Method for producing arylamide derivative

Abstract

To provide a method for producing a specific arylamide derivative that has RAF / MEK composite stabilizing activity and / or MEK inhibitory activity, and is useful for a cell proliferative disease, particularly treatment or prevention of cancer, in which the arylamide derivative can be obtained by a smaller number of processes.SOLUTION: There is provided a method for producing 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methyl sulfamoylamino)pyridine-4-yl]methyl]benzamide or its pharmaceutically acceptable salt, or pharmaceutically acceptable solvate of the compound or salt, for example, where (2-amino-3-fluoro pyridine-4-yl)methanol is allowed to react with chloroformate methyl and N,N- dimethylaminopyridine in acetonitrile to obtain (2-amino-3-fluoro pyridine-4-yl)methyl methyl carbonate.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to a method for producing arylamide derivatives. The present disclosure also relates to compounds that can be used to produce arylamide derivatives and methods for producing the same. [Background technology]

[0002] MEK (mitogen-activated protein kinase kinase) is a serine-threonine kinase in the MAPK signaling pathway, and is known to transmit signals intracellularly and be deeply involved in cell proliferation (see Non-Patent Document 1). MEK inhibitors such as PD0325901, CH4987655, trametinib, cobimetinib, and selumetinib have been reported (see Patent Document 1 and Non-Patent Document 2), and they have been reported to show clinical efficacy against cancers with RAF mutations, such as malignant melanoma with BRAF mutations, either as single agents or in combination with RAF inhibitors (see Non-Patent Documents 3 and 4).

[0003] On the other hand, it is known that some MEK inhibitors do not necessarily have sufficient clinical effects on cancers with RAS mutations, such as non-small cell lung cancer with RAS mutations. In fact, it has been reported that selumetinib and trametinib were ineffective in clinical trials of non-small cell lung cancer with KRAS mutations (see Non-Patent Documents 5 and 6).

[0004] CH5126766, which is known not only as an MEK inhibitor but also as a stabilizer of the RAF / MEK complex (see Patent Document 2 and Non-Patent Documents 7 and 8), has been reported to exhibit clinical efficacy against non-small cell lung cancer with RAS mutations (see Non-Patent Document 9). It has also been reported that CH5126766 stabilizes the RAF / MEK complex and inhibits increased MEK phosphorylation (feedback activation of the MAPK signal pathway) (see Non-Patent Document 10) (see Non-Patent Documents 7 and 8). This feedback activation is thought to be one of the reasons why MEK inhibitors are not always sufficiently effective in the clinical setting against cancers with RAS mutations (see Non-Patent Document 10). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2006 / 011466 [Patent Document 2] International Publication No. 2007 / 091736 [Non-patent literature]

[0006] [Non-Patent Document 1] Nat.Rev.Clin.Oncol.2018,vol.15,p.709-720 [Non-patent document 2] Molecules.2017,vol.22,e1551 [Non-patent document 3] N.Engl.J.Med.2012,vol.367,p.107-114 [Non-patent document 4] N.Engl.J.Med.2012,vol.367,p.1694-1703 [Non-patent document 5] JAMA.2017,vol.317,no.18,p.1844-1853 [Non-patent document 6] Ann.Oncol.2015,vol.26,no.5,p.894-901 [Non-Patent Document 7] Cancer Res.2013,vol.73,no.13,p.4050-4060 [Non-patent document 8] Cancer Cell.2014,vol.25,no.5,p.697-710 [Non-Patent Document 9] J.Clin.Oncol.2017,vol.35,no.15,suppl.,2506 [Non-Patent Document 10] Nat.Rev.Clin.Oncol.2014,vol.11,p.385-400 Summary of the Invention [Problem to be solved by the invention]

[0007] Although several RAF / MEK complex stabilizers or MEK inhibitors that are useful for the treatment or prevention of cell proliferative diseases, particularly cancer, the reality is that there are still not enough options available to meet the diverse needs of consumers.

[0008] Under these circumstances, it has been newly discovered that certain arylamide derivatives (compounds represented by the general formula (1) described below) have RAF / MEK complex stabilizing activity and / or MEK inhibitory activity and are useful for the treatment or prevention of cell proliferative diseases, particularly cancer.

[0009] An object of the present disclosure is to provide a method for producing such an arylamide derivative, which method enables the production of an arylamide derivative with a small number of steps. [Means for solving the problem]

[0010] The present disclosure provides the methods described in (A1) to (A31) below. (A1) A method for producing a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, comprising: (I) A step of reacting a compound represented by the following general formula (2) with a compound represented by X1-R9 and a base in a solvent to obtain a compound represented by the following general formula (4): A method comprising: [ka] [ka] [In the formula, R1 is -S(=O)2-NH-R 11 or -S(=O)2-R 11 and R 11 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), or a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), R2 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group; R3 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group, or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group), or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a halogen atom, a hydroxy group, or a C1-6 alkoxy group), R4 is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-7 alkenyl group, a C2-7 alkynyl group, a C3-6 cycloalkyl group, or a C1-6 alkylthio group; R5 is a halogen atom or a C1-6 alkyl group; R6 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group; R7 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group; R8 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group; X1 is a halogen atom or —O—R9, R9 is -C(=O)-R 12 , -C(=O)-OR 12 Or -P(=O)(-OR 12 )2, R 12 is a C1-6 alkyl group or an aryl group.]

[0011] (A2) The method according to (A1), wherein the base used in step (I) is at least one selected from the group consisting of N,N-dimethylaminopyridine and 1-methylimidazole. (A3) The method according to (A2), wherein the base used in step (I) is N,N-dimethylaminopyridine.

[0012] (A4) The method according to any one of (A1) to (A3), wherein the solvent used in step (I) is at least one selected from the group consisting of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, cyclopentyl methyl ether, and tert-butyl methyl ether. (A5) The method according to (A4), wherein the solvent used in step (I) is acetonitrile.

[0013] (A6) (II) A step of reacting a compound represented by general formula (4) with a compound represented by general formula (10) below in a solvent in the presence of a catalyst to obtain a compound represented by general formula (5) below: The method according to any one of (A1) to (A5), further comprising: [ka] [ka] [In the formula, R 13 is -B(-OR 14 )(-OR15 ) or -BF3K, R 14 and R 15 are each independently a hydrogen atom or a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a C1-6 alkoxy group or an aryl group), or R 14 and R 15 forms a 5- to 8-membered saturated or unsaturated ring together with the intervening oxygen atom and boron atom (the ring may be substituted with a C1-6 alkyl group, a C1-6 alkoxy group or an aryl group, and may be condensed with a benzene ring), R2 to R9 have the same meanings as above.]

[0014] (A7) The method according to (A6), wherein the catalyst used in step (II) is a palladium catalyst or a nickel catalyst.

[0015] (A8) The method according to (A7), wherein the catalyst used in step (II) is a palladium catalyst. (A9) The method according to (A8), wherein the palladium catalyst is a combination of at least one selected from the group consisting of bis(allylchloropalladium), tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, and palladium(II) acetate, and a compound represented by the following general formula (L1): [ka] [In the formula, R 20 and R 21 are each independently a C3-6 cycloalkyl group, R 22 is a C1-6 alkoxy group or an amino group (the amino group may be substituted with a C1-6 alkyl group or an aryl group), R 23 is a hydrogen atom or a C1-6 alkoxy group, R 24is a hydrogen atom or -S(=O)2-O-Na. (A10) R 20 and R 21 is a cyclohexyl group, R 22 is a methoxy group, an isopropoxy group, or an N,N-dimethylamino group, R 23 is a hydrogen atom, a methoxy group, or an isopropoxy group, R 24 is a hydrogen atom, The method described in (A9). (A11) The method according to (A10), wherein the palladium catalyst is a combination of at least one selected from the group consisting of bis(allylchloropalladium), tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, and palladium(II) acetate, and at least one selected from the group consisting of 2',6'-dimethoxy-2-(dicyclohexylphosphino)biphenyl, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl. (A12) The method according to (A11), wherein the palladium catalyst is a combination of bis(allylchloropalladium) and at least one selected from the group consisting of 2',6'-dimethoxy-2-(dicyclohexylphosphino)biphenyl, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl. (A13) The method according to (A8), wherein the palladium catalyst is a compound represented by the following general formula (L2): [ka] [In the formula, R 20 and R 21 are each independently a C3-6 cycloalkyl group, R 22 is a C1-6 alkoxy group or an amino group (the amino group may be substituted with a C1-6 alkyl group or an aryl group), R 23 is a hydrogen atom or a C1-6 alkoxy group, R 24 is a hydrogen atom, R 25 is a hydrogen atom or a C1-6 alkyl group, R 26 is a C1-6 alkyl group, The arrows represent coordinate bonds.] (A14) R 20 and R 21 is a cyclohexyl group, R 22 is a methoxy group, an isopropoxy group, or an N,N-dimethylamino group, R 23 is a hydrogen atom, a methoxy group, or an isopropoxy group, R 25 is a hydrogen atom or a methyl group, R 26 is a methyl group, The method described in (A13). (A15) The palladium catalyst is (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, 2-Dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate, and (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate The method according to (A14), wherein the compound is at least one selected from the group consisting of: (A16) The method according to (A15), wherein the palladium catalyst is (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate.

[0016] (A17) The method according to (A7), wherein the catalyst used in step (II) is a nickel catalyst. (A18) The method according to (A17), wherein the nickel catalyst is a combination of at least one selected from the group consisting of bis(1,5-cyclooctadiene)nickel and nickel(II) chloride, and at least one selected from the group consisting of tricyclohexylphosphine, 1,1′-bis(diphenylphosphino)ferrocene, and 1,3-bis(diphenylphosphino)propane. (A19) The nickel catalyst is Dichlorobis(tricyclohexylphosphine)nickel(II), Dichloro[1,1'-bis(diphenylphosphino)ferrocene]nickel(II), and Dichloro[1,3-bis(diphenylphosphino)propane]nickel(II) The method according to (A17), wherein the compound is at least one selected from the group consisting of:

[0017] (A20) The catalyst used in step (II) is A combination of bis(allylchloropalladium) and 2',6'-dimethoxy-2-(dicyclohexylphosphino)biphenyl, A combination of bis(allylchloropalladium) and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, A combination of bis(allylchloropalladium) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, 2-Dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate, and (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate The method according to (A6), wherein the compound is at least one selected from the group consisting of: (A21) The method according to (A20), wherein the catalyst used in step (II) is (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate.

[0018] (A22) The method according to any one of (A6) to (A21), wherein the solvent used in step (II) contains a C1-6 alcohol. (A23) The method according to (A22), wherein the solvent used in step (II) comprises a C2-3 alcohol. (A24) The method according to (A23), wherein the solvent used in step (II) comprises ethanol.

[0019] (A25) (III) The compound represented by the general formula (5) is X2-S(=O)2-NH-R 11 or X2-S(=O)2-R 11 to obtain a compound represented by general formula (1) or a salt thereof, or a solvate of said compound or salt. The method according to any one of (A6) to (A24), further comprising: [Wherein X2 is a halogen atom, R 11 has the same meaning as above.]

[0020] (A26) R9 is -C(=O)-OR 12 and R 12 is a C1-6 alkyl group or an aryl group, The method according to any one of (A1) to (A25). (A27) The method according to (A26), wherein R2 is a halogen atom. (A28) R2 is a fluorine atom, R9 is —C(═O)—O—CH3; X1 is a chlorine atom; The method described in (A27). (A29) R2 is a fluorine atom, R1 is -S(=O)2-NH-R 11 and R 11 is a C1-4 alkyl group, R3 is a hydrogen atom or a cyclopropyl group; R5 is a fluorine atom, R6 is a hydrogen atom, R4 is an iodine atom or a cyclopropyl group; R7 is a fluorine atom, R8 is a fluorine atom, X1 is a chlorine atom; The method according to any one of (A1) to (A28).

[0021] (A30) The method according to any one of (A1) to (A29), wherein the compound represented by general formula (1) is 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide.

[0022] (A31) The method according to any one of (A1) to (A30), which is a method for producing a sodium salt of a compound represented by general formula (1).

[0023] The present disclosure provides the following methods (B1) to (B26). (B1) A method for producing a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, comprising: (II) A step of reacting a compound represented by the following general formula (4) with a compound represented by the following general formula (10) in a solvent in the presence of a catalyst to obtain a compound represented by the following general formula (5): A method comprising: [ka] [ka] [ka] [In the formula, R1 is -S(=O)2-NH-R 11 or -S(=O)2-R 11 and R 11 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), or a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), R2 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group; R3 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group, or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group), or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a halogen atom, a hydroxy group, or a C1-6 alkoxy group), R4 is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-7 alkenyl group, a C2-7 alkynyl group, a C3-6 cycloalkyl group, or a C1-6 alkylthio group; R5 is a halogen atom or a C1-6 alkyl group; R6 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group; R7 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group; R8 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group; R9 is -C(=O)-R 12 , -C(=O)-OR 12 Or -P(=O)(-OR 12 )2, R 12 is a C1-6 alkyl group or an aryl group, R 13 is -B(-OR 14 )(-OR 15 ) or -BF3K, R 14 and R 15 are each independently a hydrogen atom or a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a C1-6 alkoxy group or an aryl group), or R 14 and R 15 forms, together with the intervening oxygen atom and boron atom, a 5- to 8-membered saturated or unsaturated ring (the ring may be substituted with a C1-6 alkyl group, a C1-6 alkoxy group or an aryl group, and may be condensed with a benzene ring).

[0024] (B2) The method according to (B1), wherein the catalyst used in step (II) is a palladium catalyst or a nickel catalyst.

[0025] (B3) The method according to (B2), wherein the catalyst used in step (II) is a palladium catalyst. (B4) The method according to (B3), wherein the palladium catalyst is a combination of at least one selected from the group consisting of bis(allylchloropalladium), tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, and palladium(II) acetate, and a compound represented by the following general formula (L1): [ka] [In the formula, R 20 and R 21 are each independently a C3-6 cycloalkyl group, R 22 is a C1-6 alkoxy group or an amino group (the amino group may be substituted with a C1-6 alkyl group or an aryl group), R 23 is a hydrogen atom or a C1-6 alkoxy group, R 24 is a hydrogen atom or -S(=O)2-O-Na. (B5) R 20 and R 21 is a cyclohexyl group, R 22 is a methoxy group, an isopropoxy group, or an N,N-dimethylamino group, R 23 is a hydrogen atom, a methoxy group, or an isopropoxy group, R 24 is a hydrogen atom, The method according to (B4). (B6) The method according to (B5), wherein the palladium catalyst is a combination of at least one selected from the group consisting of bis(allylchloropalladium), tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, and palladium(II) acetate, and at least one selected from the group consisting of 2',6'-dimethoxy-2-(dicyclohexylphosphino)biphenyl, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl. (B7) The method according to (B6), wherein the palladium catalyst is a combination of bis(allylchloropalladium) and at least one selected from the group consisting of 2',6'-dimethoxy-2-(dicyclohexylphosphino)biphenyl, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl. (B8) The method according to (B3), wherein the palladium catalyst is a compound represented by the following general formula (L2): [ka] [In the formula, R 20 and R 21 are each independently a C3-6 cycloalkyl group, R 22 is a C1-6 alkoxy group or an amino group (the amino group may be substituted with a C1-6 alkyl group or an aryl group), R 23 is a hydrogen atom or a C1-6 alkoxy group, R 24 is a hydrogen atom, R 25 is a hydrogen atom or a C1-6 alkyl group, R 26 is a C1-6 alkyl group, The arrows represent coordinate bonds.] (B9) R 20 and R 21 is a cyclohexyl group, R 22 is a methoxy group, an isopropoxy group, or an N,N-dimethylamino group, R 23 is a hydrogen atom, a methoxy group, or an isopropoxy group, R 25 is a hydrogen atom or a methyl group, R 26 is a methyl group, The method according to (B8). (B10) The palladium catalyst is (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, 2-Dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate, and (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate The method according to (B9), wherein the compound is at least one selected from the group consisting of: (B11) The method according to (B10), wherein the palladium catalyst is (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate.

[0026] (B12) The method according to (B2), wherein the catalyst used in step (II) is a nickel catalyst. (B13) The method according to (B12), wherein the nickel catalyst is a combination of at least one selected from the group consisting of bis(1,5-cyclooctadiene)nickel and nickel(II) chloride, and at least one selected from the group consisting of tricyclohexylphosphine, 1,1′-bis(diphenylphosphino)ferrocene, and 1,3-bis(diphenylphosphino)propane. (B14) The nickel catalyst is Dichlorobis(tricyclohexylphosphine)nickel(II), Dichloro[1,1'-bis(diphenylphosphino)ferrocene]nickel(II), and Dichloro[1,3-bis(diphenylphosphino)propane]nickel(II) The method according to (B12), wherein the compound is at least one selected from the group consisting of:

[0027] (B15) The catalyst used in step (II) is A combination of bis(allylchloropalladium) and 2',6'-dimethoxy-2-(dicyclohexylphosphino)biphenyl, A combination of bis(allylchloropalladium) and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, A combination of bis(allylchloropalladium) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, 2-Dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate, and (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate The method according to (B1), wherein the compound is at least one selected from the group consisting of: (B16) The method according to (B15), wherein the catalyst used in step (II) is (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate.

[0028] (B17) The method according to any one of (B1) to (B16), wherein the solvent used in step (II) contains a C1-6 alcohol. (B18) The method according to (B17), wherein the solvent used in step (II) contains a C2-3 alcohol. (B19) The method according to (B18), wherein the solvent used in step (II) comprises ethanol.

[0029] (B20) (III) The compound represented by the general formula (5) is X2-S(=O)2-NH-R 11 or X2-S(=O)2-R 11 to obtain a compound represented by general formula (1) or a salt thereof, or a solvate of said compound or salt. The method according to any one of (B1) to (B19), further comprising: [Wherein X2 is a halogen atom, R 11 has the same meaning as above.]

[0030] (B21) R9 is -C(=O)-OR 12 and R 12 is a C1-6 alkyl group or an aryl group, The method according to any one of (B1) to (B20). (B22) The method according to (B21), wherein R2 is a halogen atom. (B23) R2 is a fluorine atom, R9 is —C(═O)—O—CH3; The method according to (B22). (B24) R2 is a fluorine atom, R1 is -S(=O)2-NH-R 11 and R 11 is a C1-4 alkyl group, R3 is a hydrogen atom or a cyclopropyl group; R5 is a fluorine atom, R6 is a hydrogen atom, R4 is an iodine atom or a cyclopropyl group; R7 is a fluorine atom, R8 is a fluorine atom; The method according to any one of (B1) to (B23).

[0031] (B25) The method according to any one of (B1) to (B24), wherein the compound represented by general formula (1) is 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide.

[0032] (B26) The method according to any one of (B1) to (B25), which is a method for producing a sodium salt of a compound represented by general formula (1).

[0033] The compound of general formula (5) can be obtained using a compound with a protected amino group, as described in Synthesis Example 4(4-2) below, but such a method requires deprotection of the amino group. In contrast, the methods described in (A1) to (A31) and (B1) to (B26) above make it possible to obtain the compound of general formula (5) using a compound with an unprotected amino group in its unprotected state, thereby enabling the arylamide derivative of general formula (1) to be obtained in a correspondingly fewer steps.

[0034] The invention provided by the present disclosure includes, for example, the method described in (C1) below. (C1) The method according to (A31) or (B26), which is a method for producing the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide, The method, wherein a compound represented by the following formula (X) or a sodium salt thereof is produced, and the amount of the compound of formula (X) or a sodium salt thereof produced is 3.0 w / w% or less, 2.0 w / w% or less, 1.0 w / w% or less, 0.8 w / w% or less, 0.5 w / w% or less, or 0.3 w / w% or less, based on the weight of the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide produced: [ka]

[0035] The invention provided by the present disclosure also includes, for example, the composition described in (D1) below. (D1) A composition comprising sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide and a compound represented by the following formula (X) or a sodium salt thereof, wherein the amount of the compound of formula (X) or a sodium salt thereof contained in the composition is 3.0 w / w% or less, 2.0 w / w% or less, 1.0 w / w% or less, 0.8 w / w% or less, 0.5 w / w% or less, or 0.3 w / w% or less, based on the weight of the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide contained in the composition. [ka]

[0036] The invention provided by the present disclosure also includes, for example, the methods described in (E1) to (E7) below. (E1) A method for producing a compound represented by the following general formula (4): (I) A step of reacting a compound represented by the following general formula (2) with a compound represented by X1-R9 and a base in a solvent to obtain a compound represented by the general formula (4): A method comprising: [ka] [In the formula, R2 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group; X1 is a halogen atom or —O—R9, R9 is -C(=O)-R 12 , -C(=O)-OR 12 Or -P(=O)(-OR 12 )2, R 12 is a C1-6 alkyl group or an aryl group.]

[0037] (E2) The method according to (E1), wherein the base used in step (I) is at least one selected from the group consisting of N,N-dimethylaminopyridine and 1-methylimidazole. (E3) The method according to (E2), wherein the base used in step (I) is N,N-dimethylaminopyridine.

[0038] (E4) The method according to any one of (E1) to (E3), wherein the solvent used in step (I) is at least one selected from the group consisting of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, cyclopentyl methyl ether, and tert-butyl methyl ether. (E5) The method according to (E4), wherein the solvent used in step (I) is acetonitrile.

[0039] (E6) R9 is -C(=O)-OR 12 and R 12 is a C1-6 alkyl group or an aryl group, The method according to any one of (E1) to (E5). (E7) The method according to (E6), wherein R2 is a halogen atom. (E8) R2 is a fluorine atom, R9 is —C(═O)—O—CH3; X1 is a chlorine atom; The method described in (E7).

[0040] The invention provided by the present disclosure also includes, for example, compounds described in (F1) below. (F1) (2-amino-3-fluoropyridin-4-yl)methyl methyl carbonate. [Effects of the Invention]

[0041] The present disclosure provides a method for producing a specific arylamide derivative that has RAF / MEK complex-stabilizing activity and / or MEK inhibitory activity and is useful for treating or preventing cell proliferative diseases, particularly cancer, which method enables the production of an arylamide derivative with a reduced number of steps. [Brief explanation of the drawings]

[0042] [Figure 1] FIG. 1 shows the powder X-ray diffraction pattern of Sample 1a (Form I). [Figure 2] FIG. 2 shows the powder X-ray diffraction pattern of Sample 1b (Form I). [Figure 3] FIG. 3 shows the powder X-ray diffraction pattern of Sample 1c. [Figure 4]Figure 4 is a sensorgram showing the time course of the amount of MEK1 binding added to the surface of a sensor chip on which RAF1 was immobilized, together with a test compound (ref-2, ref-3, ref-4, A-1, ref-1, ref-5 or B-1). [Figure 5] Figure 5 is a sensorgram showing the time course of the amount of MEK1 binding added to the surface of a sensor chip on which RAF1 was immobilized, together with a test compound (A-2, A-25, J-1, E-1, M-1, N-1 or H-3). [Figure 6] Figure 6 is a sensorgram showing the time course of the amount of MEK1 bound to the surface of a sensor chip on which RAF1 was immobilized, when the test compound (I-1, H-4, L-1, P-1, E-7, or A-27) was added. [Figure 7] Figure 7 is a sensorgram showing the time course of the amount of MEK1 bound to the surface of a sensor chip on which RAF1 was immobilized, when the surface was added with a test compound (A-33, A-18, N-2, A-20, A-8, E-13, or H-1). [Figure 8] Figure 8 is an electrophoretic image showing the results of Western blotting of proteins (p-MEK, MEK, p-ERK, and ERK) extracted from A549 cells cultured in the presence of a test compound (ref-5 or compound A-1). [Figure 9] FIG. 9 is a graph showing the change over time in tumor volume (mean±standard deviation) in nude mice subcutaneously implanted with the human lung cancer cell line Calu-6. DETAILED DESCRIPTION OF THE INVENTION

[0043] Exemplary embodiments of the present disclosure will now be described.

[0044] In the present disclosure, a halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0045] In the present disclosure, a C1-6 alkyl group refers to a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms. Examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, a 1-methylpropyl group, an n-pentyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 3-methylbutyl group, a 1,1-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1,2-dimethylpropyl group, a 1-ethylpropyl group, an n-hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a 2,3-dimethylbutyl group, a 3,3-dimethylbutyl group, a 1-ethylbutyl group, and a 2-ethylbutyl group.

[0046] In the present disclosure, a C2-7 alkenyl group refers to a linear or branched alkenyl group having 2 to 7 carbon atoms. Examples include a vinyl group, an allyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a pentenyl group, a pentadienyl group, a hexenyl group, a hexadienyl group, a heptenyl group, a heptadienyl group, and a heptatrienyl group.

[0047] In the present disclosure, a C2-7 alkynyl group refers to a straight-chain or branched-chain alkynyl group having 2 to 7 carbon atoms. Examples include an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 3-butynyl group, a pentynyl group, a pentadiynyl group, a hexynyl group, a hexadiynyl group, a heptynyl group, a heptadiynyl group, and a heptatriynyl group.

[0048] In the present disclosure, a C1-6 alkoxy group refers to an alkyloxy group having a linear or branched alkyl group having 1 to 6 carbon atoms. Examples include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentoxy group, and an n-hexoxy group.

[0049] In the present disclosure, a C1-6 alkylthio group refers to an alkylthio group having a straight or branched alkyl group having 1 to 6 carbon atoms. Examples include a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, a sec-butylthio group, a tert-butylthio group, an n-pentylthio group, and an n-hexylthio group.

[0050] In the present disclosure, a C3-6 cycloalkyl group refers to a monocyclic cyclic alkyl group having 3 to 6 atoms constituting the ring, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

[0051] In the present disclosure, an aryl group refers to an aromatic hydrocarbon group having 6 to 10 carbon atoms, such as a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.

[0052] In the present disclosure, examples of pharmaceutically acceptable salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate; sulfonates such as methanesulfonate, benzenesulfonate, and toluenesulfonate; carboxylates such as formate, acetate, oxalate, maleate, fumarate, citrate, malate, succinate, malonate, gluconate, mandelate, benzoate, salicylate, fluoroacetate, trifluoroacetate, tartrate, propionate, and glutarate; alkali metal salts such as lithium salt, sodium salt, potassium salt, cesium salt, and rubidium salt; alkaline earth metal salts such as magnesium salt and calcium salt; and ammonium salts such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, and tetraalkylammonium salt. Among these, alkali metal salts such as lithium salt, sodium salt, potassium salt, cesium salt, and rubidium salt are preferred, and sodium salt and potassium salt are more preferred.

[0053] In the present disclosure, a pharmaceutically acceptable solvate is, for example, a solvate with water, an alcohol (e.g., methanol, ethanol, 1-propanol, or 2-propanol), acetone, dimethylformamide, or dimethylacetamide. The solvate may be with a single solvent or with multiple solvents. Preferred solvates include, for example, hydrates.

[0054] A first aspect of the present disclosure provides a method for producing a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt, the method comprising the following step (I): A second aspect of the present disclosure provides a method for producing a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt, the method comprising the following step (II): [ka] [In the formula, R1 is -S(=O)2-NH-R 11 or -S(=O)2-R 11 and R 11 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), or a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), R2 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group; R3 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group, or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group), or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a halogen atom, a hydroxy group, or a C1-6 alkoxy group), R4 is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-7 alkenyl group, a C2-7 alkynyl group, a C3-6 cycloalkyl group, or a C1-6 alkylthio group; R5 is a halogen atom or a C1-6 alkyl group; R6 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group; R7 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group; R8 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group.]

[0055] In a preferred embodiment, the method of the first aspect of the present disclosure further comprises the following step (II): In a preferred embodiment, the method of the first aspect of the present disclosure further comprises the following steps (II) and (III). In one preferred embodiment, the method according to the second aspect of the present disclosure further comprises the following step (III):

[0056] A third aspect of the present disclosure provides a method for producing a compound represented by the following general formula (4), the method comprising the following step (I):

[0057] Process (I): A step of reacting a compound represented by the following general formula (2) with a compound represented by X1-R9 and a base in a solvent to obtain a compound represented by the following general formula (4): [ka] [In the formula, R2 has the same meaning as above, X1 is a halogen atom or —O—R9, R9 is -C(=O)-R 12 , -C(=O)-OR 12 Or -P(=O)(-OR 12 )2, R 12 is a C1-6 alkyl group or an aryl group.]

[0058] Process (II): A step of reacting a compound represented by general formula (4) with a compound represented by the following general formula (10) in a solvent in the presence of a catalyst to obtain a compound represented by the following general formula (5): [ka] [ka] [In the formula, R 13 is -B(-OR 14 )(-OR 15 ) or -BF3K, R 14 and R 15 are each independently a hydrogen atom or a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a C1-6 alkoxy group or an aryl group), or R 14 and R 15 forms a 5- to 8-membered saturated or unsaturated ring together with the intervening oxygen atom and boron atom (the ring may be substituted with a C1-6 alkyl group, a C1-6 alkoxy group or an aryl group, and may be condensed with a benzene ring), R2 to R9 have the same meanings as above.]

[0059] Process (III): The compound represented by general formula (5) is X2-S(=O)2-NH-R 11 or X2-S(=O)2-R 11 to obtain a compound represented by general formula (1) or a salt thereof, or a solvate of said compound or salt. [Wherein X2 is a halogen atom, R 11 has the same meaning as above.]

[0060] R1 is preferably -S(=O)2-NH-R 11 is. R 11is preferably a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom or a C1-6 alkoxy group) or a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), more preferably a C1-4 alkyl group (the C1-4 alkyl group may be substituted with a fluorine atom or a C1-4 alkoxy group) or a cyclopropyl group (the cyclopropyl group may be substituted with a C1-4 alkyl group), and even more preferably a C1-4 alkyl group. R2 is preferably a hydrogen atom or a halogen atom, more preferably a halogen atom, and even more preferably a fluorine atom. R3 is preferably a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxy group), more preferably a hydrogen atom, a C1-4 alkyl group, a cyclopropyl group or a C1-4 alkoxy group (the C1-4 alkoxy group may be substituted with a hydroxy group), and even more preferably a hydrogen atom or a cyclopropyl group. R4 is preferably a halogen atom or a cyclopropyl group, more preferably an iodine atom or a cyclopropyl group. R5 is preferably a halogen atom, more preferably a fluorine atom. R6 is preferably a hydrogen atom. R7 is preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, and even more preferably a fluorine atom. R8 is preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, and even more preferably a fluorine atom. X1 is preferably a halogen atom, more preferably a chlorine atom. R9 is preferably -C(=O)-OR 12 (where R 12 is a C1-6 alkyl group or an aryl group.) and more preferably -C(=O)-O-CH3.

[0061] An example of the compound of general formula (1) is 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide.

[0062] An example of the compound of general formula (4) is (2-amino-3-fluoropyridin-4-yl)methyl methyl carbonate.

[0063] An example of the compound of general formula (2) is (2-amino-3-fluoropyridin-4-yl)methanol. For example, (2-amino-3-fluoropyridin-4-yl)methanol is available as a commercially available reagent.

[0064] Examples of the compound X1-R9 include methyl chloroformate, ethyl chloroformate, acetic anhydride, acetyl chloride, dimethyl chlorophosphate, diethyl chlorophosphate, and diphenyl chlorophosphate. Preferably, the compound is at least one selected from the group consisting of methyl chloroformate and ethyl chloroformate, and more preferably methyl chloroformate. For example, methyl chloroformate is available as a commercially available reagent.

[0065] Examples of the base used in step (I) include triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, imidazole, pyridine, N,N-dimethylaminopyridine, 2,6-dimethylpyridine, 1-methylimidazole, and 1,8-diazabicyclo[5.4.0]undec-7-ene. Preferably, the base is at least one selected from the group consisting of N,N-dimethylaminopyridine and 1-methylimidazole, and more preferably, N,N-dimethylaminopyridine.

[0066] Examples of the solvent used in step (I) include acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, acetonitrile, N,N-dimethylacetamide, N,N-dimethylformamide, N,N-dimethylimidazolidinone, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, cyclopentyl methyl ether, tert-butyl methyl ether, toluene, xylene, heptane, and cyclohexane. Preferably, the solvent is at least one selected from the group consisting of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, cyclopentyl methyl ether, and tert-butyl methyl ether, and more preferably, acetonitrile.

[0067] The reaction in step (I) can be carried out by stirring the reaction mixture at an appropriate temperature (for example, 0° C. to 40° C.) for a certain period of time (for example, 0.5 hours to 24 hours).

[0068] After completion of the reaction in step (I), the mixture may be directly subjected to the next step, or may be subjected to the next step after, for example, isolation or purification.

[0069] R 13 is preferably a group of the following formula (a), a group of the following formula (b), -B(-OH)2, or -BF3K, and more preferably a group of the following formula (a). [ka]

[0070] An example of the compound of general formula (10) is 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzamide.

[0071] An example of the compound of general formula (5) is 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide.

[0072] The catalyst used in step (II) includes, for example, a palladium catalyst or a nickel catalyst.

[0073] Examples of the palladium catalyst include a combination of at least one selected from the group consisting of bis(allylchloropalladium), tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, and palladium(II) acetate, and a compound represented by the following general formula (L1): [ka] [In the formula, R 20 and R 21 are each independently a C3-6 cycloalkyl group, R 22 is a C1-6 alkoxy group or an amino group (the amino group may be substituted with a C1-6 alkyl group or an aryl group), R 23 is a hydrogen atom or a C1-6 alkoxy group, R 24 is a hydrogen atom or -S(=O)2-O-Na.

[0074] The palladium catalyst also includes, for example, a compound represented by the following general formula (L2). [ka] [In the formula, R 20 and R 21 are each independently a C3-6 cycloalkyl group, R 22is a C1-6 alkoxy group or an amino group (the amino group may be substituted with a C1-6 alkyl group or an aryl group), R 23 is a hydrogen atom or a C1-6 alkoxy group, R 24 is a hydrogen atom, R 25 is a hydrogen atom or a C1-6 alkyl group, R 26 is a C1-6 alkyl group, The arrows represent coordinate bonds.]

[0075] R 20 and R 21 is preferably a cyclohexyl group. R 22 is preferably a methoxy group, an isopropoxy group or an N,N-dimethylamino group. R 23 is preferably a hydrogen atom, a methoxy group or an isopropoxy group. R 24 is preferably a hydrogen atom. R 25 is preferably a hydrogen atom or a methyl group. R 26 is preferably a methyl group.

[0076] The compound represented by general formula (L1) is preferably at least one selected from the group consisting of, for example, 2',6'-dimethoxy-2-(dicyclohexylphosphino)biphenyl, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl.

[0077] The compound represented by general formula (L2) is preferably, for example, (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, 2-Dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate, and (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate At least one selected from the group consisting of, more preferably, (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate is.

[0078] Examples of nickel catalysts include a combination of at least one selected from the group consisting of bis(1,5-cyclooctadiene)nickel and nickel(II) chloride, and at least one selected from the group consisting of tricyclohexylphosphine, 1,1′-bis(diphenylphosphino)ferrocene, and 1,3-bis(diphenylphosphino)propane.

[0079] Nickel catalysts also include, for example: Dichlorobis(tricyclohexylphosphine)nickel(II), Dichloro[1,1'-bis(diphenylphosphino)ferrocene]nickel(II), and Dichloro[1,3-bis(diphenylphosphino)propane]nickel(II) At least one selected from the group consisting of:

[0080] The catalyst used in step (II) is preferably, for example, A combination of bis(allylchloropalladium) and 2',6'-dimethoxy-2-(dicyclohexylphosphino)biphenyl, A combination of bis(allylchloropalladium) and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, A combination of bis(allylchloropalladium) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, 2-Dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate, and (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate and more preferably, at least one selected from the group consisting of (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate is.

[0081] When a combination of two or more compounds is used as the catalyst, they may, for example, form a complex in the solvent.

[0082] The solvent used in step (II) can be, for example, a C1-6 alcohol, preferably a C2-3 alcohol, more preferably ethanol.

[0083] The reaction in step (II) can be carried out by stirring the reaction mixture at an appropriate temperature (for example, 40° C. to 90° C.) for a certain period of time (for example, 0.5 hours to 24 hours).

[0084] After completion of the reaction in step (II), the mixture may be directly subjected to the next step, or may be subjected to the next step after, for example, isolation or purification.

[0085] The compound (X2-S(=O)2-NH-R) to be reacted with the compound of general formula (5) in step (III) 11 or X2-S(=O)2-R 11 ) is preferably X2-S(=O)2-NH-R 11 and more preferably N-methylsulfamoyl chloride.

[0086] Examples of the solvent used in step (III) include acetonitrile, N,N-dimethylacetamide, N,N-dimethylformamide, N,N-dimethylimidazolidinone, N,N-dimethylpropyleneurea, tetramethylurea, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, pyridine, dichloromethane, and a mixed solvent thereof. Preferred examples include N,N-dimethylacetamide, N,N-dimethylimidazolidinone, tetrahydrofuran, 2-methyltetrahydrofuran, and a mixed solvent thereof, and more preferred examples include a mixed solvent of N,N-dimethylimidazolidinone and tetrahydrofuran.

[0087] When producing, for example, a sodium salt in step (III), examples of the solvent used for producing the sodium salt include acetone, acetonitrile, methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, and mixed solvents thereof. Preferred are, for example, acetone, tetrahydrofuran, or mixed solvents thereof.

[0088] In the case of producing, for example, a sodium salt in step (III), examples of the solvent used to precipitate the sodium salt as crystals include acetone, acetonitrile, methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, cyclopentyl methyl ether, tert-butyl methyl ether, toluene, xylene, heptane, and mixed solvents thereof. Preferred are, for example, acetone, tetrahydrofuran, tert-butyl methyl ether, heptane, or mixed solvents thereof, and more preferred is, for example, a mixed solvent of acetone, tetrahydrofuran, and tert-butyl methyl ether.

[0089] The reaction in step (III) can be carried out by stirring the reaction mixture at an appropriate temperature (for example, −10° C. to 30° C.) for a certain period of time (for example, 0.5 hours to 24 hours).

[0090] When the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide is produced by the method of the first or second aspect, a compound represented by the following formula (X) or its sodium salt can be produced. [ka]

[0091] That is, in one aspect, the present disclosure provides a compound represented by formula (X) or a sodium salt thereof.

[0092] In one aspect, the present disclosure provides a composition comprising the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide and a compound represented by Formula (X) or a sodium salt thereof.

[0093] In one embodiment, the composition is a pharmaceutical composition, preferably a pharmaceutical composition containing the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide as an active ingredient.

[0094] In one embodiment, the pharmaceutical composition is for treating or preventing a cell proliferative disorder, particularly cancer.

[0095] When the compound of formula (X) or its sodium salt is produced, the amount of the compound of formula (X) or its sodium salt produced is small, for example, 3.0 w / w% or less, 2.0 w / w% or less, 1.0 w / w% or less, 0.8 w / w% or less, 0.5 w / w% or less, or 0.3 w / w% or less, based on the weight of the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide produced.

[0096] That is, the amount of the compound of formula (X) or its sodium salt contained in the composition is, for example, 3.0 w / w% or less, 2.0 w / w% or less, 1.0 w / w% or less, 0.8 w / w% or less, 0.5 w / w% or less, or 0.3 w / w% or less, relative to the weight of the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide contained in the composition.

[0097] The amount of the compound of formula (X) or its sodium salt in the composition can be measured, for example, by HPLC analysis. Examples of HPLC analysis conditions include analysis condition C shown in Table 1 below.

[0098] When the amount of the compound of formula (X) or its sodium salt contained in the above composition is measured by HPLC analysis, the peak area of ​​the compound of formula (X) is, for example, 3.0% or less, 2.0% or less, 1.0% or less, 0.8% or less, 0.5% or less, or 0.3% or less relative to the sum of the peak areas of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide, the compound of formula (X), and other decomposition products of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide.

[0099] In carrying out the invention of the present disclosure, seed crystals of a certain compound or its salt may be used. Generally, seed crystals can be obtained by methods well known to those skilled in the art, such as cooling a solution of the compound or salt, adding a solvent (antisolvent) in which the compound or salt has low solubility, scraping the wall of a container containing a solution of the compound or salt with a spatula, or purifying the compound or salt by silica gel column chromatography and then concentrating the solution of the compound or salt under reduced pressure.

[0100] Examples of abbreviations used in this specification are listed below along with their meanings. AA: Ammonium acetate tAmOH: tert-amyl alcohol Boc: tert-butoxycarbonyl tBuOH: tert-butanol 2-BuOH: 2-butanol tBuXPhos: 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl tBuDavePhos: 2-di-tert-butylphosphino-2'-(N,N-dimethylamino)biphenyl COMU: (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate CPME: Cyclopentyl methyl ether CyJohnPhos: 2-(dicyclohexylphosphino)biphenyl DavePhos: 2-Dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl DBU: Diazabicycloundecene DCC: N,N'-dicyclohexylcarbodiimide DCM: dichloromethane DIPEA: N,N-diisopropylethylamine DMA: N,N-dimethylacetamide DMAP: N,N-dimethylaminopyridine DMF: N,N-dimethylformamide DMI: 1,3-dimethyl-2-imidazolidinone DMSO: dimethyl sulfoxide EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EDC·HCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EtOH: Ethanol FA: Formic acid HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HOAt: 1-hydroxy-7-azabenzotriazole HOOBt: 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine IPA: Isopropanol JohnPhos: (2-biphenyl)di-tert-butylphosphine LDA: lithium diisopropylamide 2-MeTHF: 2-methyltetrahydrofuran MTHP: 4-methyltetrahydropyran MeCN: acetonitrile MeOH: Methanol MePhos: 2-dicyclohexylphosphino-2'-methylbiphenyl NMP: N-methyl-2-pyrrolidone 1-PrOH: 1-propanol [PdCl(allyl)]2: Bis(allylchloropalladium) RuPhos: 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl RuPhos-Pd-G3: (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate SPhos: 2',6'-dimethoxy-2-(dicyclohexylphosphino)biphenyl TBME: tert-butyl methyl ether TBS: tert-butyldimethylsilyl TFA: trifluoroacetic acid THF: tetrahydrofuran Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene XPhos-Pd-G3: (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0101] In this specification, "room temperature" means a temperature of about 20°C to about 25°C. [Example]

[0102] The present disclosure will be described in more detail below based on examples, but the present disclosure is not limited to the following examples.

[0103] [Synthesis example] In the following synthesis examples, high performance liquid chromatography (HPLC) analysis was performed using one of the analytical conditions listed in Table 1. Each compound was detected using a photodiode array detector or a mass spectrometer, but other techniques such as evaporative light scattering detection may also be used. [Table 1-1] [Table 1-2]

[0104] NMR was measured using a nuclear magnetic resonance spectrometer JNM-ECZ500R (manufactured by JEOL). NMR data are shown in ppm (parts per million) (δ) and referenced to the deuterium lock signal from the sample solvent.

[0105] Commercially available reagents were used without further purification. All non-aqueous reactions were carried out in anhydrous solvents. Concentration under reduced pressure or solvent distillation was carried out using a rotary evaporator.

[0106] (Synthesis Example 1) Synthesis of (2-amino-3-fluoropyridin-4-yl)methyl methyl carbonate (compound 4A) [ka] (1-1) Synthesis of (2-amino-3-fluoropyridin-4-yl)methyl methyl carbonate (compound 4A) (2-Amino-3-fluoropyridin-4-yl)methanol (Compound 2A) (30.0 g, 211 mmol) and DMAP (28.4 g, 232 mmol) were added to a reaction vessel, followed by nitrogen substitution. MeCN (885 mL) was added, and after confirming the homogenization of the reaction solution, methyl chloroformate (Compound 3A) (16.2 mL, 211 mmol) was added dropwise over 1 hour. MeCN (15 mL) was added, and the mixture was stirred at 25°C for 2 hours. The solvent was evaporated under reduced pressure at 40°C until the solution volume reached 90 mL, after which isopropyl acetate (900 mL) was added. This solution was washed once with 15% aqueous sodium chloride solution (300 mL), once with 15% aqueous ammonium chloride solution (300 mL), and twice with water (150 mL). The solvent was evaporated under reduced pressure at 40°C until the solution volume reached 90 mL. Toluene (300 mL) was added to the resulting solution, and the solvent was distilled off under reduced pressure at 40°C until the volume of the solution reached 90 mL. Toluene (300 mL) was added again, and the solvent was distilled off under reduced pressure at 40°C until the volume of the solution reached 90 mL. Further toluene (30 mL) was added, and the internal temperature of the solution was raised to 60°C to dissolve the precipitated solid, and then the temperature was lowered to 40°C over 30 minutes. Seed crystals (75 mg) obtained in (1-2) below were added, and the solution was stirred for 30 minutes. The internal temperature of the solution was then lowered to 25°C over 30 minutes and stirred for 30 minutes. Heptane (60 mL) was added over 30 minutes, and the mixture was stirred for 30 minutes. Heptane (60 mL) was added again over 30 minutes, and the mixture was stirred for 1 hour and 30 minutes. Heptane (120 mL) was added over 30 minutes, and the mixture was stirred for 30 minutes. The precipitated solid was collected by filtration, washed with a mixed solvent of heptane (45 mL) and toluene (15 mL), and then dried under reduced pressure to obtain Compound 4A (35.1 g, yield 83%). HPLC purity: 98.86% (Analysis conditions A) 1 H-NMR(DMSO-d6) δ: 7.69(1H,d,J=5.2Hz),6.47(1H,t,J=4.9Hz),6.26(2H,s),5.15(2H,s),3.73(3H,s). MS(ESI + ) m / z: 201[M+H] +

[0107] (1-2) Synthesis of seed crystals of (2-amino-3-fluoropyridin-4-yl)methyl methyl carbonate (compound 4A) Under a nitrogen atmosphere, (2-amino-3-fluoropyridin-4-yl)methanol (Compound 2A) (10.0 g, 70.4 mmol) and DMAP (12.9 g, 106 mmol) were added to a reaction vessel, followed by nitrogen substitution. MeCN (300 mL) was added, and the mixture was stirred to obtain a homogeneous solution. To the resulting solution, methyl chloroformate (Compound 3A) (5.4 mL, 70 mmol) was added dropwise over 1 hour at an external temperature of 25°C. The resulting reaction solution was stirred for 3 hours and then concentrated under reduced pressure. 2-MeTHF (100 mL) was added to the concentrated residue, followed by concentration under reduced pressure. 2-MeTHF (100 mL) was added to the residue, followed by further concentration under reduced pressure. 2-MeTHF (50 mL) was added to the concentrated residue, and the precipitated solid was filtered off. The filter cake was then washed with 2-MeTHF (30 mL) (the resulting washing solution is referred to as washing solution 1). The remaining cake was washed again with 2-MeTHF (100 mL) (the resulting wash solution is referred to as wash solution 2). The filtrate and wash solution 1 were combined and concentrated under reduced pressure to a total volume of 25 mL. 2-MeTHF (5 mL) was then added and the mixture was heated and stirred at an external temperature of 40 °C to obtain a homogeneous solution. Heptane (30 mL) was added to this solution over 1 hour and then cooled to an external temperature of 35 °C. Heptane (30 mL) was added again to the resulting mixture over 1 hour and the mixture was cooled to an external temperature of 25 °C. The precipitated solid was filtered off, and the cake was washed with a heptane / 2-MeTHF mixture (3:1, 28 mL). The filtrate and wash solution were combined and concentrated under reduced pressure. This concentrated residue, the residue remaining in the reaction vessel after filtration, and the residue obtained by concentrating wash solution 2 under reduced pressure were combined and purified by silica gel column chromatography using ethyl acetate and heptane as the mobile phase. The resulting ethyl acetate / heptane solution of compound 4A was concentrated under reduced pressure. The colorless solid obtained by concentration was dried under reduced pressure at an external temperature of 40° C. to obtain compound 4A (4.2 g, yield 30%) as crystals. HPLC purity: 99.99% (Analysis conditions A)

[0108] (1-3) Reaction selectivity and reaction rate in various solvents The reaction selectivity and reaction rate were investigated for the solvents listed in Table 2 below as follows. (2-amino-3-fluoropyridin-4-yl)methanol (Compound 2A), DMAP, and the solvent were added to a reaction vessel, and the mixture was stirred at room temperature. After adding 1.0 equivalent of methyl chloroformate (Compound 3A) relative to Compound 2A, stirring was continued for a predetermined time (the time listed in Table 2). The resulting reaction mixture was analyzed by HPLC using analytical condition A.

[0109] The results are shown in Table 2. Table 2 shows the peak area ratio of the following impurity A, impurity B, or impurity C to compound 4A, and the reaction rate calculated according to the following formula. Reaction rate = [Peak area of ​​compound 4A / (Peak area of ​​compound 2A+Peak area of ​​compound 4A)] × 100%

[0110] Compound 2A HPLC retention time approximately 0.77 minutes Compound 4A HPLC retention time 1.63 minutes Impurity A LCMS m / z 258 HPLC retention time 2.24 minutes Impurity B LCMS m / z 369 HPLC retention time 2.47 minutes Impurity C LCMS m / z 427 HPLC retention time 3.11 minutes

[0111] [Table 2]

[0112] As is clear from the above results, MeCN is superior in terms of reaction selectivity and reaction rate.

[0113] (Synthesis Example 2) Synthesis of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzamide (Compound 10A) [ka] (2-1) Synthesis of 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzoic acid (Compound 8A) [ka] A reaction vessel containing 1 M lithium bis(trimethylsilyl)amide in THF (206 mL, 206 mmol) was cooled to an external temperature of -15 °C, and a solution of 4-cyclopropyl-2-fluoroaniline (11.6 g, 76.5 mmol) in THF (30 mL) was added dropwise. A solution of 5-bromo-2,3,4-trifluorobenzoic acid (15.0 g, 58.8 mmol) in THF (120 mL) was then added dropwise over 30 minutes, followed by stirring for 30 minutes. 5 M hydrochloric acid (118 mL) was added to the reaction mixture, which was then warmed to room temperature and extracted with isopropyl acetate (75 mL). The organic layer was washed twice with water (75 mL) and once with 15% aqueous sodium chloride (75 mL) and concentrated under reduced pressure. Acetone (120 mL) was added to the resulting residue, which was then heated and dissolved. Water (45 mL) and seed crystals (150 mg) were then added to precipitate crystals. Water (45 mL) was added to the resulting slurry, and the crystals were collected by filtration, washed with a mixed solution of acetone / water (1 / 2), and dried under reduced pressure at an external temperature of 40°C to obtain Compound 8A (19.4 g, yield 85%). LCMS m / z: 386[M+H] + HPLC retention time: 0.62 minutes (analysis condition B)

[0114] (2-2) Synthesis of 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 9A) [ka] To a reaction vessel containing 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzoic acid (compound 8A) (13.0 g, 33.7 mmol), MeCN (104 mL), THF (26 mL), and 1,1'-carbonyldiimidazole (8.2 g, 50.5 mmol) were added and stirred at room temperature for 2 hours. 28% aqueous ammonia (13 mL) was added to the reaction mixture, which was then stirred at room temperature for 30 minutes. Water (117 mL) was then added over 1 hour. The crystals were collected by filtration, washed with water, and dried under reduced pressure at an external temperature of 40 °C to give compound 9A (12.0 g, 93% yield). LCMS m / z: 385[M+H] + HPLC retention time: 0.52 minutes (analysis condition B)

[0115] (2-3) Synthesis of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzamide (Compound 10A) Under a nitrogen atmosphere, potassium acetate (7.64 g, 77.8 mmol), 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 9A) (10.0 g, 26.0 mmol), and bispinacoldiboron (7.25 g, 28.6 mmol) were suspended in 2-MeTHF (150 mL), and the atmosphere in the reaction vessel was purged with nitrogen. XPhos-Pd-G3 (440 mg, 0.519 mmol) was added to the resulting mixture, and the atmosphere in the reaction vessel was purged with nitrogen again. The mixture was heated to an external temperature of 80 °C and stirred for 6 hours. The mixture was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. Cyclopentyl methyl ether (50 mL) was added to the residue, and the mixture was again concentrated under reduced pressure. To the resulting concentrated residue was added cyclopentyl methyl ether (50 mL), and the mixture was concentrated under reduced pressure again. To the residue was added cyclopentyl methyl ether (50 mL), and the precipitated solid was collected by filtration. The filter cake was washed with cyclopentyl methyl ether (30 mL) and then dried under reduced pressure at 40°C to give Compound 10A (7.02 g, yield 63%). HPLC purity: 97.60% (Analysis conditions A) 1H-NMR(DMSO-d6) δ: 9.83(1H,brs),8.40-8.32(1H,brs),7.77(1H,d,J=5.2Hz),7.72-7.63(1H,brs),6.96-6.90(2H,m), 6.83(1H,dd,J=1.7,8.0Hz),1.93-1.86(1H,m),1.30(12H,s),0.95-0.90(2H,m),0.67-0.63(2H,m). MS(ESI + ) m / z: 433[M+H] + During HPLC analysis, Compound 10A is partially hydrolyzed to form boronic acid. Therefore, the purity of Compound 10A was determined by the following formula: Compound 10A (retention time 4.57 min, m / z 433 [M+H] + ) and boronic acid (retention time approximately 3.48 min, m / z 351 [M+H] + ) was calculated from the sum of the peak areas.

[0116] (Synthesis Example 3) Synthesis of 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 5A) [ka] (3-1) Synthesis of 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 5A) 5-Bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 9A) (15.00 g, 38.9 mmol), potassium acetate (11.47 g, 117 mmol), bispinacoldiboron (10.88 g, 42.8 mmol), and 2-MeTHF (113 mL) were added to a reaction vessel, and the atmosphere inside the reaction vessel was then purged with nitrogen. XPhos-Pd-G3 (659 mg, 0.779 mmol) was added to the reaction solution, and the atmosphere inside the reaction vessel was then purged with nitrogen. The internal temperature of the reaction solution was raised to 80 °C and stirred for 4 hours. After the internal temperature of the reaction mixture was lowered to 25°C, (2-amino-3-fluoropyridin-4-yl)methyl methyl carbonate (compound 4A) (11.69 g, 58.4 mmol), potassium carbonate (16.15 g, 117 mmol), and RuPhos-Pd-G3 (1.629 g, 1.947 mmol) were added. The atmosphere in the reaction vessel was replaced with nitrogen (oxygen concentration in the reaction vessel ≦0.1%), and the internal temperature of the reaction mixture was raised to 75°C. EtOH (52 mL, 900 mmol) was slowly added dropwise (so that the internal temperature did not fall below 60°C), followed by stirring for 4 hours and 30 minutes. After confirming the decomposition of compound 4A (less than 1%), 2-MeTHF (113 mL) and an aqueous solution of N-acetyl-L-cysteine ​​(1.271 g, 113 mL) were added, and the mixture was stirred for 1 hour. The internal temperature of the reaction solution was lowered to 40°C, and then extraction was performed. The organic layer was washed successively with 0.1 M hydrochloric acid (113 mL), 0.1 M aqueous potassium phosphate solution (113 mL), and 2% aqueous sodium chloride solution (113 mL), and the resulting organic layer was filtered. The filtrate was concentrated under reduced pressure to a total volume of 75 mL, and toluene (225 mL) was added to the concentrated residue. The solvent was distilled off under reduced pressure until the solution volume was 75 mL, and then toluene (225 mL) was added again. The solvent was distilled off under reduced pressure until the solution volume was 75 mL, and then 1-butanol (12 mL) was added as an internal standard, and 1The toluene content was calculated by H-NMR, and toluene was added to make a solution with a toluene volume of 240 mL. The internal temperature of the reaction solution was raised to 110°C, and after confirming complete dissolution of the solid, the temperature was lowered to 90°C. After adding the seed crystals (75 mg) obtained in (4-2)(5) described below, the internal temperature of the reaction solution was lowered to 80°C and stirred for 1 hour. The solution temperature was lowered to 60°C and stirred for 30 minutes. The solution temperature was lowered to 40°C and stirred for 30 minutes. The solution temperature was lowered to 25°C and stirred for 30 minutes. The solution temperature was lowered to 5°C and stirred for 30 minutes. The precipitated solid was collected by filtration, washed with toluene (45 mL), and filtered under reduced pressure to obtain Compound 5A (12.6 g, yield 75%). HPLC purity: 99.69% (Analysis conditions A) 1 H-NMR(DMSO-d6) δ: 9.38(1H,brs),8.19(1H,brs),7.70(1H,brs),7.65(1H,d,J=5.2Hz),7.58(1H,d,J=6.9Hz),6.90(1H,d,J=13.2),6.81-6 .76(2H,m),6.38(1H,t,J=5.2Hz),6.14(2H,brs),3.91(2H,s),1.90-1.84(1H,m),0.92-0.88(2H,m),0.64-0.61(2H,m). MS(ESI + ) m / z: 431[M+H] +

[0117] (3-2) Reaction selectivity and reaction rate in various solvents The reaction selectivity and reaction rate were investigated for the solvents listed in Table 3 below as follows: 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzamide (Compound 10A) (100 mg, 0.231 mmol), MeTHF (1.5 mL), (2-amino-3-fluoropyridin-4-yl)methyl methyl carbonate (Compound 4A) (93 mg, 0.46 mmol), and potassium carbonate (96 mg, 0.69 mmol) were sequentially added to a reaction vessel, and the atmosphere in the reaction vessel was replaced with nitrogen. To the resulting mixture were added bis(allylchloropalladium) (2.1 mg, 5.8 μmol), 2',6'-dimethoxy-2-(dicyclohexylphosphino)biphenyl (4.8 mg, 12 μmol), and solvent (1.5 mL). The reaction vessel was again purged with nitrogen, and the reaction mixture was heated to 70°C with stirring. Additive (H2O) (30 μL) was added over approximately 30 minutes, and stirring was continued for another hour without adding additive (H2O). The resulting reaction mixture was analyzed by HPLC using analytical condition A.

[0118] The results are shown in Table 3. Table 3 shows the peak area ratio of compound 5A to impurity D below, and the reaction rate calculated according to the following formula. Conversion rate = [(peak area of ​​compound 5A + peak area of ​​impurity D + peak area of ​​impurity E) / (peak area of ​​compound 10A + peak area of ​​boronic acid + peak area of ​​compound 5A + peak area of ​​impurity D + peak area of ​​impurity E)] × 100%

[0119] Compound 5A HPLC retention time approximately 3.31 minutes Impurity D HPLC retention time approximately 3.98 minutes Impurity E LCMS m / z 611 HPLC retention time approximately 5.06 minutes

[0120] [Table 3]

[0121] As is clear from the above results, EtOH is superior in terms of reaction selectivity and reaction rate.

[0122] The structural formula, NMR data, and m / z of impurity D are as follows: [ka] 1 H-NMR(DMSO-d6) δ: 9.63(1H,brs),8.25-8.20(1H,brs),7.75-7.70(1H,brs),7.61(1H,ddd,J=1.7,5.7,8.0Hz),7.09-7.02(1H, m),6.91(1H,dd,J=1.7,12.0Hz),6.85-6.80(2H,m),1.91-1.85(1H,m),0.93-0.89(2H,m),0.65-0.62(2H,m). MS(ESI + ) m / z: 307[M+H] +

[0123] (3-3) Reaction selectivity and reaction rate of various catalysts The reaction selectivity and reaction rate of the catalysts listed in Table 4 below were investigated as follows. 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzamide (Compound 10A) (100 mg, 0.231 mmol), MeTHF (1.5 mL), (2-amino-3-fluoropyridin-4-yl)methyl methyl carbonate (Compound 4A) (93 mg, 0.463 mmol), and potassium carbonate (96 mg, 0.694 mmol) were sequentially added to a reaction vessel, and the atmosphere inside the reaction vessel was purged with nitrogen. The catalyst and EtOH (0.7 mL) were added to the resulting mixture, and the atmosphere inside the reaction vessel was purged with nitrogen again. The reaction solution was stirred at 70 °C for 1.5 hours, and the resulting reaction mixture was analyzed by HPLC using analytical condition A.

[0124] The results are shown in Table 4. Table 4 shows the peak area ratio of compound 5A to impurity D described in (3-2) above, and the reaction rate calculated according to the formula described in (3-2) above. [Table 4]

[0125] As is clear from the above results, the combination of [PdCl(allyl)]2 and Sphos, the combination of [PdCl(allyl)]2 and RuPhos, the combination of [PdCl(allyl)]2 and DavePhos, and RuPhos-Pd-G3 are superior in terms of reaction selectivity and reaction rate.

[0126] (Synthesis Example 4) Synthesis of the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound 1A) [ka] (4-1) Preparation of Sample 1a (Form I) 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 5A) (3.00 g, 6.97 mmol) was added to a reaction vessel, followed by the addition of 1,3-dimethyl-2-imidazolidinone (12 mL) and THF (6 mL) for dissolution. The reaction vessel was purged with nitrogen, and pyridine (1.69 mL, 20.91 mmol) was added and cooled to 0 °C. N-methylsulfamoyl chloride (0.67 mL, 7.67 mmol) was added and stirred for 45 minutes. After that, pyridine (0.10 mL, 1.26 mmol) and N-methylsulfamoyl chloride (0.30 mL, 3.42 mmol) were added and stirred for 35 minutes. Subsequently, pyridine (0.24 mL, 2.93 mmol) and N-methylsulfamoyl chloride (0.13 mL, 1.46 mmol) were added and stirred for 35 minutes. After that, pyridine (0.09 mL, 1.12 mmol) and N-methylsulfamoyl chloride (0.05 mL, 0.56 mmol) were added and stirred for 3 hours. The reaction mixture was diluted with THF (18 mL) and TBME (24 mL) and then quenched by the addition of 10% aqueous sodium chloride (15 g). The temperature was raised to 25 °C. The reaction mixture was separated, and the upper layer (organic layer) was washed with 10% aqueous sodium chloride (24 g). The resulting organic layer was concentrated under reduced pressure to 15 mL and diluted with THF (45 mL). This procedure was repeated two more times, after which the precipitated inorganic salts were filtered off. The separated inorganic salts were washed with THF (15 mL), combined with the filtrate, and concentrated under reduced pressure to 15 mL. The residue was diluted with acetone (11 mL), and THF (9.3 mL) was added. The resulting solution was heated to 40°C, and 5 M aqueous sodium hydroxide (1.32 mL, 6.62 mmol) and a suspension of seed crystals (1.82 mg) of the sodium salt of Compound 1A (Sample 1b described below) in acetone (0.7 mL) were added sequentially, followed by stirring for 2 hours and 30 minutes. Acetone (6.6 mL) was added over 30 minutes, followed by stirring for 2 hours. Acetone (18.2 mL) was added over 20 minutes, followed by stirring for 45 minutes. TBME (24 mL) was added over 20 minutes, followed by stirring for 50 minutes. The resulting suspension was cooled to 25°C over 30 minutes, stirred for 1 hour, and then allowed to stand at room temperature overnight. After standing overnight, the suspension was stirred at 25°C for 2 hours and 30 minutes.The precipitated solid was collected by filtration, washed with a mixed solvent of acetone (11.0 mL) and TBME (11.0 mL), and then dried under reduced pressure to obtain the sodium salt of Compound 1A (2.77 g, yield 73%) (Sample 1a (Form I)). HPLC purity: 99.49% (Analysis condition C) HPLC retention time: 7.02 minutes (analysis condition C) 1 H-NMR(DMSO-d6) δ: 9.36(1H,brs),8.21(1H,brs),7.68(1H,brs),7.60-7.55(2H,m),6.89(1H,brd,J=13.5Hz),6.82-6.75(2H,m),6.17(1H,t,J =5.0Hz),5.50(1H,q,J=6.0Hz),3.85(2H,s),2.28(3H,d,J=6.0Hz),1.90-1.83(1H,m),0.92-0.87(2H,m),0.64-0.60(2H,m). MS(ESI + ) m / z: 524[M+2H-Na] +

[0127] In HPLC analysis of the obtained sample 1a (Form I), a compound represented by the following formula (X) was detected. The ratio of the peak area of ​​the compound of formula (X) to the sum of the peak areas of compound 1A, the compound of formula (X), and other degradation products of compound 1A was 100, and it was 0.27. It can be said that the content of the compound of formula (X) or its sodium salt in sample 1a (Form I) is sufficiently low. [ka] HPLC retention time: 8.81 minutes (analysis condition C) MS(ESI + ) m / z: 506[M+H] +

[0128] (4-2) Preparation of Sample 1b (Form I) (1) Synthesis of N-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-fluoropyridin-2-yl]acetamide A reaction vessel was charged with tert-butyl-[(2-chloro-3-fluoropyridin-4-yl)methoxy]dimethylsilane (180 g, 653 mmol), Xantphos (22.7 g, 39.2 mmol), potassium carbonate (135 g, 979 mmol), acetamide (77.1 g, 1.31 mol), and 2-methyl-2-butanol (540 mL), and the mixture was degassed under reduced pressure and purged with nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (14.9 g, 16.3 mmol) and toluene (540 mL) were added, and the mixture was further degassed under reduced pressure and purged with nitrogen. Under a nitrogen atmosphere, the mixture was heated to an external temperature of 120 °C and stirred for 7 hours. The external temperature was cooled to room temperature, and the reaction mixture was filtered and washed with toluene (450 mL). Activated carbon (9.00 g, 749 mmol) was added to the filtrate, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and washed twice with toluene (270 mL for the first time and 180 mL for the second time) to give the crude product of N-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-fluoropyridin-2-yl]acetamide as a toluene solution. LCMS m / z: 299[M+H] + HPLC retention time: 0.81 min (analysis condition B)

[0129] (2) Synthesis of N-[3-fluoro-4-(hydroxymethyl)pyridin-2-yl]acetamide methanesulfonate (Compound 13A) [ka] The resulting toluene solution of N-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-fluoropyridin-2-yl]acetamide, toluene (175 mL), and MeOH (195 mL) were added to a reaction vessel, which was then degassed under reduced pressure and purged with nitrogen. Methanesulfonic acid (188 g, 1.96 mol) was added dropwise at an external temperature of 10°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to an external temperature of 0°C and stirred for 3 hours. The precipitate was collected by filtration and washed with a cooled mixture of toluene (312 mL) and MeOH (78 mL). The collected solid and a mixture of toluene (1.1 L) and EtOH (492 mL) were added to a reaction vessel, and the mixture was stirred at an external temperature of 0°C for 1 hour. The solid was collected by filtration, washed with a mixture of toluene (281 mL) and EtOH (117 mL), and dried under reduced pressure at an external temperature of 40° C. to obtain Compound 13A (149 g, yield 81%). LCMS m / z: 185[M+H] + HPLC retention time: 0.30 min (analysis condition D)

[0130] (3) Synthesis of (2-acetamido-3-fluoropyridin-4-yl)methyl methyl carbonate (compound 14A) [ka] DMAP (52.3 g, 428 mmol) was added to a reaction vessel containing N-[3-fluoro-4-(hydroxymethyl)pyridin-2-yl]acetamide methanesulfonate (Compound 13A) (50.0 g, 178 mmol) and 2-MeTHF (750 mL) at room temperature. The external temperature was cooled to 0 °C, and methyl chloroformate (21.9 g, 232 mmol) was added. The mixture was then warmed to room temperature and stirred. The precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure at an external temperature of 40 °C. Ethyl acetate (300 mL) was added to the concentrated residue, and the mixture was dissolved at room temperature. DIPEA (31.2 mL, 178 mmol), heptane (150 mL), and seed crystals were then added. After confirming the precipitation of crystals, heptane (1 L) was added. The slurry was cooled to an external temperature of 0 °C, and the crystals were collected by filtration and washed with a mixture of ethyl acetate and heptane (2 / 7). Drying under reduced pressure at an external temperature of 40° C. gave Compound 14A (31.3 g, yield 72%) as a colorless solid. LCMS m / z: 243[M+H] + HPLC retention time: 0.37 min (analysis condition B)

[0131] (4) Synthesis of 5-[(2-acetamido-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 15A) [ka] A reaction vessel was charged with 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 9A) (10.0 g, 26.0 mmol), bis(pinacolato)diboron (7.3 g, 28.6 mmol), potassium acetate (7.6 g, 77.9 mmol), and 2-MeTHF (150 mL). The mixture was degassed under reduced pressure and purged with nitrogen. (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (440 mg, 0.52 mmol) was added, and the mixture was further degassed under reduced pressure and purged with nitrogen. The mixture was heated to an external temperature of 80°C under a nitrogen atmosphere and stirred for 6 hours. The mixture was cooled to room temperature, potassium carbonate (10.8 g, 77.9 mmol) was added, and the mixture was degassed under reduced pressure and purged with nitrogen. (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (1.1 g, 1.3 mmol) was added, and the mixture was further degassed under reduced pressure and purged with nitrogen. After this, a solution of (2-acetamido-3-fluoropyridin-4-yl)methyl methyl carbonate (Compound 14A) (12.6 g, 51.9 mmol) in 2-MeTHF (150 mL) was added. Under a nitrogen atmosphere, the mixture was heated to an external temperature of 70 °C, and water (935 μL, 51.9 mmol) was added three times every 20 minutes, followed by stirring for 20 minutes. Further, water (7.0 mL) was added dropwise and stirred for 2 hours. A solution prepared from N-acetylcysteine ​​(847 mg, 5.2 mmol) and water (150 mL) was added and stirred for 1 hour. After cooling to an external temperature of 40°C, the aqueous layer was drained. The organic layer was washed with 15% aqueous sodium chloride solution (150 mL), and insoluble matter was filtered off and concentrated under reduced pressure. MeCN (500 mL) was added to the resulting concentrated residue, and the mixture was heated to an external temperature of 100°C to dissolve the solids, followed by cooling to room temperature. The crystals were collected by filtration, washed with MeCN (200 mL), and dried under reduced pressure at an external temperature of 40°C to obtain compound 15A (8.34 g, yield 68%). LCMS m / z: 471[MH] - HPLC retention time: 0.74 min (analysis condition B)

[0132] (5) Synthesis of 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 5A) [ka] To a reaction vessel containing 5-[(2-acetamido-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (compound 15A) (100 mg, 0.21 mmol), MeOH (3 mL) and 5 M hydrochloric acid (0.42 mL, 2.1 mmol) were added and stirred at an external temperature of 50 °C for 6 hours. The reaction mixture was cooled to room temperature, and 2 M aqueous sodium hydroxide solution (1.1 mL, 2.1 mmol) was added. Water (0.5 mL) was added to the resulting slurry, and the crystals were collected by filtration. The crystals were washed with a mixture of MeOH / water (3 / 2) and dried under reduced pressure at an external temperature of 40 °C to obtain compound 5A (77.7 mg, 85% yield) as a colorless solid. LCMS m / z: 431[M+H] + HPLC retention time: 0.61 min (analysis condition B)

[0133] (6) Synthesis of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound 1A) [ka] 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 5A) (100 mg, 0.232 mmol) was dissolved in anhydrous DMA (1 mL) and pyridine (56.4 μL, 0.697 mmol) was added. After cooling to 0 °C, methylsulfamoyl chloride (30.2 μL, 0.349 mmol) was added and stirred for 1 hour. To the reaction mixture were added MeCN (0.6 mL), water (0.3 mL), and seed crystals (obtained in Preparation A-1-1 below) (1 mg). The mixture was warmed to room temperature, water (0.7 mL) and MeCN (0.4 mL) were added, and the mixture was stirred for 20 hours. The precipitate was collected by filtration and washed with a mixture of MeCN / water (1 / 1) to obtain compound 1A (93.1 mg, yield 77%) as a colorless solid. LCMS m / z: 524[M+H] + HPLC retention time: 1.13 minutes (analysis condition E)

[0134] (7) Preparation of the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound 1A) (i) Preparation of Sample 1b (Form I) 2-(4-Cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound 1A) (3.03 g) was dissolved in acetone (10.6 mL) and DMSO (1.51 mL) at room temperature. 20% sodium ethoxide in EtOH (3.03 mL) and seed crystals of the sodium salt of Compound 1A (Sample 1c described below) were added to this solution and stirred at room temperature for 1 hour. EtOH (15.1 mL) was then added and stirred at room temperature for 4 hours. Further EtOH (15.1 mL) was then added and stirred at room temperature for 4 hours to obtain the sodium salt of Compound 1A (2.74 g) as a powdery crystal (Sample 1b (Form I)).

[0135] (ii) Preparation of Sample 1c Compound 1A (53.6 mg) was added to 20% sodium ethoxide EtOH solution (0.054 mL) and methyl isobutyl ketone (0.161 mL) and stirred at room temperature for 30 minutes, then methyl isobutyl ketone (0.161 mL) was added and stirred at 60° C. for 4 days. DMSO (0.054 mL) was then added and stirred at 60° C. for 5 hours to obtain the sodium salt of compound 1A (25.6 mg) as powdery crystals (Sample 1c).

[0136] (4-3) Powder X-ray diffraction measurement Sample 1a (Form I) was subjected to powder X-ray diffraction measurement under the following conditions. Measurement device: Empyrean (PANalytical) Anode: Cu Tube voltage: 45kV Tube current: 40mA Scanning method: Continuous Step width: 0.0262606° Scan axis: 2θ Sampling time per step: 5.100 seconds Scanning range: 3~25°

[0137] Sample 1b (Form I) and Sample 1c were subjected to powder X-ray diffraction measurement under the following conditions. Measurement equipment: SmartLab, D / Tex Ultra detector (Rigaku Corporation) Anode: Cu Tube voltage: 45kV Tube current: 200mA Sampling width: 0.02°

[0138] The results of the powder X-ray diffraction measurements are shown in Figures 1 to 3. Figure 1 shows the powder X-ray diffraction pattern of Sample 1a (Form I). Figure 2 shows the powder X-ray diffraction pattern of Sample 1b (Form I). Figure 3 shows the powder X-ray diffraction pattern of Sample 1c. In Figures 1 to 3, the horizontal axis (X axis) represents the diffraction angle 2θ (°), and the vertical axis (Y axis) represents the diffraction intensity.

[0139] [Reference example] Reference examples (production examples and test examples) of specific arylamide derivatives are shown below. Among the arylamide derivatives described in the following reference examples (compounds A-1, A-2, A-8, A-18, A-20, A-25, A-27, A-33, B-1, E-1, E-7, E-13, H-1, H-3, H-4, I-1, J-1, K-10, L-1, M-1, N-1, N-2, and P-1), compounds A-1, A-2, A-8, A-18, A-20, A-25, A-27, A-33, B-1, and I-1 are compounds of the above-mentioned general formula (1) (compound A-1 is also referred to as compound 1A in this specification).

[0140] [Manufacturing example] In the following preparation examples, NMR analyses were carried out using a BRUKER AVANCE III HD400 (400 MHz) spectrometer. NMR data are given in ppm (parts per million) (δ) and were referenced to the deuterium lock signal from the sample solvent.

[0141] Mass spectral data were obtained using a Shimadzu single quadrupole mass spectrometer (LCMS-2020) equipped with an ultra-high performance liquid chromatograph (Nexera UC) or a Waters single quadrupole mass spectrometer (SQD or SQD2) equipped with an Acquity ultra-high performance liquid chromatograph (UPLC or UPLC I-Class).

[0142] High performance liquid chromatography (HPLC) analysis was carried out using one of the analytical conditions listed in Table 5 below. [Table 5-1] [Table 5-2]

[0143] The microwave reaction was carried out using an Initiator manufactured by Biotage Inc. A snap-cap reaction vial was used for the microwave reaction.

[0144] Commercially available reagents were used without further purification. All non-aqueous reactions were carried out in anhydrous solvents. Concentration under reduced pressure or solvent distillation was carried out using a rotary evaporator.

[0145] In the following Preparation Examples, "Preparation Example for Compound A-1" means Preparation Example A-1-1, and "Preparation Example for Compound a9" means Preparation Example a9-1.

[0146] Compound a1: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-formylbenzoate methyl ester [ka] A suspension of 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-formylbenzoic acid (5.50 g, 13.1 mmol) in toluene (44 mL) and MeOH (11 mL) was cooled to 0 °C, and 10% diazomethyltrimethylsilane hexane solution (21.8 mL, 13.1 mmol) was added and stirred at room temperature for 64 hours. To the reaction mixture was added acetic acid (0.748 mL), and the mixture was concentrated under reduced pressure. The resulting residue was purified by trituration (hexane / ethyl acetate) to give the title compound (5.01 g, 88%) as a colorless solid. LCMS m / z: 436[M+H] + HPLC retention time: 1.00 minutes (Analysis condition I)

[0147] Compound a2: Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzoate [ka] To a suspension of methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-formylbenzoate (compound a1, 5.00 g, 11.5 mmol) in EtOH (100 mL) was added 4-methylbenzenesulfonyl hydrazide (2.14 g, 11.5 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then hexane (150 mL) was added. The mixture was cooled to 0°C, filtered, and washed with hexane (30 mL) to give the title compound (7.05 g, quant.) as a solid. LCMS m / z: 604[M+H] + HPLC retention time: 1.06 minutes (analysis condition I)

[0148] Compound a3: N-(2,4-dimethoxybenzyl)-3-fluoro-4-iodopyridin-2-amine [ka] To a solution of 2,3-difluoro-4-iodopyridine (2.09 g, 8.67 mmol) in NMP (32 mL), triethylamine (3.63 mL, 26.0 mmol) and 1-(2,4-dimethoxyphenyl)methanamine (3.26 mL, 21.7 mmol) were added, and the mixture was stirred at 100°C for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 13% brine, dried over anhydrous sodium sulfate, and the drying agent was removed by filtration. The mixture was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (3.20 g, 95%) as an oil. LCMS m / z: 389[M+H] + HPLC retention time: 0.94 minutes (analysis condition B)

[0149] Compound a4: [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid [ka] A 1,4-dioxane solution (27 mL) of N-(2,4-dimethoxybenzyl)-3-fluoro-4-iodopyridin-2-amine (Compound a3, 2.70 g, 6.96 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (568 mg, 0.696 mmol), potassium acetate (2.05 g, 20.9 mmol), and bis(pinacolato)diboron (2.65 g, 10.4 mmol) was stirred at 90° C. for 5 hours and then at 110° C. for 19 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.1% formic acid in water / 0.1% formic acid in acetonitrile) to give the title compound (2.07 g, 97%) as an oil. LCMS m / z: 307[M+H] + HPLC retention time: 0.44 minutes (analysis condition B)

[0150] Compound a5: 5-[[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate methyl ester [ka] A suspension of methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzoate (Compound A2, 1.30 g, 2.16 mmol), [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (Compound A4, 1.98 g, 6.46 mmol), and potassium carbonate (357 mg, 2.59 mmol) in 1,4-dioxane (59 mL) was stirred at 100°C for 2.5 hours and then at 110°C for 3 hours under a nitrogen atmosphere. Ethyl acetate was added to the reaction mixture, which was washed with water and 13% brine. The organic layer was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (524 mg, 36%) as a foam. LCMS m / z: 682[M+H] + HPLC retention time: 1.03 minutes (analysis condition I)

[0151] Compound a6: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid methyl ester [ka] A DCM solution (16 mL) of methyl 5-[[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (compound a5, 523 mg, 0.768 mmol) was cooled to 0 ° C., trifluoroacetic acid (15.7 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.05% trifluoroacetic acid aqueous solution / 0.05% trifluoroacetic acid acetonitrile solution) to give the title compound (321 mg, 79%) as an oil. LCMS m / z: 532[M+H] + HPLC retention time: 0.55 min (analysis condition I)

[0152] Compound a7: 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride [ka] A solution of methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (compound a6, 4.00 g, 7.53 mmol) in THF (64 mL) and water (32 mL) was cooled to 0 °C, lithium hydroxide monohydrate (948 mg, 22.6 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. After cooling to 0 °C, 5 M hydrochloric acid (15.1 mL) was added to the reaction mixture, which was then concentrated under reduced pressure. The resulting residue was washed with water and TBME to give the title compound (4.20 g, quant.) as a purple solid. LCMS m / z: 518[M+H] + HPLC retention time: 0.68 min (analysis condition B)

[0153] Compound a8: 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide [ka] A solution of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride (Compound a7, 200 mg, 0.361 mmol) in anhydrous DMF (3.6 mL) was cooled to 0 °C, and HOOBt (67.8 mg, 0.415 mmol) and EDC·HCl (80.0 mg, 0.415 mmol) were added and stirred at room temperature for 1.5 h. HOOBt (8.8 mg, 0.054 mmol) and EDC·HCl (10.4 mg, 0.054 mmol) were added and stirred at room temperature for 1 h. After stirring at room temperature, 7 M ammonia in MeOH (0.103 mL, 0.722 mmol) and DIPEA (0.189 mL, 1.08 mmol) were added at 0 °C and stirred at room temperature for 30 min. Water and saturated aqueous sodium bicarbonate solution were added to the reaction mixture in a 1:1 ratio, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (1 mL), and hexane (10 mL) was added. The resulting solid was collected by filtration and washed with hexane to give the title compound (162 mg, 87%) as a colorless solid. LCMS m / z: 517[M+H] + HPLC retention time: 0.64 minutes (analysis condition B)

[0154] Compound a9: 5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluorobenzamide [ka] Manufacturing example a9-1: Tetrakis(triphenylphosphine)palladium(0) (11.2 mg, 9.68 μmol) and 0.5 M cyclopropylzinc bromide (1.94 mL, 0.969 mmol) were added to a solution of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (compound a8, 100 mg, 0.194 mmol) in anhydrous THF (1.9 mL), and the mixture was stirred at room temperature under a nitrogen atmosphere for 2.5 hours. Ethyl acetate (5 mL) was added to the reaction mixture, which was then filtered through Celite and washed with ethyl acetate (3 mL). The filtrate was washed with water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the mixture was concentrated under reduced pressure. Dichloromethane / hexane (1 / 10, 11 mL) was added to the obtained residue, and the solid was collected by filtration and washed with hexane (3 mL) to obtain compound a9 (63.4 mg, 76%) as a colorless solid. LCMS m / z: 431[M+H] + HPLC retention time: 0.61 min (analysis condition B)

[0155] Compound r1: 4-Nitrophenyl methylsulfamate [ka] A solution of 4-nitrophenol (5.00 g, 35.9 mmol) and triethylamine (11.3 mL, 81.0 mmol) in dichloromethane (60 mL) was cooled to −78° C., and a solution of methylsulfamoyl chloride (5.82 g, 44.9 mmol) in dichloromethane (15 mL) was added, followed by stirring for 1.5 hours at −78° C. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) and reverse-phase column chromatography (0.1% formic acid in water / 0.1% formic acid in acetonitrile) to give the title compound (5.51 g, 66%) as a colorless solid. HPLC retention time: 0.63 minutes (analysis condition B) 1H-NMR(400MHz,CDCl3) δ: 8.31(2H,m),7.46(2H,m),4.68(1H,m),3.00(3H,d,J=5.4Hz).

[0156] Compound A-1: 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide [ka] Manufacturing example A-1-1: 5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluorobenzamide (Compound A9, 2.47 g, 5.74 mmol) was dissolved in anhydrous DMF (28.7 mL), and pyridine (2.78 mL, 34.4 mmol) and 4-nitrophenyl methylsulfamate (Compound R1, 4.00 g, 17.2 mmol) were added, followed by stirring at 40° C. for 2.5 hours. The reaction mixture was cooled to room temperature, and water (24.7 mL) was added. Acetonitrile (3 mL) and water (19.8 mL) were added, followed by stirring for 10 minutes, and the solid was collected by filtration. The resulting solid was washed with water / acetonitrile (1 / 1, 49.4 mL) to obtain Compound A-1 (2.56 g, 85%) as a colorless solid. LCMS m / z: 524[M+H] + HPLC retention time: 1.13 minutes (analysis condition E)

[0157] Compound a10: 5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-cyclopropyl-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide [ka] 5-((2-Amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride (Compound a7, 100 mg, 0.193 mmol) was dissolved in anhydrous DMF (1 mL) and HOOBt (63.1 mg, 0.387 mmol) and EDC·HCl (74.1 mg, 0.387 mmol) were added at room temperature. After stirring at room temperature for 3 hours, aminocyclopropane (33.1 mg, 0.580 mmol) and DIPEA (0.101 mL, 0.580 mmol) were added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid in water / 0.1% formic acid in acetonitrile) to give the title compound (103 mg, 96%) as a brown solid. LCMS m / z: 557[M+H] + HPLC retention time: 0.73 minutes (Analysis condition B)

[0158] Compound A-2: N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-cyclopropyl-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (Compound a10) under the same conditions as in the production example for Compound A-1. LCMS m / z: 650[M+H] + HPLC retention time: 1.65 minutes (analysis condition H)

[0159] Compound a12: 5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-(tert-butoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide [ka] 5-[(2-Amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid hydrochloride (Compound a7, 100 mg, 0.181 mmol) was dissolved in anhydrous DMF (0.9 mL). HOOBt (58.9 mg, 0.361 mmol) and EDC·HCl (69.2 mg, 0.361 mmol) were added and the mixture was stirred at room temperature for 3.5 h. tert-Butoxyamine hydrochloride (68.1 mg, 0.542 mmol) and DIPEA (0.95 mL, 0.542 mmol) were then added and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid in water / 0.1% formic acid in acetonitrile) to afford the title compound (89 mg, 84%) as a colorless solid. LCMS m / z: 589[M+H] + HPLC retention time: 0.77 min (analysis condition B)

[0160] Compound A-8: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide [ka] The title compound was synthesized from 5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-(tert-butoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (compound a12) under the same conditions as in the production example for compound A-1. LCMS m / z: 682[M+H] + HPLC retention time: 1.69 minutes (analysis condition H)

[0161] Compound a16: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-methylsulfanylanilino)benzamide [ka] 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8, 30.0 mg, 0.058 mmol) was dissolved in anhydrous 1,4-dioxane (0.3 mL), and methyl mercaptan sodium (12.2 mg, 0.174 mmol), DIPEA (30.4 μL, 0.174 mmol) and [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium (II) methanesulfonate (11.2 mg, 0.012 mmol) were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. The reaction mixture was purified by reverse-phase column chromatography (0.1% aqueous formic acid / 0.1% formic acid acetonitrile solution) to give the title compound (15 mg, 59%) as a colorless solid. LCMS m / z: 437[M+H] + HPLC retention time: 0.60 minutes (Analysis condition B)

[0162] Compound A-18: 3,4-Difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-methylsulfanylanilino)benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-methylsulfanylanilino)benzamide (Compound a16) under the same conditions as in the production example for Compound A-1. LCMS m / z: 530[M+H] + HPLC retention time: 1.09 minutes (analysis condition E)

[0163] Compound a18: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-[2-fluoro-4-(2-trimethylsilylethynyl)anilino]benzamide [ka] 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8, 2.67 g, 5.17 mmol) in anhydrous THF (26 mL) was added triethylamine (31.7 mL, 228 mmol), trimethylsilylacetylene (1.43 mL, 10.3 mmol), bis(triphenylphosphine)palladium(II) dichloride (363 mg, 0.517 mmol) and copper(I) iodide (296 mg, 1.55 mmol) and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give the title compound (2.57 g, 83%) as a colorless solid. LCMS m / z: 487[M+H] + HPLC retention time: 0.84 minutes (analysis condition G)

[0164] Compound a19: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-ethynyl-2-fluoroanilino)-3,4-difluorobenzamide [ka] 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-[2-fluoro-4-(2-trimethylsilylethynyl)anilino]benzamide (compound a18, 20.0 mg, 0.041 mmol) in MeOH solution (0.411 mL) was added potassium carbonate (17.0 mg, 0.123 mmol) and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give the title compound (14 mg, 82%) as a colorless solid. LCMS m / z: 415[M+H] + HPLC retention time: 0.60 minutes (analysis condition G)

[0165] Compound A-20: 2-(4-ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-ethynyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound a19) and the corresponding 4-nitrophenyl sulfamate under the same conditions as in the production example for Compound A-1. LCMS m / z: 536[M+H] + HPLC retention time: 1.18 minutes (analysis condition E)

[0166] Compound A-25: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide [ka] 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8, 10.0 mg, 0.019 mmol) was dissolved in anhydrous DMA (0.1 mL), and pyridine (2.3 μL, 0.029 mmol) and methylsulfamoyl chloride (2.5 μL, 0.029 mmol) were added at 0 ° C. and stirred at room temperature for 1 hour. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give the title compound (10.2 mg, 86%) as a colorless solid. LCMS m / z: 610[M+H] + HPLC retention time: 1.15 minutes (analysis condition E)

[0167] Compound A-33: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8) and the corresponding sulfamoyl chloride under the same conditions as in the production example of compound A-25. LCMS m / z: 654[M+H] + HPLC retention time: 1.17 minutes (analysis condition E)

[0168] Compound a21: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-bromo-2-fluoroanilino)-3,4-difluorobenzamide [ka] 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8, 60.0 mg, 0.116 mmol) was dissolved in anhydrous DMF (1.2 mL), copper (I) bromide (83.0 mg, 0.581 mmol) was added, and the mixture was stirred at 100 ° C. for 24 hours. The reaction mixture was purified by preparative HPLC (TSK-gel ODS 80TS 5 μm, 20 × 250 mm column (TOSOH), 0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to obtain the title compound (35.6 mg) as a solid. LCMS m / z: 469[M+H] + HPLC retention time: 0.61 min (analysis condition B)

[0169] Compound A-27: 2-(4-Bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-bromo-2-fluoroanilino)-3,4-difluorobenzamide (Compound a21) under the same conditions as in the production example for Compound A-25. LCMS m / z: 562[M+H] + HPLC retention time: 1.13 minutes (analysis condition E)

[0170] Compound b1: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoic acid methyl ester [ka] The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound a6) under the same conditions as in the preparation example for Compound A-25, except that anhydrous NMP was used instead of anhydrous DMA. LCMS m / z: 436[M+H] + HPLC retention time: 1.00 minutes (Analysis condition I)

[0171] Compound b2: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoic acid [ka] A solution of methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoate (Compound b1, 158 mg, 0.253 mmol) in THF (4.8 mL) and water (2.4 mL) was cooled to 0°C, lithium hydroxide monohydrate (60.6 mg, 2.53 mmol) was added, and the mixture was stirred at room temperature for 2 hours. 2M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the mixture was concentrated under reduced pressure to give the title compound (161 mg) as a foam. LCMS m / z: 611[M+H] + HPLC retention time: 0.67 min (analysis condition I)

[0172] Compound B-1: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide [ka] The title compound was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoic acid (compound b2) and the corresponding amine under the same conditions as in the production example for compound a8. LCMS m / z: 670[M+H] + HPLC retention time: 1.07 minutes (analysis condition E)

[0173] Compound c1: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzamide [ka] To a solution of 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-formylbenzoic acid (5.00 g, 11.9 mmol) in anhydrous DMF (59 mL) was added 4-methylbenzenesulfonyl hydrazide (2.21 g, 11.9 mmol) and the mixture was stirred at room temperature for 30 minutes. Next, HOOBt (1.94 g, 11.9 mmol) and EDC·HCl (2.28 g, 11.9 mmol) were added and the mixture was stirred at room temperature for 1.5 hours. 7 M ammonia in MeOH (3.39 mL, 23.8 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The solid was filtered off and washed with DMF (30 mL). Acetonitrile (90 mL) and 0.1 M hydrochloric acid (90 mL) were added to the filtrate, and the resulting solid was washed with an acetonitrile / water mixture to give the title compound (6.27 g, 90%) as a colorless solid. LCMS m / z: 589[M+H] + HPLC retention time: 0.90 minutes (Analysis condition B)

[0174] Compound c5: 5-Ethenyl-3,4-difluoro-2-(4-iodo-2-methylanilino)benzoic acid [ka] A solution of 4-iodo-2-methylaniline (636 mg, 2.73 mmol) in anhydrous THF (1.8 mL) was cooled to -78 °C, and a 1.3 M solution of lithium bis(trimethylsilyl)amide in THF (5.08 mL, 6.60 mmol) was added over 1 h and stirred for 1 h. Next, a solution of 2,3,4-trifluoro-5-vinylbenzoic acid (460 mg, 2.28 mmol) in anhydrous THF (3.9 mL) was added and stirred at 0 °C for 2 h. Water and 2 M hydrochloric acid were added to the reaction mixture, which was then extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was removed by filtration. The mixture was then concentrated under reduced pressure. The resulting residue was suspended and washed with DCM to give the title compound (631 mg, 67%) as a brown solid. LCMS m / z: 416[M+H] + HPLC retention time: 0.99 minutes (analysis condition D)

[0175] Compound c6: 3,4-Difluoro-5-formyl-2-(4-iodo-2-methylanilino)benzoic acid [ka] To a solution of 5-ethenyl-3,4-difluoro-2-(4-iodo-2-methylanilino)benzoic acid (Compound C5, 626 mg, 1.51 mmol) in anhydrous THF (6.3 mL), 1 M aqueous sodium bicarbonate (3.02 mL, 3.02 mmol), sodium periodate (1.29 g, 6.03 mmol), and osmium(VIII) oxide, microencapsulated (38.3 mg, 0.015 mmol) were added and stirred at room temperature for 6 hours. Ethyl acetate was added to the reaction mixture, which was then washed with 1 M hydrochloric acid and 0.2 M aqueous sodium thiosulfate. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the mixture was concentrated under reduced pressure. The resulting residue was suspended and washed in ethyl acetate / hexane (1 / 25, 42 mL), and the solid was collected by filtration. The resulting solid was washed with hexane to give the title compound (558 mg, 89%) as a colorless solid. LCMS m / z: 418[M+H] + HPLC retention time: 0.86 minutes (Analysis condition B)

[0176] Compound d1: 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid methyl ester [ka] The title compound was synthesized from methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzoate (Compound a2) under the same conditions as in the preparation example for Compound a5, except that (3-amino-2-fluorophenyl)boronic acid hydrochloride was used instead of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (Compound a4). LCMS m / z: 531[M+H] + HPLC retention time: 0.96 minutes (analysis condition I)

[0177] Compound E-1: 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide [ka] The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of Compound A-25, Compound b2, and Compound a12. However, pyridine was used as the solvent in the sulfonamidation step. In addition, the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the preparation example of Compound a12. LCMS m / z: 638[M+H] + HPLC retention time: 1.68 minutes (analysis condition H)

[0178] Compound E-7: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide [ka] The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) under the same conditions as in the preparation examples of Compound A-25, Compound b2, and Compound a12. However, pyridine was used as the solvent in the sulfamidation step. Furthermore, the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the preparation example of Compound a12. LCMS m / z: 609[M+H] + HPLC retention time: 1.23 minutes (analysis condition E)

[0179] Compound e20: Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzoate [ka] The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation example for Compound A-25, except that pyridine was used as a solvent. LCMS m / z: 609[M+H] + HPLC retention time: 1.01 min (analysis condition B)

[0180] Compound E-13: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzamide [ka] To a solution of methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzoate (compound e20, 23.0 mg, 0.038 mmol) in THF (0.7 mL) and water (0.3 mL) was added lithium hydroxide monohydrate (7.9 mg, 0.19 mmol) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and 1 M hydrochloric acid (0.76 mL) was added and further concentrated under reduced pressure. To a solution of the resulting mixture in anhydrous DMF (0.3 mL) were added HOOBt (9.3 mg, 0.057 mmol) and EDC·HCl (10.9 mg, 0.057 mmol) and stirred at room temperature for 3 hours. Next, 7 M ammonia in MeOH (22 μL, 0.15 mmol) was added at 0 °C and stirred for 30 minutes. To the reaction mixture was added 10% aqueous trifluoroacetic acid solution (1 mL), and the mixture was purified by reverse phase column chromatography (0.1% aqueous formic acid / 0.1% formic acid acetonitrile solution) to give the title compound (19.7 mg, 97%) as a colorless solid. LCMS m / z: 594[M+H] + HPLC retention time: 1.61 minutes (analysis condition H)

[0181] Compound h1: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-[3-(2-ethylhexoxy)-3-oxopropyl]sulfanyl-2-fluoroanilino]-3,4-difluorobenzoate methyl ester [ka] A suspension of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate (compound a6, 500 mg, 0.941 mmol), 2-ethylhexyl 3-mercaptopropionate (226 mg, 1.04 mmol), Xantphos (109 mg, 0.188 mmol), tris(dibenzylideneacetone)dipalladium(0) (86 mg, 0.094 mmol), and DIPEA (0.492 mL, 2.82 mmol) in 1,4-dioxane (17 mL) was stirred at 110 ° C. for 1 hour. Acetonitrile was added to the reaction mixture, which was then filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (0.1% aqueous formic acid / 0.1% formic acid acetonitrile solution) to give the title compound (584 mg, quant.) as a yellow viscous oily substance. LCMS m / z: 622[M+H] + HPLC retention time: 1.14 minutes (analysis condition G)

[0182] Compound h2: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluorobenzoate methyl ester [ka] A methanol solution (9 mL) of 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-[3-(2-ethylhexoxy)-3-oxopropyl]sulfanyl-2-fluoroanilino]-3,4-difluorobenzoate methyl (Compound H1, 584 mg, 0.939 mmol) was cooled to 0 ° C., and 25% sodium methoxide methanol solution (1.29 mL, 5.64 mmol) was added and stirred at room temperature for 3 hours. Then, (bromodifluoromethyl)diethyl phosphonate (1.00 g, 3.76 mmol) was added at 0 ° C. and stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0 ° C., and 25% sodium methoxide methanol solution (1.29 mL, 5.64 mmol) and (bromodifluoromethyl)diethyl phosphonate (1.51 g, 5.64 mmol) were added and stirred at room temperature for 20 minutes. The reaction mixture was cooled to 0° C., and formic acid (0.213 mL, 5.64 mmol) was added, followed by concentration under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give the title compound (195 mg, 43%) as a colorless solid. LCMS m / z: 488[M+H] + HPLC retention time: 0.81 min (analysis condition G)

[0183] Compound h3: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluorobenzamide [ka] A mixture of methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluorobenzoate (Compound H2, 60.0 mg, 0.123 mmol) and 7M ammonia in MeOH (1.80 mL, 12.6 mmol) was stirred in a sealed tube at 85 ° C. for 6 hours using a microwave reactor. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.05% trifluoroacetic acid aqueous solution / 0.05% trifluoroacetic acid acetonitrile solution) to give the title compound (53.2 g, 91%) as a yellow oil. LCMS m / z: 473[M+H] + HPLC retention time: 0.63 minutes (analysis condition B)

[0184] Compound H-1: 2-[4-(Difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluorobenzamide (Compound h3) under the same conditions as in the production example for Compound A-1. LCMS m / z: 566[M+H] + HPLC retention time: 1.49 minutes (analysis condition H)

[0185] Compound H4: 2-(1-benzothiophen-5-ylamino)-3,4-difluoro-5-formylbenzoic acid [ka] A solution of 2,2,6,6-tetramethylpiperidine (2.53 g, 17.9 mmol) in anhydrous THF (30 mL) was cooled to -78°C, and 1.6 M n-butyllithium in hexane (11.2 mL, 17.9 mmol) was added under a nitrogen atmosphere and stirred for 5 minutes. The reaction mixture was added to a solution of 2,3,4-trifluorobenzoic acid (1.50 g, 8.52 mmol) in THF (9.0 mL) at -78°C and stirred for 10 minutes. Anhydrous DMF (0.759 mL, 9.80 mmol) was then added and stirred at 0°C for 2 hours. In a separate flask, a THF solution (30 mL) of benzo[b]thiophenone-5-amine (1.65 g, 11.1 mmol) was cooled to -78 °C, and 1.3 M lithium bis(trimethylsilyl)amide THF solution (15.1 mL, 19.6 mmol) and the reaction mixture were added. The mixture was stirred at room temperature for 24 hours. 2 M hydrochloric acid was added to the reaction mixture, and after stirring for 24 hours, water and 2 M hydrochloric acid were added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. The resulting residue was purified by reverse-phase column chromatography (0.1% formic acid in water / 0.1% formic acid in acetonitrile) to afford the title compound (609 mg, 21%) as a gray solid. LCMS m / z: 334[M+H] + HPLC retention time: 0.80 minutes (analysis condition B)

[0186] Compound h5: 2-(1-benzothiophen-5-ylamino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzamide [ka] To a suspension of 2-(1-benzothiophen-5-ylamino)-3,4-difluoro-5-formylbenzoic acid (compound h4, 608 mg, 1.82 mmol) in anhydrous DMF (9.1 mL) were added HOOBt (595 mg, 3.65 mmol) and EDC·HCl (699 mg, 3.65 mmol) and the mixture was stirred at room temperature for 1.5 h. Next, 7 M ammonia in MeOH (0.912 mL, 6.38 mmol) was added at 0 °C and the mixture was stirred for 30 min. 4-Methylbenzenesulfonyl hydrazide (340 mg, 1.82 mmol) was added at 0 °C and the mixture was stirred at room temperature for 16 h. The reaction mixture was filtered, and acetonitrile (14 mL) and 0.1 M hydrochloric acid (100 mL) were added to the filtrate. The solid was filtered and washed with water to give the title compound (412 mg, 45%) as a light brown solid. LCMS m / z: 501[M+H] + HPLC retention time: 0.83 minutes (analysis condition B)

[0187] Compound h7: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(1-benzothiophen-5-ylamino)-3,4-difluorobenzamide [ka] The title compound was synthesized from 2-(1-benzothiophen-5-ylamino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzamide (Compound h5) under the same conditions as in the production examples for Compound a5 and Compound a6. LCMS m / z: 429[M+H] + HPLC retention time: 0.57 min (analysis condition B)

[0188] Compound h8: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]benzamide [ka] A solution of 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(1-benzothiophen-5-ylamino)-3,4-difluorobenzamide (Compound H7, 22 mg, 0.051 mmol) in anhydrous acetonitrile (0.3 mL) was cooled to 0 °C, and N-fluoro-N'-(chloromethyl)triethylenediaminebis(tetrafluoroborate) (9.5 mg, 0.027 mmol) was added and stirred for 2.5 hours. Next, N-fluoro-N'-(chloromethyl)triethylenediaminebis(tetrafluoroborate) (8.0 mg, 0.023 mmol) was added and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.05% aqueous trifluoroacetic acid / 0.05% acetonitrile trifluoroacetic acid solution) to afford the title compound (8.0 mg, 35%) as a brown solid. LCMS m / z: 447[M+H] + HPLC retention time: 0.61 min (analysis condition B)

[0189] Compound H-3: 3,4-Difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]benzamide (Compound h8) under the same conditions as in the production example for Compound A-1. LCMS m / z: 540[M+H] + HPLC retention time: 1.10 minutes (analysis condition E)

[0190] Compound h9: 1,2,3-Trifluoro-4-[(4-methoxyphenyl)methoxy]benzene [ka] Potassium carbonate (9.90 g, 71.6 mmol) and 4-methoxybenzyl chloride (5.55 mL, 40.9 mmol) were added to a solution of 2,3,4-trifluorophenol (5.05 g, 34.1 mmol) in anhydrous acetone (101 mL), and the mixture was stirred at 70°C for 8 hours. Water (150 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the mixture was concentrated under reduced pressure. DMSO (15 mL) and water (100 mL) were added to the resulting residue, and the resulting solid was washed to give the title compound (8.72 g, 95%) as a gray solid. LCMS m / z: 267[MH] - HPLC retention time: 0.92 minutes (Analysis condition B)

[0191] Compound h10: 2,3,4-Trifluoro-5-[(4-methoxyphenyl)methoxy]benzoic acid [ka] A solution of 2,2,6,6-tetramethylpiperidine (4.15 mL, 24.6 mmol) in anhydrous THF (15 mL) was cooled to -78 °C. Under a nitrogen atmosphere, 1.6 M lithium bis(trimethylsilyl)amide hexane solution (15.4 mL, 24.6 mmol) was added and stirred for 10 minutes. The reaction mixture was added to a solution of 1,2,3-trifluoro-4-[(4-methoxyphenyl)methoxy]benzene (Compound H9, 3.00 g, 11.2 mmol) in anhydrous THF (15 mL) at -78 °C and stirred for 3 hours. Then, carbon dioxide gas was introduced into the mixture while stirring for 30 minutes. 1 M hydrochloric acid (60 mL) was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the drying agent was removed by filtration. The mixture was then concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% aqueous formic acid / 0.1% formic acid acetonitrile solution) to give the title compound (1.32 g, 34%) as a gray solid. LCMS m / z: 311[MH] - HPLC retention time: 0.80 minutes (analysis condition B)

[0192] Compound h13: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-hydroxybenzoic acid methyl ester [ka] The title compound was synthesized from 2,3,4-trifluoro-5-[(4-methoxyphenyl)methoxy]benzoic acid (Compound H10) under the same conditions as in the preparation examples of Compound C5, Compound A1, and Compound A6. However, 2-fluoro-4-iodoaniline was used instead of 4-iodo-2-methylaniline used in the preparation example of Compound C5, and anhydrous THF was used instead of toluene used in the preparation example of Compound A1. LCMS m / z: 424[M+H] + HPLC retention time: 0.91 min (analysis condition B)

[0193] Compound h14: 5-[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]oxy-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate methyl ester [ka] Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-hydroxybenzoate (compound h13, 375 mg, 0.886 mmol) in DCM (15 mL) was added with [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4, 814 mg, 2.66 mmol), molecular sieves 4A (375 mg), tetrakis(acetonitrile)copper(I) hexafluorophosphate (495 mg, 1.33 mmol), and pyridine (0.287 mL, 3.55 mmol), and the mixture was stirred at room temperature for 2.5 hours. Then, [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4, 231 mg, 0.753 mmol) was added and the mixture was stirred for 4 hours. N-acetylcysteine ​​(434 mg, 2.66 mmol) was added to the reaction mixture and stirred for 3 hours. The solid matter was filtered and washed with DCM (10 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% formic acid in water / 0.1% formic acid in acetonitrile) to give the title compound (168 mg, 28%) as a foam. LCMS m / z: 684[M+H] + HPLC retention time: 1.07 minutes (analysis condition B)

[0194] Compound H-4: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]oxybenzamide [ka] The title compound was synthesized from methyl 5-[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]oxy-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (compound h14) under the same conditions as in the production examples of compound a6, compound E-13, and compound A-1. LCMS m / z: 612[M+H] + HPLC retention time: 1.55 minutes (analysis condition H)

[0195] Compound I-1: 4-Fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide [ka] The title compound was synthesized from 2,4-difluoro-5-vinylbenzoic acid under the same conditions as in the preparation examples for Compound c5, Compound c6, Compound c1, Compound a5, Compound a6, and Compound A-1, except that 2-fluoro-4-iodoaniline was used instead of 4-iodo-2-methylaniline used in the preparation example for Compound c5. LCMS m / z: 592[M+H] + HPLC retention time: 1.17 minutes (analysis condition E)

[0196] Compound j1: Methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate [ka] To a suspension of (2-amino-3-fluoropyridin-4-yl)methanol (10.3 g, 72.7 mmol) in DCM (91 mL) was added thionyl chloride (10.6 mL, 145 mmol) over 10 minutes, followed by stirring at room temperature for 65 minutes. The reaction mixture was filtered, and the resulting solid was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, the drying agent was removed by filtration, and the mixture was concentrated under reduced pressure to give crude 2-amino-4-(chloromethyl)-3-fluoropyridine (10.3 g).

[0197] 2-Amino-4-(chloromethyl)-3-fluoropyridine crude product (3.47 g) and tripotassium phosphate (5.00 g, 23.6 mmol) were added to a 1,3-dimethyl-2-imidazolidinone solution (39 mL) of methyl 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (7.90 g, 19.7 mmol) and tetrabutylammonium iodide (0.726 g, 1.97 mmol), and the mixture was stirred at 50 ° C. for 4 hours. Water was added to the reaction mixture, and the resulting solid was collected by filtration and washed with a mixture of acetonitrile and water to give the title compound (10.3 g, 60%). LCMS m / z: 527[M+H] + HPLC retention time: 0.63 minutes (analysis condition B)

[0198] Compound j2: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid hydrochloride [ka] The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (Compound j1) under the same conditions as in the production example for Compound a7. LCMS m / z: 513[M+H] + HPLC retention time: 0.76 minutes (analysis condition D)

[0199] Compound j3: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid hydrochloride (Compound J2) under the same conditions as in the production example for Compound A8. LCMS m / z: 512[M+H] + HPLC retention time: 0.84 minutes (analysis condition D)

[0200] Compound J-1: 2-(2-Fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide (Compound j3) under the same conditions as in the production example for Compound A-25. LCMS m / z: 605[M+H] + HPLC retention time: 0.95 minutes (analysis condition E)

[0201] Compound k1: Methyl 2-(2-fluoro-4-iodoanilino)-5-formyl-1-methyl-6-oxopyridine-3-carboxylate [ka] To a solution of methyl 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (132 mg, 0.328 mmol) in acetonitrile (2.7 mL), (chloromethylene)dimethyliminium chloride (168 mg, 1.31 mmol) was added and stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was stirred for 30 minutes. The solid was then filtered to give the title compound (108 mg, 76%). LCMS m / z: 431[M+H] + HPLC retention time: 0.80 minutes (analysis condition B)

[0202] Compound k4: Methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate [ka] The title compound was synthesized from methyl 2-(2-fluoro-4-iodoanilino)-5-formyl-1-methyl-6-oxopyridine-3-carboxylate (Compound K1) under the same conditions as in the preparation examples for Compound A2, Compound A5, and Compound A6. However, 2-nitrobenzene-1-sulfonohydrazide was used instead of 4-methylbenzenesulfonylhydrazide used in the preparation example for Compound A2. In addition, [2-fluoro-3-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]boronic acid and DIPEA were used instead of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (Compound A4) and potassium carbonate used in the preparation example for Compound A5, respectively. LCMS m / z: 526[M+H] + HPLC retention time: 0.90 minutes (Analysis condition B)

[0203] Compound k11: 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid [ka] The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (Compound k4) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for Compound A-25 and Compound b2, except that pyridine was used as a solvent in the sulfonamidation step. LCMS m / z: 604[M+H] + HPLC retention time: 0.77 min (analysis condition B)

[0204] Compound K-10: 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide [ka] To a solution of 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid (Compound k11, 22.0 mg, 0.036 mmol) in anhydrous DMF (0.264 mL), HOOBt (8.92 mg, 0.055 mmol) and EDC·HCl (10.5 mg, 0.055 mmol) were added and stirred at room temperature for 3 hours. Then, 7 M ammonia in MeOH (20.8 μL, 0.146 mmol) was added at 0 °C and stirred for 1 hour. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid in water / 0.1% formic acid in acetonitrile) to afford the title compound (15.8 mg, 72%) as a colorless solid. LCMS m / z: 603[M+H] + HPLC retention time: 1.42 minutes (analysis condition H)

[0205] Compound l2: Methyl 2-bromo-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate [ka] The title compound was obtained from 2-bromo-5-fluoropyridine-4-carboxylic acid under the same conditions as in the preparation example for Compound C5 and Compound A1, except that 2-fluoro-4-trimethylsilylaniline was used instead of 4-iodo-2-methylaniline used in the preparation example for Compound C5. LCMS m / z: 397[M+H] + HPLC retention time: 1.17 minutes (analysis condition G)

[0206] Compound l3a: Methyl 5-(2-fluoro-4-trimethylsilylanilino)-2-formylpyridine-4-carboxylate [ka] Compound l3b: 5-(2-Fluoro-4-trimethylsilylanilino)-4-methoxycarbonylpyridine-2-carboxylic acid [ka] Methyl 2-bromo-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate (Compound 12, 2.5 g, 6.29 mmol), 1,1,3-trioxo-1,2-benzothiazole-2-carbaldehyde (2.66 g, 612.6 mmol), Xantphos (728 mg, 1.26 mmol), palladium acetate (141 mg, 0.629 mmol), and sodium carbonate (1.67 g, 15.7 mmol) were added to a suspension of methyl 2-bromo-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate (Compound 12, 2.5 g, 6.29 mmol) in anhydrous DMF (63 mL). A solution of triethylsilane (2.01 mL, 12.6 mmol) in anhydrous DMF (63 mL) was added and stirred at room temperature for 10 minutes, then at 75° C. for 2.5 hours. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give compound 13a (0.4 g, 18%) and compound 13b (1.4 g, 61%), each as a yellow solid. compound l3a LCMS m / z: 347[M+H] + HPLC retention time: 1.06 minutes (analysis condition G) compound l3b LCMS m / z: 363[M+H] + HPLC retention time: 0.92 minutes (analysis condition G)

[0207] Compound l4: Methyl 5-(2-fluoro-4-trimethylsilylanilino)-2-(hydroxymethyl)pyridine-4-carboxylate [ka] To a solution of methyl 5-(2-fluoro-4-trimethylsilylanilino)-2-formylpyridine-4-carboxylate (Compound 13a, 500 mg, 1.44 mmol) in anhydrous THF (14 mL), 1 M borane tetrahydrofuran complex THF solution (4.33 mL, 4.33 mmol) was added and stirred at room temperature for 1 hour. To the reaction mixture, acetic acid (0.496 mL, 8.66 mmol) was added and concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% formic acid in water / 0.1% formic acid in acetonitrile) to afford the title compound (360 mg, 72%) as a pale yellow solid. LCMS m / z: 349[M+H] + HPLC retention time: 0.91 min (analysis condition G)

[0208] Compound l4: Methyl 5-(2-fluoro-4-trimethylsilylanilino)-2-(hydroxymethyl)pyridine-4-carboxylate [ka] Borane dimethyl sulfide complex (0.747 mL, 7.86 mmol) was added to a solution of 5-(2-fluoro-4-trimethylsilylanilino)-4-methoxycarbonylpyridine-2-carboxylic acid (Compound 13b, 570 mg, 1.57 mmol) in anhydrous THF (16 mL) and stirred at room temperature for 2 hours. Acetic acid (1.58 mL, 27.6 mmol) was added to the reaction mixture, which was then concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% formic acid in water / 0.1% formic acid in acetonitrile) to afford the title compound (350 mg, 64%) as a pale yellow solid. LCMS m / z: 349[M+H] + HPLC retention time: 0.91 min (analysis condition G)

[0209] Compound l5: Methyl 2-(chloromethyl)-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate [ka] To a solution of methyl 5-(2-fluoro-4-trimethylsilylanilino)-2-(hydroxymethyl)pyridine-4-carboxylate (Compound 14, 400 mg, 1.15 mmol) in DCM (12 mL), thionyl chloride (0.168 mL, 2.30 mmol) was added and stirred at room temperature for 50 minutes. The reaction mixture was concentrated under reduced pressure to give the crude product (400 mg) of the title compound. LCMS m / z: 367[M+H] + HPLC retention time: 1.11 minutes (analysis condition G)

[0210] Compound l6: Methyl 2-[[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]methyl]-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate [ka] A suspension of methyl 2-(chloromethyl)-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate (Compound I5, 584 mg, 1.59 mmol), [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (Compound A4, 731 mg, 2.39 mmol), tetrakistriphenylphosphine palladium (184 mg, 0.159 mmol), and potassium carbonate (660 mg, 4.78 mmol) in 1,4-dioxane (17 mL) was stirred at 110 °C for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was removed by filtration. The mixture was then concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane / ethyl acetate) to afford the title compound (583 mg, 62%) as a yellow solid. LCMS m / z: 593[M+H] + HPLC retention time: 1.13 minutes (analysis condition G)

[0211] Compound l7: Methyl 2-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate [ka] The title compound was synthesized from methyl 2-[[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]methyl]-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate (Compound l6) under the same conditions as in the production example for Compound a6. LCMS m / z: 443[M+H] + HPLC retention time: 0.83 minutes (analysis condition G)

[0212] Compound l8: Methyl 2-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)pyridine-4-carboxylate [ka] A solution of methyl 2-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate (Compound 17, 300 mg, 0.678 mmol) in anhydrous DCM (14 mL) was cooled to 0 ° C., and iodine monochloride (220 mg, 1.36 mmol) was added. The mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography to give the title compound (320 mg, 95%) as a yellow solid. LCMS m / z: 497[M+H] + HPLC retention time: 0.69 minutes (analysis condition G)

[0213] Compound L-1: 5-(2-Fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide [ka] The title compound was synthesized from methyl 2-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)pyridine-4-carboxylate (Compound l8) under the same conditions as in the production examples for Compound a7, Compound K-10, and Compound A-1. LCMS m / z: 575[M+H] + HPLC retention time: 1.36 minutes (analysis condition H)

[0214] Compound m1: Methyl 2-amino-6-(aminomethyl)pyridine-3-carboxylate diacetate [ka] To a solution of methyl 2-amino-6-cyanopyridine-3-carboxylate (9.14 g, 51.6 mmol) in acetic acid (100 mL) and methanol (100 mL), palladium-on-activated carbon powder catalyst (10% palladium) (933 mg, 0.877 mmol) was added and stirred under a hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the crude product (15.3 g) of the title compound. LCMS m / z: 182[M+H] + HPLC retention time: 0.26 minutes (analysis condition G)

[0215] Compound m2: Methyl 2-amino-6-(formamidomethyl)pyridine-3-carboxylate [ka] Acetic anhydride (115 mL, 1.22 mol) was added over 30 minutes to a formic acid solution (230 mL) of methyl 2-amino-6-(aminomethyl)pyridine-3-carboxylate diacetate (Compound m1, 14.7 g, 48.8 mmol), and the mixture was stirred at 70°C overnight. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the drying agent was removed by filtration. The mixture was then concentrated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography to give the title compound (8.16 g, 80%) as a yellow solid. LCMS m / z: 210[M+H] + HPLC retention time: 0.29 minutes (analysis condition G)

[0216] Compound m3: Methyl 2-amino-5-bromo-6-(formamidomethyl)pyridine-3-carboxylate [ka] N-Bromosuccinimide (7.87 g, 44.2 mmol) was added in several portions to a solution of methyl 2-amino-6-(formamidomethyl)pyridine-3-carboxylate (compound m2, 9.25 g, 44.2 mmol) in anhydrous acetonitrile (400 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and water was added to the resulting residue. The resulting solid was washed with water to give the title compound (12.0 g, 94%) as a yellow solid. LCMS m / z: 288[M+H] + HPLC retention time: 0.52 minutes (analysis condition G)

[0217] Compound m4: Methyl 5-amino-8-bromoimidazo[1,5-a]pyridine-6-carboxylate [ka] Phosphoryl chloride (17.5 mL, 187 mmol) was added to a suspension of methyl 2-amino-5-bromo-6-(formamidomethyl)pyridine-3-carboxylate (Compound m3, 12.0 g, 41.7 mmol) in anhydrous toluene (200 mL), and the mixture was stirred at 95°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution and water were added to the resulting residue. The resulting solid was washed with water, dissolved in DCM, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the mixture was concentrated under reduced pressure to give the title compound (10.5 g, 93%) as a pale brown solid. LCMS m / z: 270[M+H] + HPLC retention time: 0.65 minutes (analysis condition G)

[0218] Compound m5: Methyl 5-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-8-bromoimidazo[1,5-a]pyridine-6-carboxylate [ka] To a solution of methyl 5-amino-8-bromoimidazo[1,5-a]pyridine-6-carboxylate (compound m4, 1.58 g, 5.85 mmol) and di-tert-butyl dicarbonate (3.19 g, 14.6 mmol) in anhydrous DCM (50 mL), 4-dimethylaminopyridine (143 mg, 1.17 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (2.5 g, 91%) as a yellow solid. LCMS m / z: 470[M+H] + HPLC retention time: 0.95 minutes (analysis condition G)

[0219] Compound m6: Methyl 5-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-8-ethenylimidazo[1,5-a]pyridine-6-carboxylate [ka] A suspension of methyl 5-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-8-bromoimidazo[1,5-a]pyridine-6-carboxylate (Compound m5, 2.5 g, 5.32 mmol), potassium vinyltrifluoroborate (1.07 g, 7.97 mmol), tetrakistriphenylphosphine palladium (614 mg, 0.532 mmol), and cesium carbonate (5.20 g, 16.0 mmol) in 1,4-dioxane (40 mL) and water (10 mL) was stirred at 100 °C for 2 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford the title compound (1.68 g, 76%) as a yellow solid. LCMS m / z: 418[M+H] + HPLC retention time: 0.89 minutes (analysis condition G)

[0220] Compound m8: Methyl 5-amino-8-formylimidazo[1,5-a]pyridine-6-carboxylate trifluoroacetate [ka] The title compound was synthesized from methyl 5-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-8-ethenylimidazo[1,5-a]pyridine-6-carboxylate (Compound M6) under the same conditions as in the production examples for Compound C6 and Compound A6. LCMS m / z: 220[M+H] + HPLC retention time: 0.48 minutes (analysis condition G)

[0221] Compound m9: Methyl 5-amino-8-(5,5-dimethyl-1,3-dioxan-2-yl)imidazo[1,5-a]pyridine-6-carboxylate [ka] A suspension of methyl 5-amino-8-formylimidazo[1,5-a]pyridine-6-carboxylate trifluoroacetate (Compound m8, 475 mg, 1.43 mmol), p-toluenesulfonic acid monohydrate (54.2 mg, 0.285 mmol), and 2,2-dimethyl-1,3-propanediol (742 mg, 7.13 mmol) in toluene (30 mL) was stirred at 110 °C overnight. DIPEA (1 mL) was added to the reaction mixture, which was then concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography to afford the title compound (340 mg, 78%) as a red solid. LCMS m / z: 306[M+H] + HPLC retention time: 0.66 minutes (analysis condition G)

[0222] Compound m10: Methyl 5-chloro-8-(5,5-dimethyl-1,3-dioxan-2-yl)imidazo[1,5-a]pyridine-6-carboxylate [ka] A suspension of methyl 5-amino-8-(5,5-dimethyl-1,3-dioxan-2-yl)imidazo[1,5-a]pyridine-6-carboxylate (Compound m9, 340 mg, 1.11 mmol) in acetonitrile (15 mL) was cooled to 0 °C, and copper(I) chloride (165 mg, 1.67 mmol) and copper(II) chloride (225 mg, 1.67 mmol) were added. tert-Butyl nitrite (172 mg, 1.67 mmol) was then added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography to afford the title compound (237 mg, 66%) as a red solid. LCMS m / z: 325[M+H] + HPLC retention time: 0.77 minutes (analysis condition G)

[0223] Compound m11: Methyl 8-(5,5-dimethyl-1,3-dioxan-2-yl)-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylate [ka] A suspension of methyl 5-chloro-8-(5,5-dimethyl-1,3-dioxan-2-yl)imidazo[1,5-a]pyridine-6-carboxylate (Compound m10, 237 mg, 0.730 mmol), cesium carbonate (713 mg, 2.19 mmol), and 2-fluoro-4-iodoaniline (346 mg, 1.46 mmol) in DMA (4 mL) was stirred at 50 °C overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the drying agent was removed by filtration. The mixture was then concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography to afford the title compound (210 mg, 55%) as a yellow solid. LCMS m / z: 526[M+H] + HPLC retention time: 1.02 minutes (analysis condition G)

[0224] Compound m12: Methyl 5-(2-fluoro-4-iodoanilino)-8-formylimidazo[1,5-a]pyridine-6-carboxylate [ka] A suspension of methyl 8-(5,5-dimethyl-1,3-dioxan-2-yl)-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylate (Compound m11, 210 mg, 0.400 mmol) in water (2 mL) and TFA (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.1% formic acid in water / 0.1% formic acid in acetonitrile) to give the title compound (168 mg, 96%) as a yellow solid. LCMS m / z: 440[M+H] + HPLC retention time: 0.84 minutes (analysis condition G)

[0225] Compound m15: Methyl 8-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylate trifluoroacetate [ka] The title compound was synthesized from methyl 5-(2-fluoro-4-iodoanilino)-8-formylimidazo[1,5-a]pyridine-6-carboxylate (Compound m12) under the same conditions as in the preparation examples for Compound a2, Compound a5, and Compound a6, except that MeOH was used instead of EtOH used in the preparation example for Compound a2. LCMS m / z: 536[M+H] + HPLC retention time: 0.54 minutes (analysis condition F)

[0226] Compound m16: 8-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylic acid trifluoroacetate [ka] A suspension of methyl 8-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylate trifluoroacetate (Compound m15, 60 mg, 0.092 mmol) and lithium hydroxide monohydrate (78 mg, 1.85 mmol) in THF (3 mL) and water (2 mL) was stirred at 50 °C overnight. The reaction mixture was acidified with formic acid and then concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% TFA aqueous solution / 0.1% TFA acetonitrile solution) to give the title compound (42 mg, 72%) as a yellow solid. LCMS m / z: 522[M+H] + HPLC retention time: 0.45 minutes (analysis condition F)

[0227] Compound m17: 8-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxamide trifluoroacetate [ka] A solution of 8-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylic acid trifluoroacetate (compound m16, 42 mg, 0.066 mmol) in DMF (1.6 mL) was cooled to 0 ° C., and HATU (390 mg, 1.03 mmol), ammonium chloride (67.2 mg, 1.26 mmol), and DIPEA (0.253 mL, 1.45 mmol) were added and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.1% TFA aqueous solution / 0.1% TFA acetonitrile solution) to give the title compound (25 mg, 60%) as a yellow solid. LCMS m / z: 521[M+H] + HPLC retention time: 0.41 min (analysis condition F)

[0228] Compound M-1: 5-(2-Fluoro-4-iodoanilino)-8-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]imidazo[1,5-a]pyridine-6-carboxamide [ka] The title compound was synthesized from 8-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxamide trifluoroacetate (Compound m17) under the same conditions as in the production example for Compound A-1. LCMS m / z: 614[M+H] + HPLC retention time: 1.18 minutes (analysis condition H)

[0229] Compound n1: 6-chloro-5-fluoro-4-(2-fluoro-4-iodoanilino)pyridine-3-carboxylic acid [ka] A solution of 2-fluoro-4-iodoaniline (2.26 g, 9.52 mmol) in anhydrous THF (8 mL) was cooled to -78 °C, and a 2M LDA solution in THF / heptane / ethylbenzene (7.14 mL, 14.3 mmol) was added and stirred for 30 minutes. A solution of 4,6-dichloro-5-fluoropyridine-3-carboxylic acid (1.00 g, 4.76 mmol) in anhydrous THF (8 mL) was then added and stirred at -78 °C for 30 minutes. The reaction mixture was then adjusted to pH 1-2 with water and 6M hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the mixture was concentrated under reduced pressure. The resulting residue was recrystallized (DCM) to give the title compound (850 mg, 44%) as a pale brown solid. LCMS m / z: 411[M+H] + HPLC retention time: 0.85 minutes (analysis condition G)

[0230] Compound n2: Methyl 6-chloro-5-fluoro-4-(2-fluoro-4-iodoanilino)pyridine-3-carboxylate [ka] The title compound was synthesized from 6-chloro-5-fluoro-4-(2-fluoro-4-iodoanilino)pyridine-3-carboxylic acid (Compound n1) under the same conditions as in the production example for Compound a1. LCMS m / z: 425[M+H] + HPLC retention time: 1.04 minutes (analysis condition G)

[0231] Compound n3: Methyl 5-fluoro-4-(2-fluoro-4-iodoanilino)-6-hydroxypyridine-3-carboxylate [ka] Potassium carbonate (570 mg, 4.12 mmol) and N-hydroxyacetamide (186 mg, 2.47 mmol) were added to a DMSO solution (2.75 mL) of methyl 6-chloro-5-fluoro-4-(2-fluoro-4-iodoanilino)pyridine-3-carboxylate (compound n2, 350 mg, 0.824 mmol), and the mixture was stirred at 100° C. for 1 hour. Water was added to the reaction mixture, and the resulting solid was washed with water and DCM to give the title compound (281 mg, 84%) as a light brown solid. LCMS m / z: 407[M+H] + HPLC retention time: 0.72 minutes (analysis condition G)

[0232] Compound n4: N-[4-(bromomethyl)-3-fluoropyridin-2-yl]-1,1-diphenylmethanimine [ka] To a solution of [2-(benzhydrylideneamino)-3-fluoropyridin-4-yl]methanol (2.30 g, 7.51 mmol) in anhydrous DCM (37.5 mL), DIPEA (3.93 mL, 22.5 mmol) and methanesulfonic anhydride (2.07 g, 11.3 mmol) were added and stirred at room temperature for 30 minutes. Next, a solution of lithium bromide (3.26 g, 37.5 mmol) in anhydrous THF (0.5 mL) was added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was then extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the mixture was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography to give the title compound (990 mg, 34%) as a yellow semi-solid. LCMS m / z: 369[M+H] + HPLC retention time: 0.94 minutes (analysis condition G)

[0233] Compound n5: Methyl 1-[[2-(benzhydrylideneamino)-3-fluoropyridin-4-yl]methyl]-5-fluoro-4-(2-fluoro-4-iodoanilino)-6-oxopyridine-3-carboxylate [ka] Lithium hydride (1.85 mg, 0.222 mmol) was added to a solution of methyl 5-fluoro-4-(2-fluoro-4-iodoanilino)-6-hydroxypyridine-3-carboxylate (compound n3, 30 mg, 0.074 mmol) in anhydrous DMF (0.739 mL) and stirred at room temperature for 30 minutes. Next, a solution of N-[4-(bromomethyl)-3-fluoropyridin-2-yl]-1,1-diphenylmethanimine (compound n4, 82 mg, 0.222 mmol) in anhydrous THF (0.5 mL) was added and stirred at room temperature for 1 hour. Lithium hydride (1 mg, 0.126 mmol) and a solution of compound n4 (25 mg, 0.068 mmol) in anhydrous THF (0.5 mL) were then added and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 °C, and acetic acid (21.1 μL) and water were added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (19 mg, 37%) as a colorless solid. LCMS m / z: 695[M+H] + HPLC retention time: 1.05 minutes (analysis condition G)

[0234] Compound n8: 1-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-fluoro-4-(2-fluoro-4-iodoanilino)-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from methyl 1-[[2-(benzhydrylideneamino)-3-fluoropyridin-4-yl]methyl]-5-fluoro-4-(2-fluoro-4-iodoanilino)-6-oxopyridine-3-carboxylate (Compound n5) under the same conditions as in the preparation example for Compound a6, Compound a7, and Compound K-10. However, in the first step, the reaction was carried out under the same conditions as in the preparation example for Compound a6, but with the addition of 4 M hydrochloric acid. LCMS m / z: 516[M+H] + HPLC retention time: 0.52 minutes (analysis condition B)

[0235] Compound N-1: 5-Fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from 1-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-fluoro-4-(2-fluoro-4-iodoanilino)-6-oxopyridine-3-carboxamide (Compound n8) under the same conditions as in the production example for Compound A-1. LCMS m / z: 609[M+H] + HPLC retention time: 0.94 minutes (analysis condition E)

[0236] Compound N-2: 5-Fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from 1-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-fluoro-4-(2-fluoro-4-iodoanilino)-6-oxopyridine-3-carboxamide (Compound n8) and the corresponding 4-nitrophenyl sulfamate under the same conditions as in the production example for Compound A-1. LCMS m / z: 637[M+H] + HPLC retention time: 1.04 minutes (analysis condition E)

[0237] Compound p3: Methyl 4-(2-fluoro-4-iodoanilino)-6-hydroxy-5-methylpyridine-3-carboxylate [ka] The title compound was synthesized from 4,6-dichloro-5-methylpyridine-3-carboxylic acid under the same conditions as in the preparation examples for Compound C5, Compound A1, and Compound N3, except that 2-fluoro-4-iodoaniline was used instead of 4-iodo-2-methylaniline used in the preparation example for Compound C5. LCMS m / z: 403[M+H] + HPLC retention time: 0.76 minutes (analysis condition G)

[0238] Compound P-1: 4-(2-Fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from methyl 4-(2-fluoro-4-iodoanilino)-6-hydroxy-5-methylpyridine-3-carboxylate (Compound p3) under the same conditions as in the preparation examples for Compound n4, Compound b2, Compound m17, Compound a6, and Compound A-1. However, 2 M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate used in the preparation example for Compound b2, and 4 M hydrogen chloride 1,4-dioxane solution was used instead of trifluoroacetic acid used in the preparation example for Compound a6. LCMS m / z: 605[M+H] + HPLC retention time: 0.66 minutes (analysis condition B)

[0239] [Test example] In the following test examples, the compounds described in the above preparation examples are represented by the compound numbers used in the above preparation examples. Ref-1 represents compound 34 in Bioorg.Med.Chem.Lett. 2008, vol. 18, no. 24, pp. 6501-6504, i.e., a compound represented by formula (A) below. Ref-2 represents compound 27 in Bioorg.Med.Chem.Lett. 2013, vol. 23, no. 8, pp. 2384-2390, i.e., a compound represented by formula (B) below. Ref-3 and ref-4 represent compound 9 and compound 10 in ChemMedChem. 2015, vol. 10, no. 12, pp. 2004-2013, i.e., compounds represented by formulas (C) and (D) below, respectively. In addition, ref-5 represents Compound 1 of ACS Medchem. Lett. 2014, vol. 5, no. 4, pp. 309-314, that is, a compound represented by the following formula (E).

[0240] ref-1: N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (PD0325901) [ka]

[0241] ref-2: 4-Fluoro-2-(2-fluoro-4-iodoanilino)-6-[3-(methylsulfamoylamino)phenoxy]benzamide [ka]

[0242] ref-3: 3-(2-Fluoro-4-iodoanilino)-5-[3-(propan-2-ylsulfonylamino)phenoxy]pyridine-4-carboxamide [ka]

[0243] ref-4: 3-[3-(cyclopropylsulfonylamino)phenoxy]-5-(2-fluoro-4-iodoanilino)pyridine-4-carboxamide [ka]

[0244] ref-5: 3-[[3-Fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one (CH5126766) [ka]

[0245] (Test Example 1) Effects on the interaction of RAF1 and MEK1 The effects of the compounds shown in Figures 4 to 7 on the interaction between RAF1 and MEK1 were examined using Biacore 8K (GE Healthcare) as follows.

[0246] GST-tagged RAF1 (Carna Biosciences) was immobilized on the surface of a Sensor Chip CM5 (GE Healthcare) using an anti-GST antibody (GE Healthcare). Then, running buffer (blank), 40 nM MEK1 solution, or a mixture of 40 nM MEK1 and 3 μM test compound was passed over the surface of the sensor chip for 120 seconds, followed by running buffer. MEK1 Recombinant Human Protein, Inactive (Thermo Fisher Scientific) was used as the MEK1. The running buffer was PBS (Sigma-Aldrich) supplemented with 1 mM DTT (Wako), 10 mM MgCl2 (Wako), 500 μM ATP (Wako), 0.01% Tween 20 (Junsei-Kagaku), and 1% DMSO (Sigma-Aldrich). The sample solution was also prepared in running buffer. Measurements were performed at 15°C. Both RAF1 and MEK1 were dephosphorylated with Lambda Protein Phosphatase (New England Biolabs) before use, and MEK1 was purified by size exclusion chromatography.

[0247] The resulting sensorgrams (graphs showing the time course of MEK1 binding to immobilized RAF1) were double-referencing-based using Biacore Insight Evaluation Software, and then normalized by the amount of RAF1 immobilized using TIBCO Spotfire. The normalized sensorgrams are shown in Figures 4 to 7. Above each sensorgram, the experiment ID, Biacore channel number, and compound number are listed in order (note that "no compound" indicates the absence of the test compound). In each sensorgram, the horizontal axis (X-axis) represents the time (seconds) after the start of sample addition, and the vertical axis (Y-axis) represents the normalized amount of MEK1 binding.

[0248] (Test Example 2) Effects on MEK and ERK phosphorylation The effects of the compounds shown in FIG. 8 (ref-5 and compound A-1) on the phosphorylation of MEK and ERK in cells were examined by Western blotting as follows.

[0249] A549 cells were seeded at 400,000 cells per well in a 12-well plate and cultured in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum (Sigma) in a 5% CO incubator at 37°C. The following day, test compounds (0.3 μM ref-5 or 0.05 μM compound A-1) or DMSO were added to the medium. After 30 minutes or 2 hours of culture, the cells were harvested with a cell scraper and solubilized. Extracted proteins were separated by SDS-PAGE and transferred to a PVDF membrane. After blocking, the PVDF membrane was treated with phospho-MEK1 / 2 (Ser217 / 221) antibody, MEK1 / 2 antibody, phospho-ERK1 / 2 (Thr202 / Tyr204) antibody, or ERK1 / 2 antibody (all from Cell Signaling Technology). After washing the primary antibody, the cells were treated with an HRP-labeled secondary antibody (Cell Signaling Technology), washed, and then the signal was detected by chemiluminescence using a Chemi-Lumi One Super (Nacalai). Figure 8 shows an electrophoretic image showing the results of Western blotting. In Figure 8, "p-MEK" and "p-ERK" represent phosphorylated MEK and phosphorylated ERK, respectively.

[0250] (Test Example 3) MEK1 inhibitory activity The MEK1 inhibitory activity of the compounds listed in Table 6 below was evaluated by the fluorescence polarization method as follows.

[0251] The test compound, CRAF (Thermo Fisher), MEK1 (Thermo Fisher), and ERK2 (Carna Biosciences) were mixed in a buffer containing ATP and reacted at 30°C for 60 minutes. Next, FAM-labeled Erktide (Molecular Devices) was added, and the mixture was reacted at 30°C for 45 minutes. Furthermore, IMAP (registered trademark) Progressive Binding Reagent (Molecular Devices) was added, and the mixture was reacted at room temperature for 15 minutes. After the reaction, fluorescence polarization was measured using a fluorescent plate reader, and the 50% inhibitory concentration (IC) was determined based on the inhibition rate relative to the control group containing no test compound. 50The results are shown in Table 6.

[0252] (Test Example 4) BRAF inhibitory activity The BRAF inhibitory activity of the compounds listed in Table 6 below was evaluated by time-resolved fluorescence-fluorescence resonance energy transfer as follows.

[0253] The test compound, BRAF (Eurofins), and MEK1 (Thermo Fisher) were mixed in a buffer containing ATP and reacted at 30°C for 90 minutes. Next, LANCE (registered trademark) Eu-Phospho-MEK1 / 2 (Ser217 / 221) antibody (PerkinElmer) was added and reacted at room temperature for 60 minutes. After the reaction, fluorescence resonance energy transfer was measured using a fluorescent plate reader, and the 50% inhibitory concentration (IC) was calculated based on the inhibition rate relative to the control group containing no test compound. 50 The results are shown in Table 6.

[0254] (Test Example 5) Cell proliferation inhibitory activity The cell growth inhibitory activity of the compounds listed in Table 6 below was evaluated by measuring the ATP content of viable cells as follows.

[0255] Test compounds were serially diluted with DMSO and then 2+ , Mg 2+ The cells were diluted 25-fold with free phosphate-buffered saline and dispensed at 5 μL per well into a 96-well plate. Cell suspensions of human lung cancer cell lines A549, Calu-6, or NCI-H2122 (all obtained from ATCC) were prepared using the following medium supplemented with 10% fetal bovine serum (Sigma) to achieve the following cell numbers. 95 μL of this cell suspension was dispensed per well into the plate containing the test compound and cultured in a 5% carbon dioxide incubator at 37°C. After 4 days, 80 μL of CellTiter-Glo® (Promega) was added to each well, and bioluminescence was measured using a fluorescent plate reader. The 50% inhibitory concentration (IC) was determined based on the inhibition rate relative to the control group containing no test compound. 50 The results are shown in Table 6. A549: Dulbecco's modified Eagle's medium (Sigma); 2000 cells / 95 μL Calu-6: Eagle's minimum essential medium (Sigma); 4000 cells / 95 μL NCI-H2122: RPMI-1640 medium (Sigma); 2000 cells / 95 μL

[0256] (Test Example 6) Human liver microsome metabolic stability For the compounds listed in Table 6 below, a metabolic stability test in human liver microsomes was carried out using Biomek3000 (Beckman Coulter) as follows.

[0257] 400 μL of 1 mg / mL human liver microsomes (XENOTECH) in 0.1 M potassium phosphate buffer (pH 7.4) was dispensed into a 96-well plate per well. Next, 4 μL of a 200 μM DMSO solution of the test compound was added and incubated until the temperature reached 37°C. To this reaction solution (200 μL), 200 μL of a solution of 2 mM NADPH (ORIENTAL YEAST) in 0.1 M potassium phosphate buffer (pH 7.4) incubated at 37°C was added. At 0, 5, 15, or 30 minutes after addition, 50 μL of the reaction solution was added to 100 μL of acetonitrile to terminate the metabolic reaction. 50 μL of 1 μM warfarin aqueous solution was added as an internal standard to each reaction solution after the metabolic reaction was terminated. The reaction solution was filtered and analyzed by LC / MS / MS (LC: NEXERA manufactured by SHIMADZU; MS: 4000Qtrap manufactured by ABSciex; column: Ascentis Express C18 HPLC column (5 cm × 2.1 mm, 2.7 μm); ionization method: electrospray ionization). The residual rate relative to the amount of test compound at 0 minutes was calculated from the peak area ratio of the test compound / internal standard obtained. The elimination rate constant (ke) was calculated from the incubation time and residual rate using the rate equation for the first-order elimination process, and the liver-specific clearance (CLint) was calculated using the following formula. The results are shown in Table 6. CLint(μL / min / mg)=ke(min -1) / human liver microsome concentration (mg protein / μL)

[0258] [Table 6]

[0259] (Test Example 7) In vivo antitumor effects The effect of compound A-1 on cancer cells with KRAS mutation was evaluated using tumor-bearing mice as follows.

[0260] Calu-6, a human lung cancer cell line carrying a KRAS mutation, was transplanted into nude mice (CAnN.Cg-Foxn1nu / CrlCrlj, female, 5 weeks old, Charles River, CA) by subcutaneous injection of a cell suspension into the flank area using a 26G needle. Tumor volumes were approximately 200 mm. 3 On the 17th day after transplantation, when the mice reached 100 mg / kg, the mice were divided into 5 groups (8 mice per group) based on the dose of the test compound, and administration of the test compound began. Mice in group 4 (A-1 administration group) were orally administered 0.0625 mg / kg, 0.25 mg / kg, 1 mg / kg, or 4 mg / kg of compound A-1 using 10% DMSO / 10% Cremophor EL / 15% PEG400 / 15% HPCD as the vehicle. Mice in the remaining group (vehicle control group) were orally administered the vehicle alone. The test compound or vehicle was administered once daily for 10 days.

[0261] Tumor volumes were measured 20, 24, and 27 days after transplantation. Tumor volumes were calculated using the following formula after measuring the long and short diameters of the tumors with a caliper. The results are shown in Figure 9. Figure 9 is a graph showing the change in tumor volume (mean ± standard deviation) over time. The horizontal axis (X axis) represents the number of days after transplantation, and the vertical axis (Y axis) represents tumor volume. Tumor volume (mm 3 ) = 1 / 2 x major axis (mm) x minor axis (mm) x minor axis (mm)

Claims

【Claim 1】 The invention described in this specification.

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