Ethyl acetate and water were added and the mixture was stirred under water cooling, 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 then the residue was purified by silica gel column chromatography to obtain Compound 101 of the reference synthesis example (yield 980 mg).

[1015] Step 6

[1016] 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 Compound 98 of the reference synthesis example (0.482 g, 2.09 mmol), cesium carbonate (1.36 g, 4.17 mmol), and Compound 101 of the reference synthesis example (0.980 g, 3.37 mmol) were added, followed by stirring at 95 °C for 1.5 hours under an argon atmosphere. After cooling, water was added to the reaction solution, 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 obtain Compound 102 of the reference synthesis example (yield 0.554 g).

[1017] Step 7

[1018] Compound 102 of the reference synthesis example (554 mg, 1.14 mmol) and ethanol (10 mL) were mixed and degassed. The reactor was purged with argon, and then 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 added. Subsequently, 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 obtain Compound 103 of the reference synthesis example (yield 272 mg).

[1019] Step 8

[1020] To Compound 103 of the reference synthesis example (270 mg, 0.557 mmol), THF (5 mL) and 10% palladium / carbon (40 mg) were sequentially added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 17 hours. The reaction solution was filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain Compound 104 of the reference synthesis example (yield 135 mg).

[1021] Step 9

[1022] To Compound 104 of the reference synthesis example (25 mg, 0.063 mmol), 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 sequentially added and stirred at 40 °C for 15 hours. Water and ethyl acetate were added to the reaction solution, stirred, and then 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, a mixed solution of n-hexane / ethyl acetate (3 / 1) was added for slurry washing, and then the solid was collected by filtration to obtain Compound 105 of the reference synthesis example containing impurities (yield 43 mg).

[1023] Step 10

[1024] Compound 105 of the reference synthesis example containing impurities (43 mg) obtained by the method described in step 9 was mixed with methanol (500 μL) and THF (500 μL), 4 mol / L aqueous sodium hydroxide solution (203 μL) was added, and the mixture was stirred at 40 °C for 2 hours. HCl was added to neutralize the reaction solution, and then the mixture was concentrated and dried under reduced pressure to obtain Compound 106 of the reference synthesis example as a sodium chloride mixture (yield 91 mg).

[1025] Step 11

[1026] To the sodium chloride mixture (91 mg) of reference synthetic 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 sequentially added, and then the mixture was stirred at room temperature for 18 hours. 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, then slurried with a mixed solution of ethyl acetate / n-hexane (1 / 3), and then the solid was collected by filtration to obtain Example compound 28 (yield 19.8 mg).

[1028] Example 29

[1029] [Chemical Figure 70]

[1030]

[1031] Steps 1 - 3

[1032] Reference synthetic example compound 109 was obtained from reference synthetic example compound 1 by the same method as in Steps 1 to 3 of Example 1.

[1033] Step 4

[1034] A suspension containing reference synthetic 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)palladium(II) dichloride (38 mg, 0.054 mmol) was added, and then the mixture was stirred at 90 °C for 5 hours under an argon atmosphere. The reaction solution was cooled and filtered. Water was added to the filtrate, and the mixture was extracted with ethyl acetate and washed with saturated brine. The filtrate 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 obtain reference synthetic example compound 110 (yield 213 mg).

[1035] Step 5

[1036] Compound 110 of the reference synthesis example (212 mg, 0.913 mmol) was mixed with 1,4-dioxane (9 mL), and then water (3 mL), 2,6-dimethylpyridine (212 μL, 1.83 mmol), sodium periodate (781 mg, 3.65 mmol), and tert-butyl alcohol (2.5 w / v%) (460 μL, 0.045 mmol) were added in sequence, followed by stirring at room temperature for 2 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The separated organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain Compound 111 of the reference synthesis example (yield 187 mg).

[1037] Step 6

[1038] Compound 111 of the reference synthesis example (71 mg, 0.30 mmol) and acetic acid (86 μL, 1.50 mmol) were added to a mixture of Compound 109 of the reference synthesis example (100 mg, 0.252 mmol) in ethanol (4 mL), and the mixture was stirred at 80 °C in an oxygen atmosphere for 17 hours. The reaction solution was cooled, saturated aqueous sodium bicarbonate and ethyl acetate were added and stirred, and then 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 obtain Compound 112 of the reference synthesis example (yield 135 mg).

[1039] Step 7

[1040] Compound 112 of the reference synthesis example (122 mg, 0.200 mmol) was mixed with methanol (2 mL), and then 4 mol / L aqueous sodium hydroxide solution (300 μL) was added, followed by stirring at 50 °C for 3 hours. 2 mol / L hydrochloric acid (600 μL) was added to the reaction solution, the mixture was diluted with water, and the precipitate was collected by filtration. The solid collected by filtration was dried under reduced pressure to obtain Example Compound 29 (yield 74.5 mg).

[1042] Example 30

[1043] [Chemical Diagram 71]

[1044]

[1045] Step 1

[1046] Compound 113 of the reference synthesis example (500 mg) was mixed with DMF (3.8 mL), the mixture was cooled in ice, sodium hydride (60% in oil) (98.4 mg, 2.46 mmol) was added, and the mixture was stirred for 10 minutes. Ethyl iodide (0.21 mL, 2.6 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The reaction solution was added dropwise to an ice-cold saturated aqueous ammonium chloride solution, water was added, and the mixture was extracted with ethyl acetate. n-Hexane was added to the extract, and the mixture was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain Compound 114 of the reference synthesis example (yield 356 mg).

[1047] Step 2

[1048] Compound 114 of the reference synthesis example (356 mg, 1.22 mmol) was mixed with MTBE (4 mL), then cooled to -78 °C, then 2.56 mol / L n-butyllithium / n-hexane (0.72 mL) was added, and the mixture was stirred for 1 hour. A solution of methyl chloroformate (230 mg, 2.43 mmol) in MTBE was added, the mixture was warmed to room temperature and stirred for 3 hours. The reaction solution was added dropwise to an ice-cold saturated aqueous ammonium chloride solution, water was added, 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 obtain Compound 115 of the reference synthesis example (yield 254 mg).

[1049] Step 3

[1050] A solution of N,N-diisopropylamine (0.39 mL, 2.8 mmol) in THF (3.7 mL) was cooled to -78 °C, 2.56 mol / L n-butyllithium / n-hexane (0.73 mL) was added, warmed to 0 °C, and the mixture was stirred for 15 minutes. After cooling to -78 °C, Compound 115 of the reference synthesis example (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 solution was added dropwise to an ice-cold saturated aqueous ammonium chloride solution, water was added, 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 obtain Compound 116 of the reference synthesis example (yield 176 mg).

[1051] Step 4

[1052] Reference synthetic example compound 116 (174 mg, 0.496 mmol), reference synthetic example compound 25 (234 mg, 0.742 mmol) and 1,4-dioxane (5 mL) were mixed, then cesium carbonate (323 mg, 0.991 mmol) and APhos-Pd-G3 (15.8 mg, 0.0249 mmol) were added, and the mixture was then stirred at 140 °C for 1 hour under microwave irradiation. Water was added to the cooled reaction solution, and the mixture was extracted with ethyl acetate. The extract was neutralized with dilute hydrochloric acid 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 obtain reference synthetic example compound 117 (yield 22.3 mg).

[1053] Step 5

[1054] Reference synthetic example compound 117 (22.3 mg, 0.0486 mmol), methanol (2.4 mL) and THF (0.6 mL) were mixed, then 4 mol / L aqueous sodium hydroxide solution (0.24 mL) was added under ice-cooling, and the mixture was then stirred at room temperature for 1 hour. After neutralizing the reaction solution, the solvent was distilled off under reduced pressure to obtain reference synthetic example compound 118 as a sodium chloride mixture (yield 78.5 mg).

[1055] Step 6

[1056] The sodium chloride mixture (39 mg) of reference synthetic example compound 118 obtained by the method described in step 5, 5-amino-2-fluorobenzamide (5.6 mg, 0.036 mmol) and acetonitrile (0.2 mL) were mixed, 1-methylimidazole (5.9 μL, 0.074 mmol) and TCFH (10.8 mg, 0.0385 mmol) were added, and the mixture was stirred at room temperature for 4 hours. Water was added, the mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the residue was purified successively by silica gel column chromatography and preparative TLC to obtain example compound 30 (yield 4.2 mg).

[1058] Example 31

[1059] [Chemical Figure 72]

[1060]

[1061] Step 1

[1062] Reference synthetic example compound 58 (1.00 g, 4.11 mmol) was mixed with THF (21 mL), then DMAP (50.3 mg, 0.412 mmol) and di-tert-butyl dicarbonate (1.17 g, 5.36 mmol) were added, and the mixture was 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 to obtain reference synthetic example compound 119 (yield 1.16 g).

[1063] Step 2

[1064] To a solution of reference synthetic example compound 119 (600 mg, 1.75 mmol) and triisopropyl borate (0.64 mL, 2.8 mmol) in THF (1.2 mL) was added 1.8 mol / L LDA / n-hexane-THF (1.2 mL), and the mixture was stirred at 0 °C for 1 hour. 2 mol / L HCl was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain reference synthetic example compound 120 (yield 317 mg).

[1065] Step 3

[1066] Reference synthetic 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, then cesium carbonate (153 mg, 0.470 mmol), XPhos (14.9 mg, 0.0313 mmol) and XPhos-palladium chloride (crotyl) (21.1 mg, 0.0313 mmol) were added, and the mixture was stirred at 90 °C for 2 hours. The reaction solution was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain reference synthetic example compound 121 (yield 129 mg).

[1067] Step 4

[1068] The cold reference synthetic example compound 121 (129 mg, 0.308 mmol) was mixed with DMF (3.1 mL), sodium hydride (60% in oil) (16.0 mg, 0.400 mmol) was added, and the mixture was 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 solution 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 then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the reference synthetic example compound 122 containing impurities (yield 108 mg).

[1069] Step 5

[1070] The reference synthetic example compound 122 containing impurities (129 mg) obtained by the method described in Step 4, methanol (1.4 mL), and THF (1.4 mL) were mixed, then 4 mol / L aqueous sodium hydroxide solution (0.72 mL) was added, and the mixture was 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 distilled off under reduced pressure to obtain the reference synthetic example compound 123 as a sodium chloride mixture (yield 284 mg).

[1071] Step 6

[1072] The sodium chloride mixture (40.0 mg) of the reference synthetic example compound 123 obtained by the method described in Step 5, 5-amino-2-fluorobenzamide (12.1 mg, 0.0785 mmol), and acetonitrile (393 μL) were mixed, 1-methylimidazole (14 μL, 0.18 mmol) and TCFH (24.3 mg, 0.0866 mmol) were added, and then the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and then the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain Example Compound 31 (yield 9.6 mg).

[1073] The Example Compounds 15 to Example Compound 128 in the following table were prepared according to the methods shown in Example 15 to Example 31 above or similar methods. In addition, the 1 1H-NMR data and / or LC / MS data of these example compounds are shown in the table.

[1074] [Table 2 - 1]

[1075]

[1076]

[1077] [Table 2 - 2]

[1078]

[1079]

[1080] [Table 2 - 3]

[1081]

[1082]

[1083] [Table 2 - 4]

[1084]

[1085] [Table 2 - 5]

[1086]

[1087] [Table 2 - 6]

[1088]

[1089] [Table 2 - 7]

[1090]

[1091]

[1092] [Table 2 - 8]

[1093]

[1094]

[1095] [Table 2 - 9]

[1096]

[1097]

[1098] [Table 2 - 10]

[1099]

[1100]

[1101] [Table 2 - 11]

[1102]

[1103]

[1104] [Table 2 - 12]

[1105]

[1106]

[1107] [Table 2 - 13]

[1108]

[1109]

[1110] [Table 2 - 14]

[1111]

[1112]

[1113] [Table 2 - 15]

[1114]

[1115]

[1116] [Table 2 - 16]

[1117]

[1118]

[1119] [Table 2 - 17]

[1120]

[1121]

[1122] [Table 2-18]

[1123]

[1124]

[1125] [Table 2 - 19]

[1126]

[1127]

[1128] [Table 2 - 20]

[1129]

[1130]

[1131] [Table 2 - 21]

[1132]

[1134] Example 129

[1135] [Chemical Figure 73]

[1136]

[1137] Step 1

[1138] To a toluene solution (10 mL) of Reference Synthetic 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) was added indium(III) acetate (22.5 mg, 0.07 mmol), and the mixture was stirred at 110 °C for 20 hours under a nitrogen atmosphere. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The above reaction operation was carried out 15 times, and the obtained crude products were combined and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 30 / 1), while separating into diastereomers, to obtain Reference Synthetic Example Compound 125 (first peak diastereomer) (yield 15 g) and Reference Synthetic Example Compound 126 (second peak diastereomer) (yield 7.0 g).

[1139] Step 2

[1140] A preparative chiral column (CHIRALART Celllose-SB, manufactured by YMC Co., Ltd.) was connected to a preparative LC system (LC-Forte / R, manufactured by YMC Co., Ltd.), and a mixture of n-heptane / 2-propanol (9 / 1) was passed through the column at room temperature and a flow rate of 21 mL / min for equilibration. 2-Propanol was added to and dissolved in the reference synthesis example compound 126 (3.55 g) to prepare a 50 mg / mL solution, and then n-heptane was added to this solution to obtain a solution (solution A) with a concentration of 5 mg / mL of the reference synthesis example compound 126. Approximately 30 mL of solution A was injected, and while observing the UV detector (detection wavelength: 250 nm), the first peak (retention time: approximately 14.5 minutes) and the second peak (retention time: approximately 18.8 minutes) were collected (this operation was repeated until the entire amount of solution A was injected). The solvent contained in each fraction was distilled off under reduced pressure, whereby the reference synthesis example compound 127 (yield 1.72 g, optical purity > 99.9% ee) was obtained from the fraction derived from the first peak, and the reference synthesis example compound 128 (yield 1.69 g, optical purity 99.4% ee) was obtained from the fraction derived from the second peak.

[1141] Step 3

[1142] The reference synthesis example compound 127 (1.40 g, 5.22 mmol) and THF (0.026 L) were mixed, and then 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) were added in sequence, and the mixture was stirred at 75 °C for 1.5 hours in an argon atmosphere. After it was cooled, the reaction solution was diluted with chloroform and passed through filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the reference synthesis example compound 129 (yield 1.38 g).

[1143] Step 4

[1144] The 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 then the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain the reference synthesis example compound 130 (yield 0.348 g).

[1145] Step 5

[1146] 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, followed by stirring at 95 °C for 1.5 hours under an argon atmosphere. After cooling, the reaction solution was diluted with water and then extracted with chloroform. The extract was dried over anhydrous sodium sulfate and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain Reference Synthesis Example Compound 131 (yield 0.370 g).

[1147] Step 6

[1148] Reference Synthesis Example Compound 131 (0.365 g, 0.932 mmol) and methanol (2.3 mL) were mixed, degassed, and the reactor was purged with argon. Then, chloro(triphenylphosphine)gold(I) (92.2 mg, 0.186 mmol) and silver bis(trifluoromethanesulfonyl)imide (72.3 mg, 0.186 mmol) were 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 obtain Reference Synthesis Example Compound 132 (yield 0.332 g).

[1149] Step 7

[1150] 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, followed by stirring at room temperature for 5 hours. 2 mol / L hydrochloric acid (1.5 mL) was added dropwise to the reaction solution under ice cooling, and the mixture was evaporated under reduced pressure. Toluene was added to the residue and stirred. The solvent was distilled off under reduced pressure to obtain Reference Synthesis Example Compound 133 as a sodium chloride mixture (yield 0.447 g).

[1151] Step 8

[1152] The sodium chloride mixture (30.0 mg) of reference synthetic example compound 133 obtained by the method described in Step 7 was mixed with acetonitrile (0.57 mL), then 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) were added, and then the mixture was stirred 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 distilled off 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 obtain Example Compound 129 (yield 18.0 mg).

[1154] Example 130

[1155] [Chemical Figure 74]

[1156]

[1157] Steps 1 - 6

[1158] Example Compound 130 (yield 11.3 mg) was obtained from reference synthetic example compound 126 by the same method as in Steps 3 to 8 of Example 129.

[1160] Example 131

[1161] [Chemical Figure 75]

[1162]

[1163] Step 1

[1164] Example Compound 131 (yield 5.0 mg) was obtained from reference synthetic example compound 138 by the same method as in Step 8 of Example 129.

[1166] Example 132

[1167] [Chemical Figure 76]

[1168]

[1169] Steps 1 - 5

[1170] Compound 132 (yield 16.6 mg) was obtained from Reference Synthetic Example Compound 135 and Reference Synthetic Example Compound 75 by the same method as in Steps 3 to 7 of Example 23.

[1172] Example 133

[1173] [Chemical Drawing 77]

[1174]

[1175] Step 1

[1176] Compound 133 (yield 18.4 mg) was obtained from Reference Synthetic Example Compound 142 by the same method as in Step 7 of Example 23.

[1178] Example 134

[1179] [Chemical Drawing 78]

[1180]

[1181] Steps 1 - 3

[1182] Compound 134 (yield 23.3 mg) was obtained from Reference Synthetic Example Compound 140 by the same method as in Steps 5 to 7 of Example 23.

[1184] Example 135

[1185] [Chemical Drawing 79]

[1186]

[1187] Step 1

[1188] Compound 135 (yield 18.4 mg) was obtained from Reference Synthetic Example Compound 144 by the same method as in Step 7 of Example 23.

[1190] Example 136

[1191] [Chemical Drawing 80]

[1192]

[1193] Steps 1 - 4

[1194] Example compound 136 (yield 8.6 mg) was obtained from Reference Synthetic Example Compound 135 and Reference Synthetic Example Compound 91 by the same method as in Steps 2 to 5 of Example 26.

[1196] Example 137

[1197] [Chemical Drawing 81]

[1198]

[1199] Step 1

[1200] Example compound 137 (yield 9.5 mg) was obtained from Reference Synthetic Example Compound 147 by the same method as in Step 5 of Example 26.

[1201] Example compounds 129 to 137 in the following table were prepared according to the methods shown in Examples 129 to 137 above or similar methods. In addition, the 1 1H-NMR data and / or LC / MS data of these example compounds are shown in the table.

[1203] [Table 3 - 1]

[1204]

[1205]

[1206] [Table 3 - 2]

[1207]

[1208]

[1210] Example 138

[1211] [Chemical Drawing 82]

[1212]

[1213] Step 1

[1214] The reference synthetic example compound 35 (500 mg, 1.02 mmol) was mixed with THF (10 mL), then a 4 mol / L lithium borohydride / THF solution (1 mL) was added, and the mixture was stirred at 60 °C for 4.5 hours. Saturated aqueous ammonium chloride solution and water were added to the cooled reaction solution, and the mixture was 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, slurried with a mixed solution of ethyl acetate / n-hexane (1 / 5), and the solid was collected by filtration to obtain the reference synthetic example compound 148 (yield 405 mg).

[1215] Step 2

[1216] The reference synthetic example compound 148 (20.0 mg, 0.0434 mmol) was mixed with THF (220 μL), 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 the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, slurried with ethyl acetate - n-hexane (1 / 3), and the precipitated solid was collected by filtration to obtain the example compound 138 (yield 18.3 mg).

[1218] Example 139

[1219] [Chemical Figure 83]

[1220]

[1221] Step 1

[1222] The reference synthetic example compound 148 (150 mg, 0.326 mmol) was mixed with dichloromethane (3.3 mL), cooled with 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 solution, and then 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 obtain the reference synthetic example compound 149 containing some impurities (yield 165 mg).

[1223] Step 2

[1224] The reference synthetic example compound 149 (15 mg), which was obtained by the method described in Step 1 and partially contained impurities, was mixed with DMF (313 μL), triethylamine (13.1 μL, 0.0942 mmol) and 3-aminobenzamide (8.5 mg, 0.062 mmol) were added, and then the mixture was stirred at 80 °C for 16 hours. 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 then the residue was purified by silica gel column chromatography, slurried with ethyl acetate / n-hexane (1 / 3), and the solid was collected by filtration to obtain Example Compound 139 (yield 6.2 mg).

[1225] The Example Compounds 138 to 139 in the following table were prepared according to the methods shown in Example 138 to Example 139 above. In addition, the 1 1H-NMR data and LC / MS data of these example compounds are shown in the table.

[1227] [Table 4]

[1228]

[1230] Example 140

[1231] [Chemical Figure 84]

[1232]

[1233] Step 1

[1234] The reference synthetic example compound 150 (300 mg, 1.20 mmol) and DMSO (5 mL) were mixed, then DIPEA (618 μL, 3.60 mmol) and 2.0 mol / L ethylamine-THF (900 μL) were added, and then the mixture was stirred at 70 °C for 3 hours. Water was added to the cooled reaction solution, and the mixture was 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 to obtain the reference synthetic example compound 151 which was partially contaminated with impurities (yield 319 mg).

[1235] Step 2

[1236] The reference synthetic example compound 151 (150 mg) containing impurities obtained by the method described in Step 1 was mixed with THF (2.5 mL), and then the reference synthetic 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, and the mixture was then stirred at 90 °C for 18 hours under an argon atmosphere. Water was added to the cooled reaction solution, 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 obtain the reference synthetic example compound 152 (yield 224 mg).

[1237] Step 3

[1238] The reference synthetic 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, and the mixture was stirred at 110 °C for 18 hours under an argon atmosphere. Water was added to the cooled reaction solution, 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 obtain the reference synthetic example compound 153 (yield 38 mg).

[1239] Step 4

[1240] The reference synthetic 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 at 60 °C for 4 hours. 2 mol / L HCl and water were added to the cooled reaction solution, and the solvent was distilled off under reduced pressure to obtain the reference synthetic example compound 154 as a mixture with sodium chloride (yield 72 mg).

[1241] Step 5

[1242] The mixture of the reference synthetic example compound 154 and sodium chloride (72 mg) obtained by the method described in Step 4 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 in sequence, and then the mixture was stirred at 40 °C for 1.5 hours. The reaction solution was diluted with water, 1 mol / L HCl was added, and then extraction was carried out using 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 slurried and washed with a mixed solvent of n-hexane / ethyl acetate (3 / 1) to obtain Example Compound 140 (yield 30.1 mg).

[1244] Example 141

[1245] [Chemical Drawing 85]

[1246]

[1247] Step 1

[1248] The reference synthetic example compound 32 (255 mg, 1.05 mmol) and DMF (5 mL) were mixed, the mixture was cooled in ice, sodium hydride (60% in oil) (54.5 mg, 1.36 mmol) was added, and the mixture was stirred for 10 minutes. Ethyl iodide (118 μL, 1.475 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was added dropwise to ice-cold saturated aqueous ammonium chloride, diluted with water, and extracted using ethyl acetate. n-Hexane was added to the extract, and the mixture was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain the reference synthetic example compound 155 (yield 214 mg).

[1249] Step 2

[1250] Compound 155 of the reference synthesis example (212 mg, 0.782 mmol) was mixed with dichloromethane (5 mL), cooled with ice, and a solution of NCS (135 mg, 1.01 mmol) in dichloromethane (1 mL) was added dropwise, followed by stirring 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 solution 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 obtain Compound 156 of the reference synthesis example (yield 170 mg).

[1251] Step 3

[1252] Compound 156 of the reference synthesis example (168 mg, 0.550 mmol) was mixed with carbon tetrachloride (5 mL), then cooled with ice, NBS (118 mg, 0.663 mmol) was added, and the mixture was stirred at 60 °C for 13 hours. Water was added to the cooled reaction solution, 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 obtain Compound 157 of the reference synthesis example (yield 117 mg).

[1253] Steps 4 - 6

[1254] Compound 141 (yield 10.2 mg) was obtained from Compound 157 of the reference synthesis example (115 mg, 0.300 mmol) by the same method as in Steps 5 to 7 of Example 17.

[1255] The compounds of Example 140 to Compound 143 in the following table were prepared by the methods shown in the above Examples 140 to 141 or similar methods. In addition, the 1 1H-NMR data and / or LC / MS data of these compounds of the examples are shown in the table.

[1257] [Table 5]

[1258]

[1259]

[1261] Example 144

[1262] [Chemical Figure 86]

[1263]

[1264] Steps 1 - 2

[1265] The reference synthetic example compound 162 was obtained from the reference synthetic example compound 160 by the same method as in Steps 1 and 2 of Example 15.

[1266] Step 3

[1267] The reference synthetic example compound 163 (3.00 g, 17.0 mmol) and DMF (85 mL) were mixed, and the mixture was cooled in ice. Sodium hydride (60% in oil) (885 mg, 22.1 mmol) was added, and the mixture was stirred for 30 minutes. p-Toluenesulfonyl chloride (4.87 g, 25.5 mmol) was added to the reaction solution, and then the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the ice-cooled reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain the reference synthetic example compound 164 (yield 2.36 g).

[1268] Step 4

[1269] The reference synthetic example compound 164 (2.36 g, 7.14 mmol) and THF (36 mL) were mixed, then cooled to -78 °C, then LDA / n-hexane-THF (1.09 mol / L, 9.2 mL) was added, and then the mixture was stirred at -78 °C for 30 minutes. Iodine (2.72 g, 10.7 mmol) was added to the reaction solution, and the mixture was stirred at -78 °C for 30 minutes, warmed to room temperature, and stirred for 1 hour. The reaction solution was cooled in ice, 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 then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain the reference synthetic example compound 165 (yield 1.53 g).

[1270] Step 5

[1271] Compound 165 (1.20 g, 2.63 mmol) of the reference synthesis example was mixed with THF (13 mL), then cooled with ice, sodium methoxide / methanol (5 mol / L, 2.6 mL) was added, and the mixture was stirred for 1 hour under ice cooling. An aqueous saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain compound 166 of the reference synthesis example (yield 429 mg).

[1272] Step 6

[1273] Compound 166 (429 mg) of the reference synthesis example was mixed with DMF (14 mL), the mixture was cooled with ice, sodium hydride (60% in oil) (85.2 mg, 2.13 mmol) was added, and the mixture was stirred for 20 minutes under ice cooling. Ethyl iodide (341 μL, 4.26 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. An aqueous saturated ammonium chloride solution was added to the ice-cold reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain compound 167 of the reference synthesis example (yield 168 mg).

[1274] Step 7

[1275] Compound 167 (168 mg, 0.488 mmol) of the reference synthesis example, methanol (1.2 mL) and THF (1.2 mL) were mixed, then 4 mol / L aqueous sodium hydroxide solution (610 μL) was added, and then the mixture was stirred at room temperature for 12 hours. 10% aqueous citric acid solution was added to the reaction solution and stirred, and then the solvent was distilled off under reduced pressure. A small amount of ethanol was added to the residue, and the precipitate was collected by filtration to obtain compound 168 of the reference synthesis example (yield 112 mg).

[1276] Step 8

[1277] Reference synthetic 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, 1-methylimidazole (100 μL, 1.27 mmol) and TCFH (178 mg, 0.634 mmol) were added, and then the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the precipitate was collected by filtration to obtain reference synthetic example compound 169 (yield 97.3 mg).

[1278] Step 9

[1279] Reference synthetic example compound 169 (20.0 mg, 0.0442 mmol), 1,4-dioxane (442 μL) and water (58 μL) were mixed, then reference synthetic 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 chloride (crotyl) (1.5 mg, 0.0022 mmol) were added, and then the mixture was stirred at 90 °C for 2 hours. Water was added to the cooled reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain example compound 144 (yield 13.6 mg).

[1281] Example 145

[1282] [Chemical figure 87]

[1283]

[1284] Step 1

[1285] Reference synthetic example compound 170 (yield 110 mg) was obtained from reference synthetic example compound 65 (100 mg, 0.372 mmol) by the same method as in step 2 of Example 15.

[1286] Steps 2 - 8

[1287] Example compound 145 (yield 15.6 mg) was obtained from reference synthetic example compound 28 by the same method as in steps 3 to 9 of Example 144.

[1289] Example 146

[1290] [Chemical Figure 88]

[1291]

[1292] Step 1

[1293] Compound 119 (10.0 g, 29.1 mmol) of the reference synthesis example was mixed with THF (290 mL), then cooled to -20 °C, and LDA / n - hexane - THF (1.09 mol / L) (29 mL) was added, followed by stirring at -20 °C for 30 minutes. Iodine (8.87 g, 34.9 mmol) was added to the reaction solution, and the mixture was stirred at -20 °C for 1 hour, warmed to room temperature, and stirred for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was 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 then the residue was purified by silica gel column chromatography to obtain Compound 177 of the reference synthesis example (yield 7.41 g).

[1294] Step 2

[1295] Compound 177 (7.41 g, 15.8 mmol) of the reference synthesis example was mixed with 1,1,1,3,3,3 - hexafluoro - 2 - propanol (34 mL) and stirred at 150 °C for 30 minutes under microwave irradiation. After allowing it to cool, the solvent was distilled off under reduced pressure to obtain Compound 178 of the reference synthesis example (yield 5.43 g).

[1296] Step 3

[1297] Compound 178 (5.00 g, 13.5 mmol) of the reference synthesis example was mixed with DMF (68 mL), the mixture was cooled in ice, sodium hydride (60% in oil) (813 mg, 20.3 mmol) was added, and the mixture was stirred for 10 minutes. Ethyl iodide (5.4 mL, 68 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the ice - cold reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain Compound 179 of the reference synthesis example (yield 4.62 g).

[1298] Steps 4 - 6

[1299] Example compound 146 (yield 29.5 mg) was obtained from reference synthetic example compound 179 by the same method as in steps 7 to 9 of Example 144.

[1301] Example 147

[1302] [Chemical Drawing 89]

[1303]

[1304] Step 1

[1305] Reference synthetic example compound 183 (yield 142 mg) was obtained from reference synthetic example compounds 168 and methyl 5 - amino - 2 - fluorobenzoate by the same method as in step 8 of Example 144.

[1306] Step 2

[1307] Reference synthetic example compound 183 (142 mg, 0.304 mmol), methanol (1.5 mL), and THF (1.5 mL) were mixed, then 4 mol / L aqueous sodium hydroxide solution (380 μL) was added, and the mixture was stirred at room temperature for 2 hours. 2 mol / L hydrochloric acid (1.2 mL) was added to the reaction solution, and the solvent was distilled off under reduced pressure to obtain reference synthetic example compound 184 as a sodium chloride mixture (yield 254 mg).

[1308] Step 3

[1309] The sodium chloride mixture (254 mg) of reference synthetic 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, and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and then extraction was performed 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 obtain reference synthetic example compound 185 (yield 114 mg).

[1310] Step 4

[1311] Reference synthetic example compound 186 (yield 103 mg) was obtained from reference synthetic example compound 127 (100 mg, 0.373 mmol) by the same method as in step 2 of Example 144.

[1312] Step 5

[1313] Compound 185 of the reference synthesis example (15.0 mg, 0.0305 mmol), 1,4-dioxane (2.0 mL) and water (400 μL) were mixed and degassed, then Compound 186 of the reference synthesis example (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 stirred at 90 °C for 2 hours. An aqueous saturated ammonium chloride solution was added to the reaction solution, and the mixture was 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 obtain Example Compound 147 (yield 12.1 mg).

[1314] The compounds of Example 144 to Example 156 in the following table were prepared according to the methods shown in Example 144 to Example 147 above or similar methods. In addition, the 1 1H-NMR data and / or LC / MS data of these example compounds are shown in the table.

[1316] [Table 6 - 1]

[1317]

[1318]

[1319] [Table 6 - 2]

[1320]

[1321]

[1322] [Table 6 - 3]

[1323]

[1325] Example 157

[1326] [Chemical Drawing 90]

[1327]

[1328] Step 1

[1329] Reference synthetic 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, and the mixture was then stirred at 100 °C for 4 hours. Water was added to the cooled reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography and the diastereomers were separated simultaneously to obtain reference synthetic example compound 188 (yield 86.3 mg) and reference synthetic example compound 189 (79.5 mg).

[1330] Step 2

[1331] Reference synthetic 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 and the mixture was stirred at 100 °C for 3 hours. Water was added to the cooled reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain reference synthetic example compound 190 (yield 53.6 mg).

[1332] Step 3

[1333] Reference synthetic example compound 181 (30.0 mg, 0.0578 mmol), 1,4-dioxane (578 μL), and water (58 μL) were mixed, and then reference synthetic 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 chloride (crotyl) (2.0 mg, 0.0030 mmol) were added, and the mixture was then stirred at 90 °C for 2 hours. Water was added to the cooled reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain example compound 157 (yield 22.5 mg).

[1335] Example 158

[1336] [Chemical Figure 91]

[1337]

[1338] Step 1 - A

[1339] The reference synthetic example compound 191 (yield 1.42 g) was obtained from the reference synthetic example compound 126 (1.00 g, 3.73 mmol) by the same method as in Step 2 of Example 157.

[1340] Step 1 - B

[1341] The reference synthetic example compound 192 (yield 38.8 mg) was obtained from the reference synthetic example compound 175 (50.0 mg, 0.159 mmol) by the same method as in Step 7 of Example 145.

[1342] Step 2

[1343] The example compound 158 (yield 18.9 mg) was obtained from the reference synthetic example compound 191 (31.4 mg, 0.0665 mmol) and the reference synthetic example compound 192 (30.0 mg, 0.0996 mmol) by the same method as in Step 3 of Example 157.

[1345] Example 159

[1346] [Chemical Figure 92]

[1347]

[1348] Steps 1 - 3

[1349] The example compound 159 (yield 10.6 mg) was obtained from the reference synthetic example compound 191 by the same method as in Steps 3 to 5 of Example 15.

[1351] Example 160

[1352] [Chemical Figure 93]

[1353]

[1354] Step 1

[1355] Compound 160 (yield 17.2 mg) was obtained from Reference Synthetic Example Compound 194 (22 mg, 0.050 mmol) by the same method as in Step 5 of Example 15.

[1357] Example 161

[1358] [Chemical Drawing 94]

[1359]

[1360] Step 1

[1361] Compound 161 (yield 5.4 mg) was obtained from Reference Synthetic Example Compound 194 (22 mg, 0.050 mmol) by the same method as in Step 5 of Example 15.

[1362] Compounds 157 to 161 in the following table were prepared according to the methods shown in Examples 157 to 161 above. In addition, the 1 1H-NMR data and LC / MS data of these compounds are shown in the table.

[1364] [Table 7]

[1365]

[1366]

[1368] Example 162

[1369] [Chemical Drawing 95]

[1370]

[1371] Step 1

[1372] To Reference Synthesis Example Compound 36 (1.50 g, 3.16 mmol), 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 sequentially added, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, then ethyl acetate and 1 mol / L hydrochloric acid were added and stirred, and then the organic layer was separated. The separated organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, then chloroform was added to the residue, followed by filtration. The filtrate was purified by silica gel column chromatography, slurried with a mixed solution (10 mL) of ethyl acetate / n-hexane (1 / 3), and then the solid was collected by filtration to obtain Reference Synthesis Example Compound 195 (yield 1.56 g).

[1373] Step 2

[1374] 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, and the mixture was stirred at room temperature for 5 hours. 2 mol / L hydrochloric acid (8 mL) was added dropwise to the reaction solution, the mixture was stirred, diluted with water, and then extracted with a chloroform / methanol (10 / 1) mixture. The extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain Example Compound 162 (yield 397 mg).

[1375] Example 163

[1376] [Chemical Drawing 96]

[1377]

[1378] Step 1

[1379] To Example Compound 162 (10 mg, 0.017 mmol), acetonitrile (500 μL) and TCFH (9.5 mL, 0.034 mmol) were added, 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 stirred at 60 °C for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (silica gel) and silica gel column chromatography in this order to obtain Example Compound 163 (yield 9.1 mg).

[1381] Example 164

[1382] [Chemical Figure 97]

[1383]

[1384] Step 1

[1385] The sodium chloride mixture (50.0 mg) of reference synthetic example compound 72 obtained by the same method as in Step 4 of Example 21 was mixed with acetonitrile (0.77 mL), 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 then the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with chloroform and water, and then the organic layer was separated. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain reference synthetic example compound 196 (yield 39.4 mg).

[1386] Step 2

[1387] Reference synthetic example compound 196 (0.340 g, 0.666 mmol) was mixed with THF (1.7 mL), methanol (1.7 mL) and 4 mol / L aqueous sodium hydroxide solution (0.666 mL, 2.66 mmol) were added, and the mixture was stirred at room temperature for 2 hours. 2 mol / L hydrochloric acid (2.0 mL) was added dropwise to the reaction solution, the solvent was distilled off under reduced pressure, and a small amount of toluene was added for azeotropic dehydration. The residue was purified by silica gel column chromatography to obtain Example compound 164 (yield 0.298 g).

[1389] Example 165

[1390] [Chemical Figure 98]

[1391]

[1392] Step 1

[1393] Compound 164 of the example (13.0 mg, 0.0262 mmol) was mixed with acetonitrile (0.26 mL), 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 then the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with chloroform and water, and then the organic layer was separated. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain Compound 165 of the example (yield 10.2 mg).

[1395] Example 166

[1396] [Chemical Drawing 99]

[1397]

[1398] Step 1

[1399] Compound 196 of the reference synthesis example (38.0 mg, 0.0744 mmol) was mixed with THF (0.19 mL), methanol (0.19 mL) and 4 mol / L aqueous sodium hydroxide solution (74.4 μL, 0.298 mmol) were added, and the mixture was stirred at room temperature for 2 hours. 2 mol / L HCl (0.25 mL) was added dropwise to the reaction solution, and the mixture was evaporated under reduced pressure. Toluene was added to the residue for azeotropic dehydration, and then dried under reduced pressure to obtain Compound 197 of the reference synthesis example as a sodium chloride mixture (yield 51.2 mg).

[1400] Step 2

[1401] The sodium chloride mixture (25.0 mg) of Compound 197 of the reference synthesis example was mixed with acetonitrile (0.33 mL), 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 then the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with chloroform and water, and then the organic layer was separated. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain Compound 166 of the example (yield 18.8 mg).

[1403] Example 167

[1404] [Chemical Drawing 100]

[1405]

[1406] Step 1

[1407] The sodium chloride mixture (20.0 mg) of reference synthetic example compound 197 obtained by the method of step 2 of Example 166 was mixed with acetonitrile (0.26 mL), 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 then the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with chloroform and water, and then the organic layer was separated. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain Example compound 167 (yield 9.3 mg).

[1409] Example 168

[1410] [Chemical Drawing 101]

[1411]

[1412] Step 1

[1413] To the sodium chloride mixture (32 mmol) of reference synthetic example compound 72 obtained by the same method as in step 4 of Example 21, acetonitrile (150 mg), methyl 5-amino-2-fluorobenzoate (78.5 mL, 0.3 mg), 1-methylimidazole (183 μL, 2.463 mmol) and TCFH (130 mg, 0.463 mmol) were added in sequence, and the mixture was stirred at 40 °C for 15 hours. Water and ethyl acetate were added to the reaction solution and stirred, and then 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 fractionated by silica gel column chromatography to obtain reference synthetic example compound 198 containing impurities (yield 127 mg).

[1414] Step 2

[1415] The reference synthetic example compound 198 (122 mg) containing impurities obtained by the method of step 1 was mixed with methanol (1.5 mL) and THF (1.5 mL), then 4 mol / L aqueous sodium hydroxide solution (346 μL) was added, and the mixture was stirred at room temperature for 2 hours. 2 mol / L hydrochloric acid was added to the reaction solution for neutralization, and then the solvent was distilled off under reduced pressure. The obtained solid was dried under reduced pressure to obtain a sodium chloride mixture of reference synthetic example compound 199 (yield 210 mg).

[1416] Step 3

[1417] To the sodium chloride mixture (5 mL) of reference synthetic example compound 199 obtained by the method of step 2, 2-aminoacetonitrile hydrochloride (39.30 mg, 0.0 mg), DMF (1.421 mmol), DIPEA (35 μL, 0.20 mmol) and HATU (25.3 mg, 0.0665 mmol) were added in sequence, and the mixture was stirred at 55 °C for 4 hours and then at room temperature for 16 hours. 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. After purifying the residue by silica gel column chromatography, the obtained solid was slurried with a mixed solution of n-hexane / ethyl acetate (4 / 1) and the solid was collected by filtration to obtain example compound 168 (yield 12.9 mg).

[1419] Example 169

[1420] [Chemical Diagram 102]

[1421]

[1422] Step 1

[1423] To reference synthetic example compound 200 (200 mg, 0.843 mmol), acetonitrile (500 μL), TCFH (355 mg, 1.27 mmol) and 1-methylimidazole (200 μL, 2.53 mmol) were added in sequence, then the mixture was stirred for 10 minutes, then 3-amino-1-methyl-pyridin-2-one (157 mg, 1.26 mmol) was added and the mixture was stirred at 40 °C for 2 hours. Ethyl acetate and saturated brine were added and stirred, then the organic layer was separated. The solvent was distilled off under reduced pressure, then the residue was subjected to slurry washing with an ethyl acetate-n-hexane mixture, and the solid was collected by filtration to obtain reference synthetic example compound 201 (yield 267 mg).

[1424] Step 2

[1425] Under ice-cooling, 4 mol / L hydrochloric acid / 1,4-dioxane (5 mL) was added to Reference Synthesis Example Compound 201 (419 mg, 1.22 mmol), and then the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure to obtain Reference Synthesis Example Compound 202 (yield 267 mg).

[1426] Step 3

[1427] To a sodium chloride mixture (15 mg) of Reference Synthesis Example Compound 72 obtained by the same method as in Step 4 of Example 21 were sequentially added acetonitrile (500 μL), TCFH (13 mg, 0.046 mmol), and 1-methylimidazole (18.3 μL, 0.232 mmol), and then 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 then the residue was purified by preparative thin-layer chromatography (silica gel), and the resulting solid was slurried and washed with a mixture of n-hexane and ethyl acetate to obtain Example Compound 169 (yield 3.1 mg).

[1428] Example Compounds 162 to 202 in the following table were prepared according to the methods shown in Example 162 to Example 169 above or similar methods. In addition, the 1 1H-NMR data and / or LC / MS data of these example compounds are shown in the table.

[1430] [Table 8 - 1]

[1431]

[1432] [Table 8 - 2]

[1433]

[1434] [Table 8 - 3]

[1435]

[1436]

[1437] [Table 8 - 4]

[1438]

[1439]

[1440] [Table 8 - 5]

[1441]

[1442]

[1443] [Table 8 - 6]

[1444]

[1445]

[1446] [Table 8-7]

[1447]

[1448] [Table 8-8]

[1449]

[1450] [Table 8-9]

[1451]

[1452]

[1454] Example 203

[1455] [Chemical Figure 103]

[1456]

[1457] Step 1

[1458] The compound of Example 14 (39.8 mg, 0.0705 mmol), the compound of Reference Synthesis Example 203 (54.3 mg, 0.367 mmol), 1,4-dioxane (700 μL) and water (64 μL) were mixed, then cesium carbonate (33.2 mg, 0.102 mmol), XPhos (3.9 mg, 0.0082 mmol) and XPhos-palladium chloride (crotyl) (4.7 mg, 0.0070 mmol) were added, and the mixture was then stirred 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 distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of Example 203 (yield 33.6 mg).

[1460] Example 204

[1461] [Chemical Figure 104]

[1462]

[1463] Step 1

[1464] The compound of Example 203 (23.0 mg, 0.0438 mmol) was mixed with methanol (1 mL), 20% palladium hydroxide-carbon (4.8 mg) was added, and then the mixture was stirred at room temperature for 17 hours under a hydrogen atmosphere. The reaction solution was passed through filtration and evaporated under reduced pressure to obtain the compound of Example 204 (yield 18.6 mg).

[1466] Example 205

[1467] [Chemical Figure 105]

[1468]

[1469] Step 1

[1470] The compound of Example 14 (50.3 mg, 0.0891 mmol) was mixed with 1,4-dioxane (886 μL), and then the compound of Reference Synthesis Example 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) were added, and the mixture was stirred 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 then the residue was purified by silica gel column chromatography to obtain the compound of Reference Synthesis Example 205 (yield 22.0 mg).

[1471] Step 2

[1472] The compound of Reference Synthesis Example 205 (18.0 mg, 0.0309 mmol) was mixed with methanol (1 mL), 20% palladium hydroxide-carbon (3.5 mg) was added, and the mixture was stirred at room temperature for 17 hours under a hydrogen atmosphere (atmospheric pressure). The reaction solution was passed through filtration and evaporated under reduced pressure to obtain the compound of Example 205 (yield 18.2 mg).

[1474] Example 206

[1475] [Chemical Figure 106]

[1476]

[1477] Step 1

[1478] Compound 14 of the example (39.7 mg, 0.0703 mmol) and 1,4-dioxane (700 μL) were mixed, 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, and the mixture was stirred 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 then the residue was purified by silica gel column chromatography to obtain Reference Synthetic Example Compound 206 (yield 11.3 mg).

[1479] Step 2

[1480] Reference Synthetic Example Compound 206 (7.0 mg, 0.012 mmol) and THF (0.4 mL) were mixed, and TBAF / THF (1.00 mol / L) (24 μL) was added, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain Example Compound 206 (yield 6.0 mg).

[1481] Example Compounds 203 to 212 in the following table were prepared by the methods shown in Example 203 to Example 206 above or similar methods. In addition, the 1 1H-NMR data and / or LC / MS data of these example compounds are shown in the table.

[1483] [Table 9-1]

[1484]

[1485]

[1486] [Table 9-2]

[1487]

[1488]

[1490] Example 213

[1491] [Chemical Figure 107]

[1492]

[1493] Step 1

[1494] The compound of Example 207 (280 mg, 0.547 mmol) and 1,4-dioxane (5.5 mL) were mixed. Then, under ice-cooling, 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 in sequence, and the mixture was stirred at room temperature for 1.5 hours. An aqueous solution of saturated sodium thiosulfate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain the compound of Reference Synthesis Example 207 (yield 280 mg).

[1495] Step 2

[1496] The compound of Reference Synthesis Example 207 (19.3 mg, 0.0376 mmol) and methanol (390 μL) were mixed, cooled with ice, sodium borohydride (14.7 mg, 0.389 mmol) was added, and then the mixture was stirred at room temperature for 7 hours. An aqueous solution of saturated ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain the compound of Example 213 (yield 9.6 mg).

[1498] Example 214

[1499] [Chemical Figure 108]

[1500]

[1501] Step 1

[1502] Compound 213 of the example (73 mg, 0.14 mmol) was mixed with dichloromethane (1.4 mL), cooled with 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 solution, and then extraction was carried out 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 obtain Compound 208 of the reference synthesis example (yield 38.5 mg).

[1503] Step 2

[1504] Compound 208 of the reference synthesis example (9.8 mg, 0.018 mmol) was mixed with DMSO (370 μL), sodium cyanide (5.1 mg, 0.10 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and then extraction was carried out with ethyl acetate. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography and then slurry-washed with a mixed solution of ethyl acetate / n-hexane (1 / 4) to obtain Compound 214 of the example (yield 4.1 mg).

[1506] Example 215

[1507] [Chemical Figure 109]

[1508]

[1509] Step 1

[1510] Compound 208 of the reference synthesis example (18.7 mg, 0.0350 mmol) was mixed with methanol (700 μL), sodium methoxide (5.9 mg, 0.11 mmol) was added, and the mixture was stirred at room temperature for 48 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain Compound 215 of the example (yield 2.1 mg).

[1512] Example 216

[1513] [Chemical Figure 110]

[1514]

[1515] Step 1

[1516] Compound 140 of the example (25.4 mg, 0.0397 mmol), ethanol (1 mL), and THF (1 mL) were mixed, 20% palladium hydroxide-carbon (2 mg) was added thereto, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered, the solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain Compound 216 of the example (yield 17.2 mg).

[1518] Example 217

[1519] [Chemical Diagram 111]

[1520]

[1521] Step 1

[1522] Compound 95 of the example (20 mg, 0.035 mmol) and pyridine (500 μL) were mixed, then methanesulfonyl chloride (4 μL, 0.05 mmol) was added, and the mixture was subsequently stirred at room temperature for 4 hours. Water was added to the reaction solution, and the mixture was 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 then the residue was purified by silica gel column chromatography to obtain Compound 217 of the example (yield 12.7 mg).

[1523] Compounds 213 to 217 of the examples in the following table were prepared by the methods shown in Examples 213 to 217 above. In addition, the 1 1H-NMR data and / or LC / MS data of these compounds of the examples are shown in the table.

[1525] [Table 10]

[1526]

[1527]

[1529] Example 218

[1530] [Chemical Diagram 112]

[1531]

[1532] Steps 1-3

[1533] Compound 218 (yield 27.0 mg) of the example was obtained from the reference synthetic example compound 2 by the same method as in Steps 2 to 4 of Example 11.

[1535] Examples 219, Example 220

[1536] [Chemical Figure 113]

[1537]

[1538] Step 1

[1539] A preparative chiral column (CHIRALPAK IC, manufactured by Daicel Corporation) was connected to a preparative LC system (LC-Forte / R, manufactured by YMC Co., Ltd.), and a mixed solution of ethanol / n-hexane (1 / 1) was passed through the column at room temperature and a flow rate of 8.0 mL / min to equilibrate. Example Compound 218 (12.8 mg, 0.0220 mmol) was dissolved in ethanol (8 mL) to obtain Solution A. Solution A (4 mL) was injected, and the first peak (retention time: about 24 minutes) and the second peak (retention time: about 37 minutes) were collected while observing the UV detector (this operation was performed twice). The solvent contained in each fraction was removed by distillation under reduced pressure, and Example Compound 219 (yield 4.9 mg) was obtained from the fraction derived from the first peak, and Example Compound 220 (yield 4.5 mg) was obtained from the fraction derived from the second peak.

[1541] Examples 221 and Example 222

[1542] [Chemical Figure 114]

[1543]

[1544] Steps 1-5

[1545] Reference Synthetic Example Compound 215 (yield 26.2 mg) was obtained from Reference Synthetic Example Compound 68 by the same method as in Steps 1 to 5 of Example 21.

[1546] Step 6

[1547] A preparative chiral column (CHIRALPAK IC, manufactured by Daicel Corporation) was connected to a preparative LC system (LC-Forte / R, manufactured by YMC Co., Ltd.), and a mixed solution of ethanol / n-hexane (4 / 1) was passed through the column at room temperature and a flow rate of 20.0 mL / min to equilibrate it. Reference synthetic example compound 215 (26.2 mg, 0.0427 mmol) was dissolved in ethanol (5.2 mL) to prepare solution A. Solution A (2 mL to 3 mL) was injected, and the first peak (retention time: about 11.5 minutes) and the second peak (retention time: about 14.0 minutes) were collected while observing the UV detector (this operation was carried out twice). By distilling off the solvent contained in each fraction under reduced pressure, example compound 221 (yield 12.0 mg) was obtained from the fraction derived from the first peak, and example compound 222 (yield 11.4 mg) was obtained from the fraction derived from the second peak.

[1549] Examples 223 and Example 224

[1550] [Chemical Diagram 115]

[1551]

[1552] Step 1

[1553] Reference synthetic example compound 216 (yield 31.2 mg) was obtained from reference synthetic example compound 214 by the same method as in step 5 of Example 21.

[1554] Step 2

[1555] A preparative chiral column (CHIRALPAK IC, manufactured by Daicel Corporation) was connected to a preparative LC system (LC-Forte / R, manufactured by YMC Co., Ltd.), and a mixed solution of ethanol / n-hexane (4 / 1) was passed through the column at room temperature and a flow rate of 20.0 mL / min to equilibrate it. Reference synthetic example compound 216 (31.2 mg, 0.0431 mmol) was dissolved in ethanol (6.2 mL) to prepare solution A. Solution A (about 3 mL) was injected, and the first peak (retention time: about 11.0 minutes) and the second peak (retention time: about 13.5 minutes) were collected while observing the UV detector (this operation was carried out twice). By distilling off the solvent contained in each fraction under reduced pressure, example compound 223 (yield 10.8 mg) was obtained from the fraction derived from the first peak, and example compound 224 (yield 11.4 mg) was obtained from the fraction derived from the second peak.

[1556] The compounds of Examples 218 to 224 in the following table were prepared by the methods shown in Examples 218 to 224 above. In addition, the 1 1H-NMR data and / or LC / MS data of these example compounds are shown in the table.

[1558] [Table 11-1]

[1559]

[1560] [Table 11-2]

[1561]

[1562] Test Example 1: Determination of the binding inhibitory activity between human STAT6 / pIL-p4Rα by fluorescence polarization method

[1563] 1) Construction of recombinant human STAT6 (region 123 to 658) fused with a histidine tag

[1564] The recombinant human STAT6 (hereinafter referred to as rhSTAT6) expression vector with a His-tag fusion [plasmid DNA in which the nucleotide sequence (region 123 - 658) of human STAT6 was inserted into the pET28a(+) vector (Novagen)] was inserted into Escherichia coli, and the culture was treated with IPTG and cultured overnight under the culture conditions of 17°C. After disrupting Escherichia coli with a high-pressure homogenizer (EmulsiFlex-C3, manufactured by AVESTIN, Inc.), affinity purification using Ni-NTA agarose (manufactured by Qiagen), cation exchange chromatography using CM-FF (manufactured by GE healthcare), and gel filtration chromatography using 200 10 / 300GL (manufactured by GE healthcare) were carried out to obtain rhSTAT6.

[1565] 2) Determination of the binding inhibitory activity between human STAT6 / pIL-4Rα by fluorescence polarization method

[1566] Dilute the DMSO solution of the compound of the example with an assay buffer [for example, a buffer containing 50 mmol / L NaCl, 10 mmol / L HEPES (pH 7.0), 1 mmol / L DTT, 1 mmol / L EDTA, and 0.01% by volume of NP-40, etc.] to prepare a solution with the compound added. Adjust the DMSO concentration in the compound-added solution to 1% or 2% by volume. Add 10 μL of the compound-added solution and the assay buffer containing 1% or 2% by volume of DMSO to each well of a 384-well plate. Add 5 μL of the assay buffer containing rhSTAT6 (rhSTAT6 concentration: for example, 1 μmol / L) or the assay buffer to each well of the 384-well plate. After standing at room temperature in the dark for 30 minutes, add 5 μL of the assay buffer containing the 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: for example, 80 nmol / L) or the assay buffer containing 2% by volume of DMSO to each well of the 384-well plate. Let the mixture stand at room temperature in the dark for 30 minutes, and then centrifuge (200 g, 1 minute, room temperature). Measure the fluorescence polarization value using Infinite (registered trademark) F500 (manufactured by Tecan Japan Co., Ltd.) (excitation: 485 nm, emission: 535 nm). Using the fluorescence polarization value (A) when rhSTAT6 and FAM-pIL-4Rp are added without adding the compound of the example, the fluorescence polarization value (B) when FAM-pIL-4Rp is added without adding the compound of the example and rhSTAT6, and the fluorescence polarization value (C) when each compound of the example, rhSTAT6, and FAM-pIL-4Rp are added, calculate the inhibition rate of each compound of the example according to the following formula.

[1567] Inhibition rate (%) = ((A - C) / (A - B)) × 100

[1568] In the evaluation of each compound of the example, the 50% inhibitory concentration (IC 50 ) is calculated from the linear function equation of the straight line connecting two points sandwiching 50%. The IC 50 values of the compounds of the examples are shown in the following table. In addition, as a comparative example, the IC 50 value of the compound PM-301H in this evaluation system is also shown (reference: WO2014 / 182928).

[1570] [Table 12-1]

[1571]

[1572]

[1573] [Table 12-2]

[1574]

[1575]

[1576] [Table 12-3]

[1577]

[1578]

[1579] [Table 12-4]

[1580] Example compound <![CDATA[IC 50 (μmol / L)]]> Example compound <![CDATA[IC 50 (μmol / L)]]> Ex.201 0.31 Ex.214 3.98 Ex.202 0.34 Ex.215 2.94 Ex.203 7.06 Ex.216 0.43 Ex.204 2.35 Ex.217 0.59 Ex.205 8.44 Ex.218 0.68 Ex.206 3.62 Ex.219 0.28 Ex.207 2.95 Ex.220 9.60 Ex.208 2.08 Ex.221 0.36 Ex.209 6.60 Ex.222 3.10 Ex.210 2.74 Ex.223 0.32 Ex.211 4.98 Ex.224 1.59 Ex.212 9.03 Comparative example compound <![CDATA[IC 50 (μmol / L)]]> Ex.213 3.47 PM-301H 0.27

[1581] Test Example 2: Determination of human STAT6-dependent reporter gene activity

[1582] 1) Construction of human STAT6-HEK293 cells

[1583] Collect HEK 293 cells maintained in culture with [1 vol% and 10 vol% penicillin-streptomycin (Thermo Fisher Scientific) and FBS (manufactured by ATCC) respectively added to DMEM high glucose (Thermo Fisher Scientific)], and suspend them in 10 mL of 0.5% BSA / PBS. Collect 1×10 6 cells, remove the supernatant by centrifugation, and suspend the cells in 100 μL of Nucleofector solution V (manufactured by Lonza K.K.). Add 2 μg of STAT6 vector [plasmid DNA incorporating the human STAT6 sequence in pcDNA3.1 (Invitrogen)], and introduce the STAT6 vector into HEK293 cells using the procedure Q-001 originally registered in 2b. Obtain a cell line that consistently expresses STAT6 (STAT6-HEK293 cells) by selecting resistant cells in a medium containing (manufactured by Thermo Fisher Scientific).

[1584] 2) STAT6 reporter gene assay using STAT6-HEK293 cells

[1585] Harvest 3×10 cells maintained in assay medium [medium supplemented with 1 vol%6 STAT6-HEK293 cells were seeded in a 10 cm culture dish. To 500 μL of Opti- (manufactured by Thermo Fisher Scientific), 3 μg of the STAT6 reporter gene vector [plasmid in which sequences containing the STAT6 binding sequence and the C / EBP binding sequence were tandemly incorporated into pGL4.27 (manufactured by Promega Corporation)] and 9 μL of HD transfection reagent (manufactured by Promega Corporation) were added to prepare a transfection solution. The transfection solution was vortexed and allowed to stand for about 5 minutes, then added dropwise to the STAT6-HEK293 cells, and then cultured overnight in a CO2 incubator to generate STAT6 reporter gene cells.

[1586] The prepared STAT6 reporter gene cells were seeded on a B&W isoplate-96TC (PerkinElmer Japan Co., Ltd.) (3×10 4 cells / 50 μL / well), and cultured overnight in a CO2 incubator (37 °C, 5% CO2). 50 μL of assay medium was added to each well instead of the STAT6 reporter gene cells. A compound addition solution was prepared by diluting the DMSO solution of the test compound 250-fold using the assay medium. 20 μL of the compound addition solution or the assay medium containing 0.4% (v / v) DMSO was added to the plate, and then the plate was cultured in a CO2 incubator for 1 hour. 10 μL of an 80 ng / mL human IL-4 solution (Peprotech) or the assay medium was added to each well, and the cells were cultured in a CO2 incubator for 6 hours.

[1587] CellTiter- Cell Viability Assay (manufactured by Promega Corporation) was used to measure the viable cell rate. After adding 20 μL of the diluted CellTiter reagent to each well, the plate was cultured in a CO2 incubator for 1 hour, and the fluorescence value was measured using F500 (excitation: 340 nm, emission: 495 nm). Using the fluorescence value (D) under the condition of IL-4 stimulation without adding the test compound, the fluorescence value (E) under the condition of not seeding the STAT6 reporter gene cells, and the fluorescence value (F) under the condition of IL-4 stimulation after treatment with each test compound, the cell viability of each test compound was calculated by the following formula.

[1588] Viability (%) = [(F - E) / (D - E)] × 100

[1589] Use Bright- The luciferase assay system (Promega) was used to measure the STAT6 reporter gene activity. 100 μL of Bright- reagent was added to each well, and the luciferase activity was measured using F500. Using the luciferase activity value (G) when the test compound was not added and IL-4 stimulation was performed, the luciferase activity value (H) when the test compound was not added and IL-4 stimulation was not performed, and the luciferase activity value (I) when each test compound was treated and IL-4 stimulation was performed, the inhibition rate of each test compound was calculated by the following formula.

[1590] Inhibition rate (%) = [(G - I) / (G - H)] × 100

[1591] The inhibition rates (%) when the concentration of each test compound was 1 μmol / L and 0.1 μmol / L are shown in Table 13. Note that the viable cell rate under each condition was 70% or higher, and it was determined that the luciferase activity inhibitory activity of each test compound was appropriately evaluated.

[1593] [Table 13-1]

[1594]

[1595] [Table 13-2]

[1596]

[1597]

[1598] [Table 13-3]

[1599]

[1600]

[1601] Industrial applicability

[1602] The compound of the present invention or a pharmaceutically acceptable salt thereof has excellent STAT6 inhibitory activity and can be used as an active ingredient in therapeutic agents and / or prophylactic agents for various diseases related to STAT6. For example, a drug containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can be used as a therapeutic agent for inflammatory diseases (such as atopic dermatitis) and allergic diseases.

Claims

1. A compound represented by the general formula (I): [Chemical Figure 1] [wherein R 1 is an optionally substituted 5-membered heteroaryl group, an optionally substituted 5- to 6-membered non-aromatic heterocyclic group, an optionally substituted pyridone group, -C(=O)-NR a R b or -NR c -C(=O)R d , wherein R a , R b , R c and R d each independently represents 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; or R 1 and R 2 which, together with the carbon atom to which they are attached, can form an optionally substituted 5- to 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 each independently is N or CR 6 wherein 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 each independently is N or CR 7 wherein R 7 is a hydrogen atom, an optionally substituted C1-C6 alkyl group or an optionally substituted C1-C6 haloalkyl group; and ring A is an optionally substituted phenyl group or an optionally substituted 5- to 6-membered heteroaryl group, wherein the phenyl group or the 5- to 6-membered heteroaryl group can further fuse with another ring to form an optionally substituted 8- to 10-membered fused ring] or a pharmaceutically acceptable salt thereof.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein in general formula (I), Q 1 is C(=O) and Q 2 is NH.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein in general formula (I), X 1 , X 2 and X 4 are each independently CH or N.

4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein in the general formula (I), (i) X 1 is CH, X 2 is CH, and X 4 is CH; (ii) X 1 is N, X 2 is CH, and X 4 is CH; or (iii) X 1 is CH, X 2 is CH, and X 4 is N.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein in general formula (I), Y 1 and Y 2 are each independently CH or N.

6. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein 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.

7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein in the general formula (I), ring A is an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted pyrazolyl group or an optionally substituted thiadiazolyl group.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein in the general formula (I), ring A is a ring selected from the group consisting of rings represented by the following formula: [Chemical Figure 2] (wherein R 8 is a hydrogen atom, a cyano group, a hydroxyl group, an amino group, a methanesulfonylamino group, a sulfonamide group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a hydroxy-C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkoxy-C1-C6 alkyl group, a C1-C6 alkylcarbonyl group, an amino-C1-C6 alkyl group, an N-acetylamino-C1-C6 alkyl group, a C1-C6 alkylaminocarbonyl group, an N-methyl-C1-C6 alkylaminocarbonyl group, an imidazolyl group, a thiazolyl group or -C(=O)NHR e group, wherein R e is a C1-C6 alkyl group which can be substituted by a hydrogen atom or a cyano group, a C1-C6 alkylcarbonyl group optionally substituted by a dimethylamino group or an optionally substituted 5- to 6-membered heteroaryl group; and R 9 is a hydrogen atom, a halogen atom or a C1-C6 alkyl group.) 9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein in the general formula (I), ring A is a ring selected from the group consisting of rings represented by the following formula: [Chemical Figure 3] wherein R 8 and R 9 as defined in claim 8.) 10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein in the general formula (I), ring A is a ring selected from the group consisting of rings represented by the following formula: [Chemical Figure 4] [wherein R 8 is a hydrogen atom, a cyano group, a C1-C6 alkyl group, an imidazolyl group, a thiazolyl group or a -C(=O)-NHR e group; and R e is a hydrogen atom, a C1-C6 alkyl group that can be substituted by a cyano group, a C1-C6 alkylcarbonyl group that can be substituted by a dimethylamino group, or a ring selected from the rings represented by the following formula: [Chemical Figure 5] wherein 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; R 11 is a hydrogen atom, a halogen atom or a cyano group; R 12 is a hydrogen atom or a C1-C6 alkyl group; R 13 is a hydrogen atom, a C1-C6 alkyl group or a C1-C6 alkyl group optionally substituted with a halogen atom; 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}.

11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein in the general formula (I), R 1 is a ring selected from the group consisting of rings represented by the following formula: [Chemical Figure 6] {wherein, R 16 is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 haloalkyl group} -C(=O)-NR a R b group or -NR c -C(=O)R d group, wherein R a 、R b 、R c and R d are each independently a hydrogen atom or a C1-C6 alkyl group; or R 1 and R 2 together with the carbon atoms to which they are attached form a ring represented by the formula: [Chemical Figure 7] {wherein, * 1 is a carbon atom bonded to R 1 bonded carbon atom, * 2 is a carbon atom bonded to R 2 group.

12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein 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 that can be substituted by a cyano group.

13. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein in the general formula (I), X 2 is a CH group, and X 3 is a CR 6 group, 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.

14. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by the general formula (I) is: [Chemical Figure 8] [Chemical Figure 9] 15. A drug, which comprises the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 as an active ingredient.

16. A drug, which comprises the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 as an active ingredient, and the drug is a prophylactic or therapeutic agent for diseases related to STAT6.

17. The drug according to claim 16, wherein the diseases related to STAT6 are allergic diseases and inflammatory diseases.

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

19. A method for preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease, atopic dermatitis, bronchial asthma, bullous pemphigoid, nasal polyps, chronic rhinosinusitis, allergic rhinitis, eosinophilic esophagitis, prurigo, and urticaria, the method comprising: A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof.

20. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof in the manufacture of a prophylactic or therapeutic agent for a disease associated with STAT6.

21. Use according to claim 20, wherein the disease associated with STAT6 is an allergic disease and an inflammatory disease.

22. Use according to claim 20 or 21, 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 rhinosinusitis, allergic rhinitis, eosinophilic esophagitis, prurigo and urticaria.

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