Method for manufacturing aryl amide derivatives

Abstract

This disclosure provides a method for manufacturing, for example, 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzoamide or a pharmaceutically permissible salt thereof, or a pharmaceutically permissible solvate of the aforementioned compound or salt, comprising the step of reacting (2-amino-3-fluoropyridin-4-yl)methanol in acetonitrile with methyl chloroformate and N,N-dimethylaminopyridine to obtain (2-amino-3-fluoropyridin-4-yl)methylmethyl carbonate. This disclosure also provides a method for manufacturing specific arylamide derivatives having RAF / MEK complex stabilizing activity and / or MEK inhibitory activity, useful for the treatment or prevention of proliferative diseases, particularly cancer, and capable of obtaining arylamide derivatives with a small number of steps.

Description

[Technical Field]

[0001] This disclosure relates to a method for manufacturing aryl amide derivatives. Furthermore, this disclosure relates to compounds that can be used to manufacture aryl amide derivatives and methods for manufacturing them. [Previous Technology]

[0002] MEK (mitogen-activated protein kinase) is known as a serine-threonine kinase in the MAPK signaling pathway, transmitting signals within cells and is closely related to cell proliferation (see Non-Patent Literature 1). As MEK inhibitors, PD0325901, CH4987655, Trametinib, Cobimetinib, and Selumetinib have been reported (see Patent Literature 1 and Non-Patent Literature 2), and clinical efficacy has been reported for cancers with RAF mutations, such as malignant melanomas with BRAF mutations, whether as a single agent or in combination with RAF inhibitors (see Non-Patent Literature 3 and 4).

[0003] On the other hand, among MEK inhibitors, some are known to have insufficient clinical efficacy against cancers with RAS mutations, such as non-small cell lung cancer with RAS mutations. In fact, selumetinib and trametinib have been reported to have lack of efficacy in clinical trials of non-small cell lung cancer with KRAS mutations (see Non-Patent Literature 5 and 6).

[0004] CH5126766 (see Patent Document 2 and Non-Patent Documents 7 and 8), known not only as a MEK inhibitor but also as a stabilizer of the RAF / MEK complex, has been reported to show clinical efficacy in non-small cell lung cancer with RAS mutations (see Non-Patent Document 9). Furthermore, CH5126766 has also been reported to stabilize the RAF / MEK complex and simultaneously inhibit the overactivation of MEK phosphorylation (feedback activation of the MAPK signaling pathway) (see Non-Patent Document 10) (see Non-Patent Documents 7 and 8). This feedback activation is considered one of the reasons why the clinical efficacy of MEK inhibitors in cancers with RAS mutations may not be sufficient (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 Document]

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

[0007] [The problem the invention aims to solve]

[0008] Although some RAF / MEK complex stabilizers or MEK inhibitors are known for the treatment or prevention of proliferative diseases, especially cancer, it is still not possible to say that there are options that can meet the diverse needs of consumers.

[0009] Under these circumstances, a specific aryl amide derivative (represented by the general formula (1) described below) has been newly discovered to have RAF / MEK complex stabilizing activity and / or MEK inhibitory activity, and is used for the treatment or prevention of cell proliferation diseases, especially cancer.

[0010] The purpose of this disclosure is to provide a method for manufacturing the above-mentioned arylamide derivatives, which can obtain arylamide derivatives in a small number of steps. [Means for solving the problem]

[0011] This 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 permissible salt thereof or a pharmaceutically permissible solvate of the aforementioned compound or salt, comprising: (I) reacting a compound represented by the following general formula (2) in a solvent with a compound represented by X 1-R 9 and a base to obtain a compound represented by the following general formula (4). [Chemical 1][Chemical 2][In the formula, R1 is -S(=O)2-NH-R11 or -S(=O)2-R11, R11 is a hydrogen atom, a C1-6 alkyl group (which may be substituted with a halogen atom, hydroxyl group or C1-6 alkoxy group) or a C3-6 cycloalkyl group (which 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 (which may be substituted with a halogen atom, hydroxyl group or C1-6 alkoxy group), a C3-6 cycloalkyl group (which may be substituted with a halogen atom or C1-6 alkyl group) or a C1-6 alkoxy group (which may be substituted with a halogen atom, hydroxyl group or C1-6 alkoxy group), R R4 is a hydrogen atom, halogen atom, C1-6 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-6 cycloalkyl, or C1-6 alkylthioyl; R5 is a halogen atom or C1-6 alkyl; R6 is a hydrogen atom, halogen atom, or C1-6 alkyl; R7 is a hydrogen atom, halogen atom, or C1-6 alkyl; R8 is a hydrogen atom, halogen atom, or C1-6 alkyl; X1 is a halogen atom or -O-R9; R9 is -C(=O)-R12, -C(=O)-O-R12, or -P(=O)(-O-R12)2; R12 is a C1-6 alkyl or aryl.

[0012] (A2) The method as described in (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 as described in (A2), wherein the base used in step (I) is N,N-dimethylaminopyridine.

[0013] (A4) The method described in 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-methyltetrahydropiperanone, cyclopentyl methyl ether, and tert-butyl methyl ether. (A5) The method described in (A4), wherein the solvent used in step (I) is acetonitrile.

[0014] (A6) The method described in any one of (A1) to (A5), further comprising: (II) reacting the compound represented by general formula (4) with the compound represented by general formula (10) in a solvent and in the presence of a catalyst to obtain the compound represented by general formula (5). [Chemical 3][Chemical 4][In the formula, R13 is -B (-OR 14) (-OR 15) or -BF 3K, R14 and R15 are each independent and are hydrogen atoms or C1-6 alkyl (which C1-6 alkyl may be substituted with C1-6 alkoxy or aryl), or R14 and R15 together with the oxygen atom and boron atom in between form a 5-8 member saturated or unsaturated ring (which may be substituted with C1-6 alkyl, C1-6 alkoxy or aryl, and may be condensed with a benzene ring), R2 to R9 have the same meaning as above.]

[0015] (A7) The method described in (A6) wherein the catalyst used in step (II) is a palladium catalyst or a nickel catalyst.

[0016] (A8) The method described in (A7), wherein the catalyst used in step (II) is a palladium catalyst. (A9) The method described in (A8), wherein the palladium catalyst is a combination of at least one selected from the group consisting of bis(allyl chloride palladium), tetra(triphenylphosphine) palladium, tris(benzylacetone) dipalladium and palladium acetate (II) with a compound represented by the following general formula (L1). [Chemical 5] [In the formula, R20 and R21 are each independent and are C3-6 cycloalkyl, R22 is C1-6 alkoxy or amino (the amino group may be substituted by C1-6 alkyl or aryl), R23 is a hydrogen atom or C1-6 alkoxy, and R24 is a hydrogen atom or -S(=O)2-O-Na. (A10) The method as described in (A9), wherein R20 and R21 are cyclohexyl, R22 is methoxy, isopropoxy, or N,N-dimethylamino, R23 is a hydrogen atom, methoxy, or isopropoxy, and R24 is a hydrogen atom. (A11) The method as described in (A10), wherein the aforementioned palladium catalyst is a combination of at least one selected from the group consisting of bis(allyl chloride palladium), tetra(triphenylphosphine)palladium, tris(benzylacetone)palladium, and palladium acetate (II) and at least one selected from the group consisting of 2',6'-dimethoxy-2-(dicyclohexylphosphine)biphenyl, 2-dicyclohexylphosphine-2',6'-diisopropoxybiphenyl, and 2-dicyclohexylphosphine-2'-(N,N-dimethylamino)biphenyl. (A12) The method described in (A11), wherein the palladium catalyst is a combination of bis(allyl palladium chloride) and at least one compound 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 described in (A8), wherein the palladium catalyst is a compound represented by the following general formula (L2). [Chemical 6] [In the formula, R20 and R21 are each independent and are C3-6 cycloalkyl, R22 is C1-6 alkoxy or amino (the amino group may be substituted by C1-6 alkyl or aryl), R23 is a hydrogen atom or C1-6 alkoxy, R24 is a hydrogen atom, R25 is a hydrogen atom or C1-6 alkyl, R26 is a C1-6 alkyl, and arrows indicate coordinate bonds.] (A14) As described in (A13), wherein R20 and R21 are cyclohexyl, R22 is methoxy, isopropoxy or N,N-dimethylamino, R23 is a hydrogen atom, methoxy or isopropoxy, R25 is a hydrogen atom or methyl, and R26 is methyl.(A15) The method described in (A14) wherein the palladium catalyst is selected from at least one of the group consisting of (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. (A16) The method described in (A15), wherein the palladium catalyst is (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate.

[0017] (A17) The method as described in (A7), wherein the catalyst used in step (II) is a nickel catalyst. (A18) The method as described in (A17), wherein the aforementioned nickel catalyst is a combination of at least one selected from the group consisting of bis(1,5-cyclooctadiene)nickel and nickel chloride (II) and at least one selected from the group consisting of tricyclohexylphosphine, 1,1'-bis(diphenylphosphine)ferrocene, and 1,3-bis(diphenylphosphine)propane. (A19) The method as described in (A17), wherein the aforementioned nickel catalyst is at least one selected from the group consisting of dichlorobis(tricyclohexylphosphine)nickel (II), dichloro[1,1'-bis(diphenylphosphine)ferrocene]nickel (II), and dichloro[1,3-bis(diphenylphosphine)propane]nickel (II).

[0018] (A20) The method described in (A6), wherein the catalyst used in step (II) is selected from a combination of bis(allyl palladium chloride) and 2',6'-dimethoxy-2-(dicyclohexylphosphino)biphenyl, a combination of bis(allyl palladium chloride) and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, a combination of bis(allyl palladium chloride) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, or (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate. At least one of the group consisting of 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. (A21) The method as described in (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.

[0019] (A22) The method described in any one of (A6) to (A21), wherein the solvent used in step (II) comprises a C1-6 alcohol. (A23) The method described in (A22), wherein the solvent used in step (II) comprises a C2-3 alcohol. (A24) The method described in (A23), wherein the solvent used in step (II) comprises ethanol.

[0020] (A25) The method described in any one of (A6) to (A24), further comprising (III) reacting the compound represented by general formula (5) with X2-S(=O)2-NH-R11 or the compound represented by X2-S(=O)2-R11 to obtain the compound represented by general formula (1) or its salt or a solvate of the aforementioned compound or salt. [Where X2 is a halogen atom, and R11 has the same meaning as described above.]

[0021] (A26) The method described in any one of (A1) to (A25), wherein R9 is -C(=O)-O-R12, and R12 is a C1-6 alkyl or aryl group. (A27) The method described in (A26), wherein R2 is a halogen atom. (A28) The method described in (A27), wherein R2 is a fluorine atom, R9 is -C(=O)-O-CH3, and X1 is a chlorine atom. (A29) The method described in any of (A1) to (A28), wherein R2 is a fluorine atom, R1 is -S(=O)2-NH-R11, R11 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, and X1 is a chlorine atom.

[0022] (A30) The method described in any of (A1) to (A29), wherein the compound represented by general formula (1) is 2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzamide.

[0023] (A31) The method described in any of (A1) to (A30) is a method for producing a sodium salt of the compound represented by general formula (1).

[0024] This disclosure provides the methods described in (B1) to (B26) below. (B1) A method for producing a compound represented by the following general formula (1) or a pharmaceutically permissible salt thereof or a pharmaceutically permissible solvate of the aforementioned compound or salt, comprising: (II) reacting a compound represented by the following general formula (4) in a solvent and in the presence of a catalyst with a compound represented by the following general formula (10) to obtain a compound represented by the following general formula (5). [Chemical 7][Chemical 8][Chemical 9][In the formula, R1 is -S(=O)2-NH-R11 or -S(=O)2-R11, R11 is a hydrogen atom, a C1-6 alkyl group (which may be substituted with a halogen atom, hydroxyl group or C1-6 alkoxy group) or a C3-6 cycloalkyl group (which 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 (which may be substituted with a halogen atom, hydroxyl group or C1-6 alkoxy group), a C3-6 cycloalkyl group (which may be substituted with a halogen atom or C1-6 alkyl group) or a C1-6 alkoxy group (which may be substituted with a halogen atom, hydroxyl group or C1-6 alkoxy group), R R4 is a hydrogen atom, halogen atom, C1-6 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-6 cycloalkyl, or C1-6 alkylthioyl; R5 is a halogen atom or C1-6 alkyl; R6 is a hydrogen atom, halogen atom, or C1-6 alkyl; R7 is a hydrogen atom, halogen atom, or C1-6 alkyl; R8 is a hydrogen atom, halogen atom, or C1-6 alkyl; R9 is -C(=O)-R12, -C(=O)-O-R12, or -P(=O)(-O-R12)2; R12 is a C1-6 alkyl or aryl; R13 is -B(-OR14)(-OR15) or -BF3K; R14 and R15 are each independent and are either hydrogen atoms or C1-6 alkyl (which may be substituted by C1-6 alkoxy or aryl), or R R14 and R15, together with the oxygen and boron atoms in between, form a 5-8 member saturated or unsaturated ring (this ring can be substituted with C1-6 alkyl, C1-6 alkoxy, or aryl groups, and can also undergo condensation with a benzene ring).

[0025] (B2) The method described in (B1), wherein the catalyst used in step (II) is a palladium catalyst or a nickel catalyst.

[0026] (B3) The method as described in (B2), wherein the catalyst used in step (II) is a palladium catalyst. (B4) The method as described in (B3), wherein the palladium catalyst is a combination of at least one selected from the group consisting of bis(allyl chloride palladium), tetra(triphenylphosphine) palladium, tris(benzylacetone) dipalladium, and palladium acetate (II) with a compound represented by the following general formula (L1). [Chemical 10] [In the formula, R20 and R21 are each independent and are C3-6 cycloalkyl, R22 is C1-6 alkoxy or amino (the amino group may be substituted by C1-6 alkyl or aryl), R23 is a hydrogen atom or C1-6 alkoxy, and R24 is a hydrogen atom or -S(=O)2-O-Na. (B5) The method as described in (B4), wherein R20 and R21 are cyclohexyl, R22 is methoxy, isopropoxy, or N,N-dimethylamino, R23 is a hydrogen atom, methoxy, or isopropoxy, and R24 is a hydrogen atom. (B6) The method as described in (B5), wherein the aforementioned palladium catalyst is a combination of at least one selected from the group consisting of bis(allyl chloride palladium), tetra(triphenylphosphine)palladium, tris(benzylacetone)palladium, and palladium acetate (II) and at least one selected from the group consisting of 2',6'-dimethoxy-2-(dicyclohexylphosphine)biphenyl, 2-dicyclohexylphosphine-2',6'-diisopropoxybiphenyl, and 2-dicyclohexylphosphine-2'-(N,N-dimethylamino)biphenyl. (B7) The method as described in (B6), wherein the palladium catalyst is a combination of bis(allyl palladium chloride) and at least one compound 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 as described in (B3), wherein the palladium catalyst is a compound represented by the following general formula (L2). [Chem. 11] [In the formula, R20 and R21 are each independent and are C3-6 cycloalkyl, R22 is C1-6 alkoxy or amino (the amino group may be substituted by C1-6 alkyl or aryl), R23 is a hydrogen atom or C1-6 alkoxy, R24 is a hydrogen atom, R25 is a hydrogen atom or C1-6 alkyl, R26 is a C1-6 alkyl, and arrows indicate coordinate bonds.] (B9) As described in (B8), wherein R20 and R21 are cyclohexyl, R22 is methoxy, isopropoxy or N,N-dimethylamino, R23 is a hydrogen atom, methoxy or isopropoxy, R25 is a hydrogen atom or methyl, and R26 is methyl.(B10) The method described in (B9) wherein the palladium catalyst is selected from at least one of the group consisting of (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. (B11) The method as described in (B10), wherein the palladium catalyst is (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate.

[0027] (B12) The method as described in (B2), wherein the catalyst used in step (II) is a nickel catalyst. (B13) The method as described in (B12), wherein the aforementioned nickel catalyst is a combination of at least one selected from the group consisting of bis(1,5-cyclooctadiene)nickel and nickel chloride (II) and at least one selected from the group consisting of tricyclohexylphosphine, 1,1'-bis(diphenylphosphine)ferrocene, and 1,3-bis(diphenylphosphine)propane. (B14) The method as described in (B12), wherein the aforementioned nickel catalyst is at least one selected from the group consisting of dichlorobis(tricyclohexylphosphine)nickel (II), dichloro[1,1'-bis(diphenylphosphine)ferrocene]nickel (II), and dichloro[1,3-bis(diphenylphosphine)propane]nickel (II).

[0028] (B15) The method as described in (B1), wherein the catalyst used in step (II) is selected from a combination of bis(allyl palladium chloride) and 2',6'-dimethoxy-2-(dicyclohexylphosphino)biphenyl, a combination of bis(allyl palladium chloride) and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, a combination of bis(allyl palladium chloride) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, At least one of the group consisting of 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. (B16) The method as described in (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.

[0029] (B17) The method described in any one of (B1) to (B16), wherein the solvent used in step (II) comprises C1-6 alcohols. (B18) The method described in (B17), wherein the solvent used in step (II) comprises C2-3 alcohols. (B19) The method described in (B18), wherein the solvent used in step (II) comprises ethanol.

[0030] (B20) The method described in any one of (B1) to (B19), further comprising (III) reacting the compound represented by general formula (5) with X2-S(=O)2-NH-R11 or the compound represented by X2-S(=O)2-R11 to obtain the compound represented by general formula (1) or its salt or a solvate of the aforementioned compound or salt. [Where X2 is a halogen atom, and R11 has the same meaning as described above.]

[0031] (B21) The method described in any one of (B1) to (B20), wherein R9 is -C(=O)-O-R12, and R12 is a C1-6 alkyl or aryl group. (B22) The method described in (B21), wherein R2 is a halogen atom. (B23) The method described in (B22), wherein R2 is a fluorine atom, and R9 is -C(=O)-O-CH3. (B24) The method described in any of (B1) to (B23), wherein R2 is a fluorine atom, R1 is -S(=O)2-NH-R11, R11 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, and R8 is a fluorine atom.

[0032] (B25) The method described in any of (B1) to (B24), wherein the compound represented by general formula (1) is 2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzamide.

[0033] (B26) The method described in any of (B1) to (B25) is a method for producing a sodium salt of the compound represented by general formula (1).

[0034] Compounds of general formula (5) can be obtained, for example, using compounds with protected amine groups as described in Synthesis Example 4 (4-2) described later, but in this method, the amine groups need to be deprotected. In contrast, in the methods described above (A1) to (A31) and (B1) to (B26), compounds of general formula (5) can be obtained directly using compounds with unprotected amine groups without protection, and thus it becomes possible to obtain arylamide derivatives of general formula (1) with fewer steps.

[0035] The invention provided by this disclosure includes, for example, the method described in (C1) below. (C1) The method described in (A31) or (B26) is a method for producing the sodium salt of 2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzoylamine. In the aforementioned method, the amount of the compound of formula (X) or its sodium salt produced, relative to the weight of the sodium salt of 2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzoamide, 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. [Chemistry 12]

[0036] The invention provided by this disclosure may also include, for example, the composition described below (D1). (D1) A composition comprising a sodium salt of 2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzoamide and a compound or its sodium salt as shown in formula (X), wherein, relative to the weight of the sodium salt of 2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzoamide contained in the composition, the amount of the compound or its sodium salt of formula (X) 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. [Chemical 13]

[0037] The invention provided by this 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), comprising: (I) reacting a compound represented by the following general formula (2) in a solvent with a compound represented by X1-R9 and a base to obtain a compound represented by general formula (4). [Chemical 14] [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)-R12, -C(=O)-O-R12, or -P(=O)(-O-R12)2, and R12 is a C1-6 alkyl group or an aryl group.]

[0038] (E2) The method as described in (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 as described in (E2), wherein the base used in step (I) is N,N-dimethylaminopyridine.

[0039] (E4) The method described in 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-methyltetrahydropiperanone, cyclopentyl methyl ether, and tert-butyl methyl ether. (E5) The method described in (E4), wherein the solvent used in step (I) is acetonitrile.

[0040] (E6) The method described in any one of (E1) to (E5), wherein R9 is -C(=O)-O-R12, and R12 is a C1-6 alkyl or aryl group. (E7) The method described in (E6), wherein R2 is a halogen atom. (E8) The method described in (E7), wherein R2 is a fluorine atom, R9 is -C(=O)-O-CH3, and X1 is a chlorine atom.

[0041] The invention provided by this disclosure also includes, for example, the compound described below (F1). (F1) (2-amino-3-fluoropyridin-4-yl)methylmethyl carbonate. [Effects of the Invention]

[0042] This disclosure provides a method for manufacturing a specific aryl acetamide derivative having RAF / MEK complex stabilizing activity and / or MEK inhibitory activity and useful for the treatment or prevention of proliferative diseases, especially cancer, which is a method for obtaining aryl acetamide derivatives using a small number of steps.

Implementation Method

[0044] [Form for implementing the invention]

[0045] Hereinafter, exemplary embodiments of the present disclosure will be described.

[0046] In this disclosure, the term "halogen atom" means fluorine atom, chlorine atom, bromine atom or iodine atom.

[0047] In this disclosure, the term C1-6 alkyl means a straight-chain or branched alkyl group having 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, and 2-ethylbutyl.

[0048] In this disclosure, the term C2-7 alkenyl refers to a straight-chain or branched alkenyl group having 2 to 7 carbon atoms. Examples include vinyl, propenyl, 1-butenyl, 2-butenyl, 3-butenyl, pentenyl, pentadienyl, hexenyl, hexadienyl, heptenyl, heptenyl, and heptentrienyl.

[0049] In this disclosure, the term C2-7 ynyl refers to a straight-chain or branched ynyl group having 2 to 7 carbon atoms. Examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, pentenyl, pentadienyl, hexynyl, hexadiynyl, heptyynyl, heptyynyl, and heptyrynyltriynyl.

[0050] In this disclosure, the term C1-6 alkoxy means an alkyloxy group having a straight-chain or branched alkyl group having 1 to 6 carbon atoms. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexyloxy.

[0051] In this disclosure, the term C1-6 alkylthio group refers to an alkylthio group of a straight-chain or branched alkyl group having 1 to 6 carbon atoms. Examples include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, and n-hexylthio.

[0052] In this disclosure, the term C3-6 cycloalkyl means a monocyclic cycloalkyl group having 3 to 6 atoms constituting the ring. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0053] In this disclosure, the term aryl refers to an aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples include phenyl, 1-naphthyl, and 2-naphthyl.

[0054] In this disclosure, pharmaceutically permissible salts may include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate; sulfonates such as methanesulfonate, benzenesulfonic acid, and toluenesulfonate; carboxylates such as formate, acetate, oxalate, maleic acid, fumarate, citrate, malate, succinate, malonate, gluconate, phenylethanolate, benzoate, salicylate, fluoroacetate, trifluoroacetate, tartrate, propionate, and glutarate; alkali metal salts such as lithium, sodium, potassium, cesium, and rubidium; alkaline earth metal salts such as magnesium and calcium; and ammonium salts such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts, and tetraalkylammonium salts. Among these, alkali metal salts such as lithium, sodium, potassium, cesium, and rubidium are preferred, and sodium and potassium salts are even more preferred.

[0055] In this disclosure, a pharmaceutically permissible solvate refers to a solvate with, for example, water, alcohols (e.g., methanol, ethanol, 1-propanol or 2-propanol), acetone, dimethylformamide or dimethylacetamide. It can be a solvate with a single solvent or a solvate with multiple solvents. Hydrates are a preferred example.

[0056] A first aspect of this disclosure provides a method for manufacturing a compound represented by the following general formula (1) or a pharmaceutically permissible salt thereof, or a pharmaceutically permissible solvate of the aforementioned compound or salt, comprising the method of step (I) below. A second aspect of this disclosure provides a method for manufacturing a compound represented by the following general formula (1) or a pharmaceutically permissible salt thereof, or a pharmaceutically permissible solvate of the aforementioned compound or salt, comprising the method of step (II) below. [Chem. 15] In the formula, R1 is -S(=O)2-NH-R11 or -S(=O)2-R11, R11 is a hydrogen atom, a C1-6 alkyl group (which may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), or a C3-6 cycloalkyl group (which 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 (which may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), a C3-6 cycloalkyl group (which may be substituted with a halogen atom or a C1-6 alkyl group), or a C1-6 alkoxy group (which may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), R R4 is a hydrogen atom, halogen atom, C1-6 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-6 cycloalkyl, or C1-6 alkylthioyl; R5 is a halogen atom or C1-6 alkyl; R6 is a hydrogen atom, halogen atom, or C1-6 alkyl; R7 is a hydrogen atom, halogen atom, or C1-6 alkyl; R8 is a hydrogen atom, halogen atom, or C1-6 alkyl.

[0057] In a preferred embodiment, the method of the first aspect of this disclosure further includes the following step (II). In a preferred embodiment, the method of the first aspect of this disclosure further includes the following steps (II) and (III). In a preferred embodiment, the method of the second aspect of this disclosure further includes the following step (III).

[0058] The third aspect of this disclosure provides a method for manufacturing a compound represented by the following general formula (4), which includes the following step (I).

[0059] Step (I): The step of reacting the compound represented by the following general formula (2) with the compound represented by X1-R9 and a base in a solvent to obtain the compound represented by the following general formula (4) [Chemical 16] [wherein, R2 has the same meaning as above, X1 is a halogen atom or -O-R9, R9 is -C(=O)-R12, -C(=O)-O-R12 or -P(=O)(-O-R12)2, and R12 is a C1-6 alkyl or aryl group.]

[0060] Step (II): The step of reacting the compound represented by general formula (4) with the compound represented by general formula (10) in a solvent and in the presence of a catalyst to obtain the compound represented by general formula (5) [Chemical 17][Chemical 18][In the formula, R13 is -B (-OR 14) (-OR 15) or -BF 3K, R14 and R15 are each independent and are hydrogen atoms or C1-6 alkyl (which C1-6 alkyl can be substituted by C1-6 alkoxy or aryl), or R14 and R15 together with the oxygen atom and boron atom in between form a 5-8 member saturated or unsaturated ring (which can be substituted by C1-6 alkyl, C1-6 alkoxy or aryl, and can also be condensed with a benzene ring), R2-R9 have the same meaning as above.]

[0061] Step (III): Reacting the compound represented by general formula (5) with X 2-S (=O) 2-NH-R 11 or the compound represented by X 2-S (=O) 2-R 11 to obtain the compound represented by general formula (1), or its salt, or a solvate of the aforementioned compound or salt [where X 2 is a halogen atom, and R 11 has the same meaning as above.]

[0062] R1 is preferably -S(=O)2-NH-R11. R11 is preferably C1-6 alkyl (which may be substituted with a halogen atom or a C1-6 alkoxy group) or C3-6 cycloalkyl (which may be substituted with a C1-6 alkyl group), more preferably C1-4 alkyl (which may be substituted with a fluorine atom or a C1-4 alkoxy group) or cyclopropyl (which may be substituted with a C1-4 alkyl group), and even more preferably C1-4 alkyl. 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 (which may be substituted with a hydroxyl group), more preferably a hydrogen atom, a C1-4 alkyl group, cyclopropyl or a C1-4 alkoxy group (which may be substituted with a hydroxyl 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)-O-R12 (here, R12 is a C1-6 alkyl or aryl group), more preferably -C(=O)-O-CH3.

[0063] As a compound of general formula (1), examples include 2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzamide.

[0064] As compounds of general formula (4), examples include (2-amino-3-fluoropyridine-4-yl)methyl methyl carbonate.

[0065] As a compound of general formula (2), for example (2-amino-3-fluoropyridin-4-yl)methanol can be listed. For example, (2-amino-3-fluoropyridin-4-yl)methanol can be obtained as a commercially available reagent.

[0066] Examples of compounds X1-R9 include methyl chloroformate, ethyl chloroformate, acetic anhydride, acetyl chloride, dimethyl chlorophosphate, diethyl chlorophosphate, and diphenyl chlorophosphate. Preferably, at least one compound is 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.

[0067] The base used in step (I) may include, for example, triethylamine, N,N-diisopropylethylamine, N-methylpyridine, imidazole, pyridine, N,N-dimethylaminopyridine, 2,6-dimethylpyridine, 1-methylimidazole, and 1,8-diacabisocyclo[5.4.0]undecane-7-ene. Preferably, it is at least one selected from the group consisting of N,N-dimethylaminopyridine and 1-methylimidazole, and more preferably, N,N-dimethylaminopyridine.

[0068] Examples of solvents used in step (I) include acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, acetonitrile, N,N-dimethylacetamide, N,N-dimethylformamide, N,N-dimethylimidazolium ketone, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropiperanone, cyclopentyl methyl ether, tert-butyl methyl ether, toluene, xylene, heptane, and cyclohexane. Preferably, it is at least one solvent selected from the group consisting of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropiperanone, cyclopentyl methyl ether, and tert-butyl methyl ether, and more preferably, acetonitrile.

[0069] The reaction in step (I) can be carried out by stirring the reaction mixture at a suitable temperature (e.g., 0°C to 40°C) for a certain period of time (e.g., 0.5 hours to 24 hours).

[0070] The mixture after the reaction in step (I) is completed can be directly fed to the next step, or it can be separated or purified before being fed to the next step.

[0071] R 13 is preferably a base of formula (a) below, a base of formula (b) below, -B(-OH) 2, or -BF 3K, and more preferably a base of formula (a) below. [Chemical 19]

[0072] As a compound of general formula (10), examples include 2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzamide.

[0073] As a compound of general formula (5), examples include 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluorobenzoamide.

[0074] Examples of catalysts used in step (II) include palladium catalysts or nickel catalysts.

[0075] As palladium catalysts, examples include combinations of at least one selected from the group consisting of bis(allyl palladium chloride), tetra(triphenylphosphine)palladium, tris(benzylacetone)palladium, and palladium acetate (II) with compounds represented by the following general formula (L1). [Chemical 20] [In the formula, R20 and R21 are each independently C3-6 cycloalkyl, R22 is C1-6 alkoxy or amino (which may be substituted by C1-6 alkyl or aryl), R23 is a hydrogen atom or C1-6 alkoxy, and R24 is a hydrogen atom or -S(=O)2-O-Na.]

[0076] As palladium catalysts, examples include compounds represented by the following general formula (L2). [Chemical 21] [In the formula, R20 and R21 are each independent and are C3-6 cycloalkyl groups, R22 is a C1-6 alkoxy or amino group (which may be substituted by a C1-6 alkyl or aryl group), R23 is a hydrogen atom or a C1-6 alkoxy group, R24 is a hydrogen atom, R25 is a hydrogen atom or a C1-6 alkyl group, R26 is a C1-6 alkyl group, and arrows indicate coordinate bonds.]

[0077] R20 and R21 are preferably cyclohexyl. R22 is preferably methoxy, isopropoxy, or N,N-dimethylamino. R23 is preferably a hydrogen atom, methoxy, or isopropoxy. R24 is preferably a hydrogen atom. R25 is preferably a hydrogen atom or a methyl group. R26 is preferably a methyl group.

[0078] The compound represented by general formula (L1) is preferably 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.

[0079] The compound represented by general formula (L2) is preferably selected, for example, from (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, At least one of the group consisting of 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, preferably for example (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate.

[0080] As a nickel catalyst, a combination of at least one selected from the group consisting of bis(1,5-cyclooctadiene)nickel and nickel(II) chloride with at least one selected from the group consisting of tricyclohexylphosphine, 1,1'-bis(diphenylphosphino)ferrocene and 1,3-bis(diphenylphosphino)propane can be cited.

[0081] As a nickel catalyst, at least one can be selected from the group consisting of dichlorobis(tricyclohexylphosphine)nickel(II), dichloro[1,1'-bis(diphenylphosphine)ferrocene]nickel(II), and dichloro[1,3-bis(diphenylphosphine)propane]nickel(II).

[0082] The catalyst used in step (II) is preferably selected, for example, from a combination of bis(allyl palladium chloride) and 2',6'-dimethoxy-2-(dicyclohexylphosphino)biphenyl, a combination of bis(allyl palladium chloride) and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, a combination of bis(allyl palladium chloride) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, or (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate. At least one of the group consisting of 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, preferably for example (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate.

[0083] When a combination of two or more compounds is used as a catalyst, they may form complexes in a solvent, for example.

[0084] Examples of solvents used in step (II) include C1-6 alcohols. More preferably, C2-3 alcohols, and even more preferably, ethanol.

[0085] The reaction in step (II) can be carried out by stirring the reaction mixture at a suitable temperature (e.g., 40°C to 90°C) for a certain period of time (e.g., 0.5 hours to 24 hours).

[0086] The mixture after the reaction in step (II) is completed can be directly fed to the next step, or it can be separated or purified before being fed to the next step.

[0087] In step (III), the compound that reacts with the compound of general formula (5) (X 2-S(=O) 2-NH-R 11 or X 2-S(=O) 2-R 11) is preferably X 2-S(=O) 2-NH-R 11, and more preferably N-methylaminesulfonyl chloride.

[0088] Examples of solvents used in step (III) include acetonitrile, N,N-dimethylacetamide, N,N-dimethylformamide, N,N-dimethylimidazolium ketone, N,N-dimethylacrylurea, tetramethylurea, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropiperanone, pyridine, dichloromethane, and mixtures thereof. Preferably, it is a mixture of N,N-dimethylacetamide, N,N-dimethylimidazolium ketone, tetrahydrofuran, 2-methyltetrahydrofuran, or mixtures thereof; more preferably, it is a mixture of N,N-dimethylimidazolium ketone and tetrahydrofuran.

[0089] In step (III), for example, when manufacturing sodium salt, examples of solvents used for manufacturing sodium salt include acetone, acetonitrile, methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropiperanone, and mixtures thereof. Preferred examples are acetone, tetrahydrofuran, and mixtures thereof.

[0090] In step (III), for example, when manufacturing a sodium salt, the solvent used to precipitate the sodium salt as crystals may include, for example, acetone, acetonitrile, methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropiperanone, cyclopentyl methyl ether, tert-butyl methyl ether, toluene, xylene, heptane, and mixtures thereof. Preferably, it is a mixture of acetone, tetrahydrofuran, tert-butyl methyl ether, heptane, or mixtures thereof, and more preferably, a mixture of acetone, tetrahydrofuran, and tert-butyl methyl ether.

[0091] The reaction in step (III) can be carried out by stirring the reaction mixture at a suitable temperature (e.g., -10°C to 30°C) for a certain period of time (e.g., 0.5 hours to 24 hours).

[0092] When the sodium salt of 2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzoamide is prepared by the method of the first or second state, a compound or its sodium salt as shown in the following formula (X) can be generated. [Chemical 22]

[0093] That is, in one state sample, this disclosure provides the compound represented by formula (X) or its sodium salt.

[0094] Furthermore, in one state sample, this disclosure provides a composition comprising a sodium salt of 2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzoylamine and a compound represented by formula (X) or a sodium salt thereof.

[0095] In one embodiment, the above composition is a pharmaceutical composition, preferably a pharmaceutical composition containing a sodium salt of 2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzoamide as an active ingredient.

[0096] In one embodiment, the above-mentioned pharmaceutical composition is a pharmaceutical composition for the treatment or prevention of cell proliferative diseases, especially cancer.

[0097] In the case of generating a compound of formula (X) or its sodium salt, the amount of the compound of formula (X) or its sodium salt generated 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, relative to the weight of the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzoamide.

[0098] That is, the amount of the compound of formula (X) or its sodium salt contained in the above composition, relative to the weight of the sodium salt of 2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzoamide 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.

[0099] The amount of the compound of formula (X) or its sodium salt contained in the above composition can be measured, for example, by HPLC analysis. Examples of HPLC analytical conditions include, for instance, analytical conditions C described in Table 1 disclosed below.

[0100] 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), relative to the total peak area of ​​2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzoamide, the compound of formula (X), and other decomposition products of 2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzoamide, 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.

[0101] Seed crystals of compounds or their salts that are associated with the implementation of the invention disclosed herein can be used. Generally, seed crystals can be obtained by methods known to those skilled in the art, such as cooling the solution of the compound or salt, adding a solvent with low solubility for the compound or salt (poor solvent), scraping the wall of the container into which the solution of the compound or salt has been placed with a spatula, or concentrating the solution of the compound or salt under reduced pressure after purification by silicone column chromatography.

[0102] The following are examples of abbreviations used in this specification and their meanings. AA: Ammonium acetate tAmOH: tert-pentyl 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-sideoxyethyleneaminooxy)dimethylamino-phosphino-carbomony hexafluorophosphate CPME: Cypentyl methyl ether CyJohnPhos: 2-(dicyclohexylphosphino)biphenyl DavePhos: 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl DBU: Dicyclohexylbis(undecyl)ene DCC: N,N'-dicyclohexyl Carbodiimide DCM: Dichloromethane DIPEA: N,N-Diisopropylethylamine DMA: N,N-Dimethylacetamide DMAP: N,N-Dimethylaminopyridine DMF: N,N-Dimethylformamide DMI: 1,3-Dimethyl-2-imidazolidine 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'-Tetramethylurea hexafluorophosphate HOAt: 1-Hydroxy-7-azabenzotriazine HOOBt: 3,4-Dihydro-3-hydroxy-4-sideoxy-1,2,3-benzotriazine IPA: Isopropanol; JohnPhos: (2-Biphenyl) di-tert-butylphosphine; LDA: Lithium diisopropylamide; 2-MeTHF: 2-Methyltetrahydrofuran; MTHP: 4-Methyltetrahydropiperanol; MeCN: Acetonitrile; MeOH: Methanol; MePhos: 2-Dicyclohexylphosphino-2'-methylbiphenyl; NMP: N-methyl-2-pyrrolidone; 1-PrOH: 1-Propanol; [PdCl(allyl)] 2: Bis(allyl chloride palladium) 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-butyl dimethylsilyl TFA: trifluoroacetic acid THF: tetrahydrofuran Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethyl phthalate XPhos-Pd-G3: (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-Biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate,

[0103] In this specification, "room temperature" means a temperature of approximately 20°C to approximately 25°C. [Example]

[0104] Hereinafter, the present disclosure will be described in more detail based on the embodiments, but the present disclosure is not limited to the following embodiments.

[0105] [Synthesis Examples] In the following synthesis examples, high-performance liquid chromatography (HPLC) analysis was performed using any of the analytical conditions described in Table 1 below. The compounds were detected using a photodiode array detector or a mass analyzer, but other methods such as evaporative light scattering detection may also be used. [Table 1-1] Table 1 Analysis conditions device tubular Column temperature Detection wavelength (PDA) A Waters H-Class InertSustain AQ-C18 HP 2.1 mm ID x 50 mm L, 3 µm 35℃ 210-400 nm B Acquity SQD / SQD2 Ascentis Express C18 2.1 mm ID x 50 mm L, 2.7 µm 35℃ 210-400 nm C Waters H-Class InertSustain AQ-C18 HP 2.1 mm ID x 50 mm L, 3 µm 35℃ 210-400 nm D Acquity SQD / SQD2 Ascentis Express C18 2.1 mm ID x 50 mm L, 5 µm 35℃ 210-400 nm E Nexera UC LCMS-2020 Ascentis Express C18 2.1 mm ID x 50 mm L, 2.7 µm 35℃ 210-400 nm [Table 1-2] Table 1 (continued) Analysis conditions Moving phase gradient Flow rate (mL / min) Time after injection (minutes) A / B A A) 0.05% TFA / H2O B) 0.05% TFA / MeCN 0-5.0 5.0-6.0 100 / 0 → 0 / 100 0 / 100 0.5 B A) 0.1% FA / MeCN B) 0.1% FA / H2O 0-1.0 1.0-1.4 5 / 95 → 100 / 0 100 / 0 1 C A) 0.05% TFA / H2O B) 0.05% TFA / MeCN 0-10.0 10.0-15.0 15.0-16.0 65 / 35 → 55 / 45 55 / 45 → 0 / 100 0 / 100 0.5 D A) MeOH B) 10 mM AA / H2O 0-1.0 1.0-1.4 5 / 95 → 100 / 0 100 / 0 0.9 E A) 0.05% TFA / MeCN B) 0.05% TFA / H2O 0-1.5 1.5-2.0 5 / 95 → 100 / 0 100 / 0 1

[0106] NMR measurements were performed using a nuclear magnetic resonance apparatus JNM-ECZ500R (manufactured by JEOL). NMR data are displayed in ppm (parts per million) (δ), with reference to the deuterium lock signal from the sample solvent.

[0107] Commercially available reagents are used without further purification. All non-aqueous reactions are carried out in anhydrous solvents. Vacuum concentration or solvent distillation is performed using a rotary evaporator.

[0108] (Synthetic Example 1) Synthesis of (2-amino-3-fluoropyridin-4-yl)methyl methyl carbonate (compound 4A) [Chemical 23] (1-1) Synthesis of (2-amino-3-fluoropyridin-4-yl)methyl methyl carbonate (compound 4A) After adding (2-amino-3-fluoropyridin-4-yl)methanol (compound 2A) (30.0 g, 211 mmol) and DMAP (28.4 g, 232 mmol) to the reaction vessel, nitrogen substitution was performed. After adding MeCN (885 mL) and 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. After distilling off the solvent under reduced pressure at 40 °C until the solution volume was 90 mL, isopropyl acetate (900 mL) was added. Wash the solution once with 300 mL of 15% sodium chloride aqueous solution, once with 300 mL of 15% ammonium chloride aqueous solution, and twice with 150 mL of water. Remove the solvent under reduced pressure and at 40°C until the solution volume is 90 mL. Add 300 mL of toluene to the resulting solution and remove the solvent under reduced pressure and at 40°C until the solution volume is 90 mL. Add 300 mL of toluene again and remove the solvent under reduced pressure and at 40°C until the solution volume is 90 mL. Add another 30 mL of toluene and heat the solution to 60°C to dissolve the precipitated solid. Then, cool the solution to 40°C over 30 minutes. Add the seed crystals (75 mg) obtained in steps (1-2) described later and stir the solution for 30 minutes. Then, cool the solution to 25°C over 30 minutes and stir for another 30 minutes. Heptane (60 mL) was added over 30 minutes, and the mixture was stirred for another 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 another 30 minutes, and the mixture was stirred for another 30 minutes. The precipitated solid was filtered, washed with a mixed solvent of heptane (45 mL) and toluene (15 mL), and dried under reduced pressure to obtain compound 4A (35.1 g, yield 83%). HPLC purity: 98.86% (analytical conditions A). 1H-NMR (DMSO-d₆) δ: 7.69 (1H, d, J = 5.2 Hz), 6.47 (1H, t, J = 4.9 Hz), 6.26 (2H, s), 5.15 (2H, s), 3.73 (3H, s). MS (ESI⁺) m / z: 201 [M⁺H⁺]⁺

[0109] (1-2) Synthesis of seed crystals of (2-amino-3-fluoropyridin-4-yl)methyl methyl carbonate (compound 4A): Under nitrogen atmosphere, nitrogen substitution was performed by adding (2-amino-3-fluoropyridin-4-yl)methanol (compound 2A) (10.0 g, 70.4 mmol) and DMAP (12.9 g, 106 mmol) to a reaction vessel. MeCN (300 mL) was added, and methyl chloroformate (compound 3A) (5.4 mL, 70 mmol) was added dropwise to the homogeneous solution obtained by stirring at 25°C for 1 hour. After stirring the resulting reaction solution for 3 hours, it was concentrated under reduced pressure. 2-MeTHF (100 mL) was added to the concentrated residue and concentrated under reduced pressure, and then 2-MeTHF (100 mL) was added to the residue again and concentrated. Add 50 mL of 2-MeTHF to the concentrated residue, filter off the precipitated solid, and wash the filtrate with 30 mL of 2-MeTHF (the resulting washing solution is called washing solution 1). Wash the remaining filtrate again with 100 mL of 2-MeTHF (the resulting washing solution is called washing solution 2). Combine the filtrate and washing solution 1, concentrate under reduced pressure until the total volume is 25 mL, add 5 mL of 2-MeTHF, and heat and stir at 40°C to obtain a homogeneous solution. Add 30 mL of heptane to this solution after 1 hour, and then cool to 35°C. Add 30 mL of heptane to the resulting mixture again, and cool the mixture to 25°C. Filter off the precipitated solid, wash the filtrate with a heptane / 2-MeTHF mixture (3:1, 28 mL), combine the filtrate and washing solution, and concentrate under reduced pressure. The concentrated residue, the residue remaining in the filtered reaction vessel, and the residue obtained from the reduced-pressure concentration of washing solution 2 were combined and purified by silicone 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 crystalline compound 4A (4.2 g, yield 30%). HPLC purity: 99.99% (analytical condition A)

[0110] (1-3) Reaction selectivity and reaction rate for various solvents The reaction selectivity and reaction rate were investigated for the solvents listed in Table 2 below as follows. (2-amino-3-fluoropyridine-4-yl)methanol (compound 2A), DMAP, and solvent were added to a reaction vessel, and the mixture was stirred at room temperature. 1.0 equivalent of methyl chloroformate (compound 3A) relative to compound 2A was added, and stirring was continued for a specified time (the time listed in Table 2). The resulting reaction mixture was analyzed by HPLC under analytical conditions A.

[0111] The results are shown in Table 2. Table 2 shows the peak area ratios of 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%

[0112] Compound 2A: HPLC holding time approximately 0.77 minutes; Compound 4A: HPLC holding time 1.63 minutes; Impurity A: LCMS m / z 258: HPLC holding time 2.24 minutes; Impurity B: LCMS m / z 369: HPLC holding time 2.47 minutes; Impurity C: LCMS m / z 427: HPLC holding time 3.11 minutes.

[0113] [Table 2] Table 2 solvent Amount of compound 2A added DMAP equivalent Stirring time Impurity A / Compound 4A Impurity B / Compound 4A Impurity C / Compound 4A Reaction rate 2-MeTHF 4 mL 200 mg 1.0 1 hour 0.017 0.001 0.010 90% MTHP 4 mL 200 mg 1.0 1 hour 0.028 0.017 0.026 73% THF 4 mL 200 mg 1.0 1 hour 0.021 0.013 0.018 80% CPME 4 mL 200 mg 1.0 1 hour 0.022 0.006 0.010 80% TBME 4 mL 200 mg 1.0 1 hour 0.021 0.001 0.006 92% MeCN 3 mL 100 mg 1.0 1 hour 0.003 ND ND 81% MeCN 3 mL 100 mg 1.1 1 hour 0.004 ND ND 88% MeCN 3 mL 100 mg 1.5 30 points ND ND ND 94% ND: Not detected

[0114] As can be seen from the above results, MeCN exhibits excellent reaction selectivity and reaction rate.

[0115] (Synthetic Example 2) Synthesis of 2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoylamine (compound 10A) [Chemical 24] (2-1) Synthesis of 5-bromo-2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluorobenzoic acid (compound 8A) [Chemical 25] The reaction vessel containing 206 mL (206 mmol) of 1 M lithium bis(trimethylsilyl)amide THF solution was cooled to -15 °C, and 30 mL of 4-cyclopropyl-2-fluoroaniline (11.6 g, 76.5 mmol) of THF solution was added dropwise. Furthermore, a THF solution of 5-bromo-2,3,4-trifluorobenzoic acid (15.0 g, 58.8 mmol) was added dropwise over 30 minutes with stirring for 30 minutes. 5M hydrochloric acid (118 mL) was added to the reaction mixture, and the mixture was heated to room temperature and extracted with isopropyl acetate (75 mL). The organic layer was washed twice with water (75 mL), once with a 15% sodium chloride aqueous solution (75 mL), and concentrated under reduced pressure. Acetone (120 mL) was added to the concentrated residue, and after heating to dissolve, water (45 mL) and seed crystals (150 mg) were added to induce crystallization. Water (45 mL) was added to the resulting slurry, and the crystals were filtered off. The crystals were washed with a mixture of acetone / water (1 / 2) and dried under reduced pressure at an external temperature of 40 °C to obtain compound 8A (19.4 g, 85% yield). LCMS m / z: 386 [M+H]+ HPLC holding time: 0.62 min (analytical condition B)

[0116] (2-2) Synthesis of 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzoic acid (compound 9A) [Chemical 26] MeCN (104 mL), THF (26 mL), and 1,1'-carbonyldiimidazole (8.2 g, 50.5 mmol) were added to a reaction vessel containing 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzoic acid (compound 8A) (13.0 g, 33.7 mmol) and stirred at room temperature for 2 hours. 28% ammonia (13 mL) was added to the reaction mixture, and after stirring at room temperature for 30 minutes, water (117 mL) was added over 1 hour. The crystals were filtered off, washed with water, and dried under reduced pressure at 40 °C to obtain compound 9A (12.0 g, 93% yield). LCMS m / z: 385 [M+H] + HPLC holding time: 0.52 min (analytical condition B)

[0117] (2-3) Synthesis of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzamide (compound 10A): Under 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 bis(pinacolato)diboron (7.25 g, 28.6 mmol) were suspended in 2-MeTHF (150 mL), and nitrogen substitution was performed in the reaction vessel. XPhos-Pd-G3 (440 mg, 0.519 mmol) was added to the resulting mixture, and nitrogen substitution was performed again in the reaction vessel. The mixture was heated to 80°C and stirred for 6 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. Cyclopentyl methyl ether (50 mL) was added to the residue, and the mixture was concentrated again under reduced pressure. Cyclopentyl methyl ether (50 mL) was added to the concentrated residue, and the mixture was concentrated again under reduced pressure. Cyclopentyl methyl ether (50 mL) was added to the residue, and the precipitated solid was collected. The filtrate was washed with cyclopentyl methyl ether (30 mL) and dried under reduced pressure at 40°C to obtain compound 10A (7.02 g, 63% yield). HPLC purity: 97.60% (analytical conditions A) ¹H-NMR (DMSO-d₆) δ: 9.83 (¹H, brs), 8.40–8.32 (¹H, brs), 7.77 (¹H, d, J = 5.2 Hz), 7.72–7.63 (¹H, brs), 6.96–6.90 (²H, m), 6.83 (¹H, dd, J = 1.7, 8.0 Hz), 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]⁺ Furthermore, compound 10A was partially hydrolyzed to boric acid during HPLC analysis. Therefore, the purity of compound 10A was calculated by combining the peak areas of compound 10A (holding time 4.57 min, m / z 433 [M+H]+) and boric acid (holding time approximately 3.48 min, m / z 351 [M+H]+).

[0118] (Synthetic Example 3) Synthesis of 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluorobenzoamide (compound 5A) [Chemical 27] (3-1) The synthesis of 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (compound 5A) was carried out in a reaction vessel after the addition of 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), bis-pinacol borate (10.88 g, 42.8 mmol), and 2-MeTHF (113 mL). Nitrogen substitution was then performed in the reaction vessel after the addition of XPhos-Pd-G3 (659 mg, 0.779 mmol). The reaction solution was heated to 80 °C and stirred for 4 hours. After cooling the reaction solution 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. After nitrogen substitution in the reaction vessel (oxygen concentration ≤ 0.1%), the reaction solution was heated to 75°C. EtOH (52 mL, 900 mmol) was slowly added dropwise (ensuring the solution temperature did not fall below 60°C), and the mixture was stirred 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. After cooling the reaction solution to 40°C, extraction was performed. The organic layer was washed sequentially with 0.1M hydrochloric acid (113 mL), 0.1M potassium phosphate aqueous solution (113 mL), and 2% sodium chloride aqueous 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 toluene (225 mL) was added again. The solvent was distilled off under reduced pressure until the solution volume was 75 mL, and 1-butanol (12 mL) was added as an internal standard. The 1H-NMR was measured to calculate the toluene content, and toluene was added to prepare a solution with a toluene volume of 240 mL. The internal temperature of the reaction solution was raised to 110 °C, and after confirming that the solid was completely dissolved, the temperature was lowered to 90 °C. The seed crystals (75 mg) obtained in (4-2) and (5) described later were added, and the internal temperature of the reaction solution was lowered to 80 °C and stirred for 1 hour. Cool the solution to 60°C and stir 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 filtered off, washed with toluene (45 mL), and then filtered under reduced pressure to obtain compound 5A (12.6 g, yield 75%). HPLC purity: 99.69% (analytical conditions A) ¹H-NMR (DMSO-d₆) δ: 9.38 (¹H, brs), 8.19 (¹H, brs), 7.70 (¹H, brs), 7.65 (¹H, d, J = 5.2 Hz), 7.58 (¹H, d, J = 6.9 Hz), 6.90 (¹H, d, J = 13.2), 6.81–6.76 (2H, m), 6.38 (¹H, t, J = 5.2 Hz), 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]⁺.

[0119] (3-2) Reaction selectivity and reaction rate for various solvents The reaction selectivity and reaction rate were investigated for the solvents listed in Table 3 below as follows. 2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-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 added sequentially to the reaction vessel to induce nitrogen substitution in the reaction vessel. The resulting mixture was added with bis(allyl palladium chloride) (2.1 mg, 5.8 μmol), 2',6'-dimethoxy-2-(dicyclohexylphosphino)biphenyl (4.8 mg, 12 μmol), and solvent (1.5 mL). After nitrogen substitution of the reaction vessel, the reaction mixture was heated to 70 °C while stirring. After approximately 30 minutes, 30 μL of additive (H₂O) was added, or no additive (H₂O) was added, and stirring was continued for 1 hour. The resulting reaction mixture was then analyzed by HPLC under analytical conditions A.

[0120] 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. Reaction rate = [(peak area of ​​compound 5A + peak area of ​​impurity D + peak area of ​​impurity E) / (peak area of ​​compound 10A + peak area of ​​boric acid + peak area of ​​compound 5A + peak area of ​​impurity D + peak area of ​​impurity E)] × 100%

[0121] Compound 5A: HPLC holding time approximately 3.31 minutes; Impurity D: HPLC holding time approximately 3.98 minutes; Impurity E: LCMS m / z 611: HPLC holding time approximately 5.06 minutes.

[0122] [Table 3] Table 3 solvent additive Compound 5A / Impurity D Reaction rate DMI H2O 0.09 71% Toluene H2O 0.33 56% 2-BuOH H2O 0.59 100% CPME H2O 0.39 57% EtOH H2O 4.97 100% 1-PrOH H2O 3.16 98% IPA H2O 1.48 100% tBuOH H2O 1.11 100% tAmOH H2O 1.02 97% EtOH none 4.84 98%

[0123] As can be seen from the above results, EtOH exhibits excellent reaction selectivity and reaction rate.

[0124] In addition, the structural formula, NMR data, and m / z series of impurity D are as follows. [Chem. 28] 1H-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, 8.0 Hz), 7.09-7.02 (1H, m), 6.91 (1H, dd, J = 1.7, 12.0 Hz), 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]+

[0125] (3-3) Reaction selectivity and reaction rate of various catalysts The reaction selectivity and reaction rate were investigated for the catalysts listed in Table 4 below as follows. 2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzamide (compound 10A) (100 mg, 0.231 mmol), MeTHF (1.5 mL), (2-amino-3-fluoropyridin-4-yl)methylmethyl carbonate (compound 4A) (93 mg, 0.463 mmol), and potassium carbonate (96 mg, 0.694 mmol) were added sequentially to the reaction vessel to substituted nitrogen. The resulting mixture was then substituted with a catalyst and EtOH (0.7 mL), and the reaction vessel was substituted nitrogen again. The reaction mixture was stirred at 70 °C for 1.5 hours, and the resulting reaction mixture was analyzed by HPLC under analytical conditions A.

[0126] 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] Table 4 catalyst Compound 5A / Impurity D Reaction rate [PdCl(allyl)]2+ SPhos 6.68 100% [PdCl(allyl)]2+ tBuXPhos 0.00 100% [PdCl(allyl)]2+ tBuDavePhos 0.01 100% [PdCl(allyl)]2+ JohnPhos 0.05 100% [PdCl(allyl)]2+ RuPhos 9.44 100% [PdCl(allyl)]2+ CyJohnPhos 0.29 55% [PdCl(allyl)]2+ DavePhos 2.16 100% [PdCl(allyl)]2+ MePhos 0.11 64% RuPhos-Pd-G3 13.37 100%

[0127] As can be seen from the above results, the combination of [PdCl(allyl)] 2 with Sphos, the combination of [PdCl(allyl)] 2 with RuPhos, the combination of [PdCl(allyl)] 2 with DavePhos, and RuPhos-Pd-G3 exhibit excellent reaction selectivity and reaction rate.

[0128] (Synthetic Example 4) Synthesis of the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzamide (compound 1A) [Chemical 29] (4-1) Preparation of Sample 1a (Form I) After adding 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (compound 5A) (3.00 g, 6.97 mmol) to the reaction vessel, 1,3-dimethyl-2-imidazolidineone (12 mL) and THF (6 mL) were added and dissolved. After nitrogen substitution of the reaction vessel, pyridine (1.69 mL, 20.91 mmol) was added and cooled to 0 °C. After adding N-methylamine sulfonyl chloride (0.67 mL, 7.67 mmol) and stirring for 45 minutes, pyridine (0.10 mL, 1.26 mmol) and N-methylamine sulfonyl chloride (0.30 mL, 3.42 mmol) were added and stirred for another 35 minutes. Next, pyridine (0.24 mL, 2.93 mmol) and N-methylamine sulfonyl chloride (0.13 mL, 1.46 mmol) were added and stirred for 35 minutes. Then, pyridine (0.09 mL, 1.12 mmol) and N-methylamine sulfonyl 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 the reaction was stopped by adding 10% sodium chloride aqueous solution (15 g). The temperature was then raised to 25°C. The reaction mixture was separated, and the upper layer (organic layer) was washed with 10% sodium chloride aqueous solution (24 g). The resulting organic layer was concentrated under reduced pressure to 15 mL and diluted with THF (45 mL). This operation was repeated twice, and the precipitated inorganic salts were filtered off. The filtered 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 5M sodium hydroxide aqueous solution (1.32 mL, 6.62 mmol) and a suspension of sodium salt seed crystals of compound 1A (1.82 mg) (sample 1b described later) in acetone (0.7 mL) were added sequentially, and the mixture was stirred for 2 hours and 30 minutes. Acetone (6.6 mL) was added after 30 minutes, and the mixture was stirred for 2 hours. Acetone (18.2 mL) was added after 20 minutes, and the mixture was stirred for 45 minutes. TBME (24 mL) was added after 20 minutes, and the mixture was stirred for 50 minutes. The resulting suspension was cooled to 25°C over 30 minutes, stirred for 1 hour, and then left to stand overnight at room temperature. After standing overnight, the suspension was stirred at 25°C for 2 hours and 30 minutes.The precipitated solid was filtered off, 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% (analytical condition C) HPLC holding time: 7.02 min (analytical condition C) 1H-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 = 13.5 Hz), 6.82–6.75 (2H, m), 6.17 (1H, t, J = 5.0 Hz), 5.50 (1H, q, J = 6.0 Hz), 3.85 (2H, s), 2.28 (3H, d, J = 6.0 Hz), 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] +.

[0129] In the HPLC analysis of the obtained sample 1a (Form I), the compound represented by the following formula (X) was detected. The ratio of the peak area of ​​the compound of formula (X) when the total peak area of ​​compound 1A, the compound of formula (X), and other decomposition products of compound 1A is set to 100 is 0.27. The content of the compound of formula (X) or its sodium salt in sample 1a (Form I) is sufficiently low. [Chemical 30] HPLC holding time: 8.81 minutes (analytical condition C) MS (ESI+) m / z: 506 [M+H]+

[0130] (4-2) Preparation of Sample 1b (Form I) (1) Synthesis of N-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-fluoropyridin-2-yl]acetamide 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) were added to a reaction vessel and degassed under reduced pressure for nitrogen substitution. Tris(dibenzylideneacetone)dipalladium (0) (14.9 g, 16.3 mmol) and toluene (540 mL) were added and degassed under reduced pressure for nitrogen substitution. Under a nitrogen atmosphere, the mixture was heated to 120°C and stirred for 7 hours. After cooling to room temperature, 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 first, 180 mL second) to obtain a crude product of N-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-fluoropyridin-2-yl]acetamide in toluene solution. LCMS m / z: 299 [M+H]+ HPLC holding time: 0.81 min (analytical condition B)

[0131] (2) Synthesis of N-[3-fluoro-4-(hydroxymethyl)pyridin-2-yl]acetamide methanesulfonate (compound 13A) [Chemical 31] A toluene solution of the obtained 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 and degassed under reduced pressure to replace with nitrogen. Methanesulfonic acid (188 g, 1.96 mol) was added dropwise at an external temperature of 10 °C and 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 filtered off and washed with a mixture of cooled toluene (312 mL) and MeOH (78 mL). The filtered solid and a mixture of toluene (1.1 L) and EtOH (492 mL) were added to the reaction vessel and stirred at an external temperature of 0 °C for 1 hour. The solid was filtered off and washed with a mixture of toluene (281 mL) and EtOH (117 mL). It was then dried under reduced pressure at 40 °C to obtain compound 13A (149 g, 81% yield). LCMS m / z: 185 [M+H]+ HPLC holding time: 0.30 min (analytical condition D)

[0132] (3) Synthesis of (2-acetylamine-3-fluoropyridin-4-yl)methyl methyl carbonate (compound 14A) [Chemical 32] In a reaction vessel containing N-[3-fluoro-4-(hydroxymethyl)pyridin-2-yl]acetylamine methanesulfonate (compound 13A) (50.0 g, 178 mmol) and 2-MeTHF (750 mL), DMAP (52.3 g, 428 mmol) was added at room temperature. The external temperature was cooled to 0 °C, methyl chloroformate (21.9 g, 232 mmol) was added, the temperature was raised to room temperature, and the mixture was 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 after it was dissolved at room temperature, DIPEA (31.2 mL, 178 mmol), heptane (150 mL) and seed crystals were added. After confirming the precipitation of crystals, heptane (1 L) was added. The slurry was cooled to 0°C, and the crystals were filtered off and washed with a mixture of ethyl acetate / heptane (2 / 7). The crystals were dried under reduced pressure at 40°C to obtain compound 14A as a colorless solid (31.3 g, yield 72%). LCMS m / z: 243 [M+H]+ HPLC holding time: 0.37 min (analytical condition B)

[0133] (4) Synthesis of 5-[(2-acetylamino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzoamide (compound 15A) [Chemical 33] 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzoamide (compound 9A) (10.0 g, 26.0 mmol), bis-pinacol borate (7.3 g, 28.6 mmol), potassium acetate (7.6 g, 77.9 mmol) and 2-MeTHF (150 mL) were added to a reaction vessel and degassed under reduced pressure, and substituted with nitrogen. Add (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (440 mg, 0.52 mmol), followed by degassing under reduced pressure and nitrogen substitution. Under a nitrogen atmosphere, heat the mixture to 80°C and stir for 6 hours. Cool to room temperature, add potassium carbonate (10.8 g, 77.9 mmol), and degas under reduced pressure for nitrogen substitution. Add (1.1 g, 1.3 mmol) of (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, followed by degassing under reduced pressure and nitrogen substitution. Then add a 150 mL solution of 2-MeTHF containing (2-acetylamino-3-fluoropyridin-4-yl)methylmethyl carbonate (compound 14A) (12.6 g, 51.9 mmol). Under a nitrogen atmosphere, heat the mixture to 70 °C, adding water (935 μL, 51.9 mmol) three times every 20 minutes, and stirring for 20 minutes. Next, add water (7.0 mL), stir for 2 hours, add a solution prepared from N-acetylcysteine ​​(847 mg, 5.2 mmol) and water (150 mL), and stir for 1 hour. After cooling to 40°C, the aqueous layer was removed. The organic layer was washed with 150 mL of 15% sodium chloride aqueous solution, the insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. MeCN (500 mL) was added to the concentrated residue, and the mixture was heated to 100°C to dissolve it. The residue was then cooled to room temperature. The crystals were filtered off, washed with 200 mL of MeCN, and dried under reduced pressure at 40°C to obtain compound 15A (8.34 g, 68% yield). LCMS m / z: 471 [M-H] - HPLC holding time: 0.74 min (analytical condition B)

[0134] (5) Synthesis of 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzoamide (compound 5A) [Chemical 34] MeOH (3 mL) and 5M hydrochloric acid (0.42 mL, 2.1 mmol) were added to a reaction vessel containing 5-[(2-acetaminophen-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzoamide (compound 15A) (100 mg, 0.21 mmol), and the mixture was stirred at 50 °C for 6 hours. The reaction mixture was cooled to room temperature, and 2M sodium hydroxide aqueous 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 compound was washed with a mixture of MeOH and water (3 / 2) and dried under reduced pressure at 40°C to obtain compound 5A as a colorless solid (77.7 mg, yield 85%). LCMS m / z: 431 [M+H]+ HPLC holding time: 0.61 min (analytical condition B)

[0135] (6) Synthesis of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzamide (compound 1A) [Chemical 35] 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, methylaminesulfonyl chloride (30.2 μL, 0.349 mmol) was added, and the mixture was stirred for 1 hour. MeCN (0.6 mL), water (0.3 mL), and seed crystals (obtained from Preparation Example A-1-1 described later) (1 mg) were added to the reaction mixture. The mixture was heated to room temperature, and water (0.7 mL) and MeCN (0.4 mL) were added. The mixture was stirred for 20 hours. The precipitate was filtered 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 holding time: 1.13 min (analytical condition E)

[0136] (7) Preparation of sodium salt of 2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzamide (compound 1A) (i) Preparation of sample 1b (Form I) Add acetone (10.6 mL) and DMSO (1.51 mL) to 2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzamide (compound 1A) (3.03 g) and dissolve it at room temperature. Add 3.03 mL of 20% sodium ethoxysulfate (EtOH) solution and seed crystals of the sodium salt of compound 1A (sample 1c described below) to this solution, stir at room temperature for 1 hour, then add 15.1 mL of EtOH, and stir at room temperature for 4 hours. Subsequently, add another 15.1 mL of EtOH, and stir at room temperature for 4 hours to obtain 2.74 g of the sodium salt of compound 1A as powdered crystals (sample 1b (Form I)).

[0137] (ii) Preparation of Sample 1c: Compound 1A (53.6 mg) was added to 20% sodium ethoxysulfate (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 the mixture was stirred at 60°C for 4 days. Subsequently, DMSO (0.054 mL) was added, and the mixture was stirred at 60°C for 5 hours to obtain sodium salt of compound 1A (25.6 mg) as powdered crystals (sample 1c).

[0138] (4-3) Powder X-ray diffraction measurement Sample 1a (Form I) was subjected to powder X-ray diffraction measurement under the following conditions. Measuring device: Empyrean (PANalytical) Cathode: Cu Tube voltage: 45kV Tube current: 40mA Scanning mode: continuous step width: 0.0262606° Scanning axis: 2θ Sampling time per step: 5.100 seconds Scanning range: 3~25°

[0139] Sample 1b (Form I) and sample 1c were subjected to powder X-ray diffraction measurement under the following conditions. Measurement apparatus: SmartLab, D / Tex Ultra detector (Rigaku Corporation) Cathode: Cu Tube voltage: 45kV Tube current: 200mA Sampling width: 0.02°

[0140] The results of the powder X-ray diffraction measurement 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.

[0141] [Reference Examples] Hereinafter, reference examples (manufacturing examples and test examples) are disclosed for specific arylamide derivatives. Among the arylamide derivatives (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) 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 and I-1 are compounds of the aforementioned general formula (1) (compound A-1 is also referred to as compound 1A in this specification).

[0142] [Manufacturing Example] In the following manufacturing example, NMR analysis was performed using a BRUKER AVANCE III HD400 (400MHz). NMR data are expressed in ppm (parts per million) (δ), with reference to the deuterium lock signal from the sample solvent.

[0143] The mass spectrometry data were obtained using a single quadrupole mass analyzer (LCMS-2020) with ultra-high performance liquid chromatography (Nexera UC) manufactured by Shimadzu Corporation or a single quadrupole mass analyzer (SQD or SQD2) with Acquity ultra-high performance liquid chromatography (UPLC or UPLC I-Class) manufactured by Waters Corporation.

[0144] High-performance liquid chromatography (HPLC) analysis was performed using any of the analytical conditions described in Table 5 below. [Table 5-1] Table 5 Analysis conditions device tubular Column temperature Detection wavelength (PDA) E Nexera UC LCMS-2020 Ascentis Express C18 2.1 mm I.D. x 50 mm L, 2.7 µm 35℃ 210-400 nm H Nexera UC LCMS-2020 XSelect CSH C18 2.1 mm I.D. x 50 mm L, 2.5 µm 35℃ 210-400 nm B Acquity SQD / SQD2 Ascentis Express C18 2.1 mm I.D. x 50 mm L, 2.7 µm 35℃ 210-400 nm I Acquity SQD / SQD2 Ascentis Express C18 2.1 mm I.D. x 50 mm L, 2.7 µm 35℃ 210-400 nm D Acquity SQD / SQD2 Ascentis Express C18 2.1 mm I.D. x 50 mm L, 5 µm 35℃ 210-400 nm F Acquity SQD / SQD2 Ascentis Express C18 2.1 mm I.D. x 50 mm L, 2.7 µm 35℃ 210-400 nm G Acquity SQD / SQD2 Ascentis Express C18 2.1 mm ID x 50 mm L, 2.7 µm 35℃ 210-400 nm [Table 5-2] Table 5 (continued) Analysis conditions Moving phase gradient Flow rate (mL / min) After injection Time (minutes) A / B E A) 0.05% TFA / MeCN B) 0.05% TFA / H2O 0-1.5 1.5-2.0 5 / 95 → 100 / 0 100 / 0 1 H A) 0.1% FA / MeCN B) 0.1% FA / H2O 0-1.75 1.75-2.00 5 / 95 → 100 / 0 100 / 0 1 B A) 0.1% FA / MeCN B) 0.1% FA / H2O 0-1.0 1.0-1.4 5 / 95 → 100 / 0 100 / 0 1 I A) 0.1% FA / MeCN B) 0.1% FA / H2O 0-1.0 1.0-1.4 40 / 60 → 100 / 0 100 / 0 1 D A) MeOH B) 10 mM AA / H2O 0-1.0 1.0-1.4 5 / 95 → 100 / 0 100 / 0 0.9 F A) 0.05% TFA / MeCN B) 0.05% TFA / H2O 0-1.0 1.0-1.4 5 / 95 → 100 / 0 100 / 0 1 G A) 0.05% FA / MeCN B) 0.05% FA / H2O 0-1.0 1.0-1.4 5 / 95 → 100 / 0 100 / 0 1

[0145] The microwave reaction was carried out using an initiator manufactured by Biotage. Furthermore, a snap-cap reaction flask was used in the microwave reaction.

[0146] Commercially available reagents are used without further purification. All non-aqueous reactions are carried out in anhydrous solvents. Vacuum concentration or solvent distillation is performed using a rotary evaporator.

[0147] In the following manufacturing examples, "manufacturing example of compound A-1" means manufacturing example A-1-1, and "manufacturing example of compound a9" means manufacturing example a9-1.

[0148] Compound a1: Methyl 3,4-difluoro-2-(2-fluoro-4-iodoaniline)-5-carboxybenzoate [Chemical 36] A suspension of 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-carboxybenzoic acid (5.50 g, 13.1 mmol) in toluene (44 mL) and MeOH (11 mL) was cooled to 0 °C, and a 10% solution of diazomethyltrimethylsilanehexane (21.8 mL, 13.1 mmol) was added. The mixture was stirred at room temperature for 64 hours. Acetic acid (0.748 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was purified with hexane / ethyl acetate to give the title compound (5.01 g, 88%) as a colorless solid. LCMS m / z: 436 [M + H] + HPLC holding time: 1.00 min (analytical condition I)

[0149] Compound a2: Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazine]methyl]benzoate [Chemical 37] 4-methylbenzenesulfonylhydrazine (2.14 g, 11.5 mmol) was added to a suspension of methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-methylbenzoate (compound a1, 5.00 g, 11.5 mmol) in EtOH (100 mL) and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and hexane (150 mL) was added. After cooling to 0 °C, the mixture was filtered and washed with hexane (30 mL) to give the title compound as a solid (7.05 g, quant.). LCMS m / z: 604 [M+H]+ HPLC holding time: 1.06 min (analytical condition I)

[0150] Compound a3: N-(2,4-dimethoxybenzyl)-3-fluoro-4-iodopyridine-2-amine [Chemical 38] Triethylamine (3.63 mL, 26.0 mmol) and 1-(2,4-dimethoxyphenyl)methaneamine (3.26 mL, 21.7 mmol) were added to a solution of 2,3-difluoro-4-iodopyridine (2.09 g, 8.67 mmol) in NMP (32 mL), and the mixture was stirred at 100 °C for 1.5 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 13% brine, dried with anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was purified by silicone column chromatography (hexane / ethyl acetate) to give the title compound (3.20 g, 95%) as an oil. LCMS m / z: 389 [M+H]+ HPLC holding time: 0.94 min (analytical condition B)

[0151] Compound a4: [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid [Chemical 39] A 1,4-dimethylamine 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(diphenylphosphine)ferrocene]dichloropalladium(II)dichloromethane adduct (568 mg, 0.696 mmol), potassium acetate (2.05 g, 20.9 mmol) and bis-pinacol boronic acid ester (2.65 g, 10.4 mmol) was stirred at 90 °C for 5 hours under nitrogen atmosphere, followed by stirring at 110 °C for 19 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 obtain the title compound (2.07 g, 97%) as an oily substance. LCMS m / z: 307 [M + H] + HPLC holding time: 0.44 min (analytical condition B)

[0152] Compound a5: Methyl 5-[[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate [Chemical 40] A suspension (59 mL) of methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazine]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-dimethylalkane was stirred at 100 °C for 2.5 h under nitrogen atmosphere, followed by stirring at 110 °C for 3 h. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and 13% brine. The organic layer was dried with anhydrous sodium sulfate, and after filtering off the drying agent, the mixture was concentrated under reduced pressure. The resulting residue was purified by silicone column chromatography (hexane / ethyl acetate) to obtain the title compound (524 mg, 36%) as a bubbly substance. LCMS m / z: 682 [M + H] + HPLC holding time: 1.03 min (analytical condition I)

[0153] Compound a6: Methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate [Chemical 41] 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, and trifluoroacetic acid (15.7 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (0.05% aqueous trifluoroacetic acid solution / 0.05% trifluoroacetic acid acetonitrile solution) to obtain the title compound (321 mg, 79%) as an oil. LCMS m / z: 532 [M+H]+ HPLC holding time: 0.55 min (analytical condition I)

[0154] Compound a7: 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate [Chemical 42] A mixture of methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoaniline)benzoate (compound a6, 4.00 g, 7.53 mmol) in THF (64 mL) and water (32 mL) was cooled to 0 °C, and lithium hydroxide monohydrate (948 mg, 22.6 mmol) was added. The mixture was stirred at room temperature for 3.5 h. After cooling to 0 °C, 5 M hydrochloric acid (15.1 mL) was added to the reaction mixture, and the mixture was 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 holding time: 0.68 min (analytical condition B)

[0155] Compound a8: 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoamide [Chemical 43] An anhydrous DMF solution (3.6 mL) of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate (compound a7, 200 mg, 0.361 mmol) was cooled to 0 °C, and HOOBt (67.8 mg, 0.415 mmol) and EDC·HCl (80.0 mg, 0.415 mmol) were added. The mixture was stirred at room temperature for 1.5 hours. HOOBt (8.8 mg, 0.054 mmol) and EDC·HCl (10.4 mg, 0.054 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Then, 7M ammonia MeOH solution (0.103 mL, 0.722 mmol) and DIPEA (0.189 mL, 1.08 mmol) were added at 0°C, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate by adding water and saturated sodium bicarbonate solution in a 1:1 ratio. The organic layer was dried with anhydrous sodium sulfate, and after filtering off the drying agent, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (1 mL), and hexane (10 mL) was added. The resulting solid was filtered off and washed with hexane to obtain the title compound as a colorless solid (162 mg, 87%). LCMS m / z: 517 [M + H] + HPLC holding time: 0.64 min (analytical condition B)

[0156] Compound a9: 5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluorobenzoamide [Chemical 44] Manufacturing Example a9-1: In an anhydrous THF solution (1.9 mL) of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoamide (compound a8, 100 mg, 0.194 mmol), tetrakis(triphenylphosphine)palladium (0) (11.2 mg, 9.68 μmol) and 0.5 M cyclopropyl zinc bromide (1.94 mL, 0.969 mmol) were added and stirred at room temperature for 2.5 hours under nitrogen atmosphere. Ethyl acetate (5 mL) was added to the reaction mixture, and the mixture was filtered through diatomaceous earth and washed with ethyl acetate (3 mL). The filtrate was washed with water and saturated brine, and the organic layer was dried with anhydrous sodium sulfate. After filtering off the desiccant, the mixture was concentrated under reduced pressure. Dichloromethane / hexane (1 / 10, 11 mL) was added to the residue, and the solid was filtered off 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 holding time: 0.61 min (analytical condition B)

[0157] Compound r1: 4-Nitrophenyl Methylamine Sulfonate [Chemical 45] A dichloromethane solution (60 mL) of 4-nitrophenol (5.00 g, 35.9 mmol) and triethylamine (11.3 mL, 81.0 mmol) was cooled to -78 °C, and a dichloromethane solution (15 mL) of methylamine sulfonyl chloride (5.82 g, 44.9 mmol) was added. The mixture was stirred at -78 °C for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silicone column chromatography (hexane / ethyl acetate) and reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to obtain the title compound (5.51 g, 66%) as a colorless solid. HPLC holding time: 0.63 min (analytical condition B) 1H-NMR (400 MHz, CDCl3) δ: 8.31 (2H, m), 7.46 (2H, m), 4.68 (1H, m), 3.00 (3H, d, J = 5.4 Hz).

[0158] Compound A-1: ​​2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzamide [Chemical 46] 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), pyridine (2.78 mL, 34.4 mmol) and 4-nitrobenzene methylaminesulfonate (compound r1, 4.00 g, 17.2 mmol) were added, and the mixture was stirred at 40 °C for 2.5 hours. The reaction mixture was cooled to room temperature, and water (24.7 mL) was added. Add acetonitrile (3 mL) and water (19.8 mL), stir for 10 minutes, and filter off the solid. Wash the obtained solid 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 holding time: 1.13 min (analytical condition E)

[0159] Compound a10: 5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-cyclopropyl-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoamide [Chemical 47] 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate (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 aqueous solution / 0.1% formic acid acetonitrile solution) to give the title compound as a brown solid (103 mg, 96%). LCMS m / z: 557 [M + H] + HPLC holding time: 0.73 min (analytical condition B)

[0160] Compound A-2: N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoaniline)-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzamide [Chemical 48] 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 preparation example of compound A-1. LCMS m / z: 650 [M+H]+ HPLC holding time: 1.65 min (analytical condition H)

[0161] Compound a12: 5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-(tert-butoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoamide [Chem. 49] 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoaniline)benzoate (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 hours. Subsequently, tert-butoxyamine hydrochloride (68.1 mg, 0.542 mmol) and DIPEA (0.95 mL, 0.542 mmol) were added, and the mixture was stirred at room temperature for 1.5 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 the title compound as a colorless solid (89 mg, 84%). LCMS m / z: 589 [M+H]+ HPLC holding time: 0.77 min (analytical condition B)

[0162] Compound A-8: 3,4-difluoro-2-(2-fluoro-4-iodoaniline)-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]-N-[(2-methylpropane-2-yl)oxy]benzamide [Chemical 50] 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 preparation example of compound A-1. LCMS m / z: 682 [M+H]+ HPLC holding time: 1.69 min (analytical condition H)

[0163] Compound a16: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-methylhydrothioanilino)benzamide [Chemical 51] 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) dissolved in anhydrous 1,4-dimethylalkanes (0 0.3 mL of sodium methanethiol (12.2 mg, 0.174 mmol), DIPEA (30.4 mL, 0.174 mmol), and [(4,5-bis(diphenylphosphino)-9,9-dimethylphosphonic acid)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (11.2 mg, 0.012 mmol) were added. The mixture was stirred at room temperature for 30 minutes under nitrogen atmosphere. 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 (15 mg, 59%) as a colorless solid. LCMS m / z: 437 [M+H]+ HPLC holding time: 0.60 min (analytical condition B)

[0164] Compound A-18: 3,4-Difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-methylhydrothioaniline)benzamide [Chemical 52] The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-methylhydrothioaniline)benzamide (compound a16) under the same conditions as in the preparation example of compound A-1. LCMS m / z: 530 [M+H]+ HPLC holding time: 1.09 min (analytical condition E)

[0165] Compound a18: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-[2-fluoro-4-(2-trimethylsilylethynyl)anilino]benzamide [Chemical 53] In an anhydrous THF solution (26 mL) of 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), triethylamine (31.7 mL, 228 mmol), trimethylsilylethynyl (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) were added 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 obtain the title compound as a colorless solid (2.57 g, 83%). LCMS m / z: 487 [M + H] + HPLC holding time: 0.84 min (analytical conditions G)

[0166] Compound a19: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-ethynyl-2-fluoroanilino)-3,4-difluorobenzamide [Chemical 54] 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 mixed with 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 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 holding time: 0.60 min (analytical condition G)

[0167] Compound A-20: 2-(4-ethynyl-2-fluoroaniline)-3,4-difluoro-5-[[3-fluoro-2-(propylaminesulfonylamino)pyridin-4-yl]methyl]benzamide [Chemical 55] was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-ethynyl-2-fluoroaniline)-3,4-difluorobenzamide (compound a19) and the corresponding 4-nitrobenzene aminesulfonic acid under the same conditions as in the preparation example of compound A-1. LCMS m / z: 536 [M+H]+ HPLC holding time: 1.18 min (analytical condition E)

[0168] Compound A-25: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzamide [Chem.56] 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), pyridine (2.3 μL, 0.029 mmol) and methylaminesulfonyl chloride (2.5 μL, 0.029 mmol) were added at 0 °C, 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 aqueous solution / 0.1% formic acid acetonitrile solution) to give the title compound as a colorless solid (10.2 mg, 86%). LCMS m / z: 610 [M+H]+ HPLC holding time: 1.15 min (analytical condition E)

[0169] Compound A-33: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylaminesulfonylamino)pyridin-4-yl]methyl]benzamide [Chemical 57] 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 aminesulfonyl chloride under the same conditions as in the preparation example of compound A-25. LCMS m / z: 654 [M+H]+ HPLC holding time: 1.17 min (analytical condition E)

[0170] Compound a21: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-bromo-2-fluoroanilino)-3,4-difluorobenzamide [Chemical 58] 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), and copper bromide (I) (83.0 mg, 0.581 mmol) was added. The mixture was stirred at 100 °C for 24 hours. The reaction mixture was purified by preparative-grade 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 give the title compound as a solid (35.6 mg). LCMS m / z: 469 [M+H]+ HPLC holding time: 0.61 min (analytical condition B)

[0171] Compound A-27: 2-(4-bromo-2-fluoroaniline)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzamide [Chemical 59] The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-bromo-2-fluoroaniline)-3,4-difluorobenzamide (compound a21) under the same conditions as in the preparation example of compound A-25. LCMS m / z: 562 [M+H]+ HPLC holding time: 1.13 min (analytical condition E)

[0172] Compound b1: Methyl 3,4-difluoro-2-(2-fluoro-4-iodoaniline)-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzoate [Chemical 60] The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoaniline)benzoate (compound a6) under the same conditions as in the preparation example of compound A-25. However, anhydrous NMP was used instead of anhydrous DMA. LCMS m / z: 436 [M+H]+ HPLC holding time: 1.00 min (analytical condition I)

[0173] Compound b2: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzoic acid [Chemical 61] A mixture of methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylaminesulfonylamino)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, and lithium hydroxide monohydrate (60.6 mg, 2.53 mmol) was added. The mixture was stirred at room temperature for 2 hours. 2 M hydrochloric acid was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtering out the desiccant, the solution was concentrated under reduced pressure to obtain the title compound (161 mg) as a bubbly substance. LCMS m / z: 611 [M + H] + HPLC holding time: 0.67 min (analytical condition I)

[0174] Compound B-1: 3,4-Difluoro-2-(2-fluoro-4-iodoaniline)-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide [Chemical 62] was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodoaniline)-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzoic acid (compound b2) and the corresponding amine under the same conditions as in the preparation example of compound a8. LCMS m / z: 670 [M+H]+ HPLC holding time: 1.07 min (analytical condition E)

[0175] Compound c1: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinyl]methyl]benzamide [Chemical 63] 4-methylbenzenesulfonylhydrazine (2.21 g, 11.9 mmol) was added to an anhydrous DMF solution (59 mL) of 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-methylbenzoic acid (5.00 g, 11.9 mmol) and stirred at room temperature for 30 minutes. Then, HOOBt (1.94 g, 11.9 mmol) and EDC·HCl (2.28 g, 11.9 mmol) were added and stirred at room temperature for 1.5 hours. The reaction mixture was added to a 7M ammonia-MeOH solution (3.39 mL, 23.8 mmol), stirred at room temperature for 30 minutes, and the solid was filtered off and washed with DMF (30 mL). Acetonitrile (90 mL) and 0.1M hydrochloric acid (90 mL) were added to the filtrate, and the resulting solid was washed with an acetonitrile / water mixture to obtain the title compound (6.27 g, 90%) as a colorless solid. LCMS m / z: 589 [M + H] + HPLC holding time: 0.90 min (analytical condition B)

[0176] Compound c5: 5-vinyl-3,4-difluoro-2-(4-iodo-2-methylaniline)benzoic acid [Chemical 64] An anhydrous THF solution (1.8 mL) of 4-iodo-2-methylaniline (636 mg, 2.73 mmol) was cooled to -78 °C and stirred for 1 hour. Then, an anhydrous THF solution (5.08 mL, 6.60 mmol) of 1.3 M bis(trimethylsilyl)amide lithium was added and stirred for 1 hour. Next, an anhydrous THF solution (3.9 mL) of 2,3,4-trifluoro-5-vinylbenzoic acid (460 mg, 2.28 mmol) was added and stirred at 0 °C for 2 hours. Water and 2 M hydrochloric acid were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The resulting residue was resuspended and washed with DCM to obtain the title compound as a brown solid (631 mg, 67%). LCMS m / z: 416 [M + H] + HPLC holding time: 0.99 min (analytical condition D)

[0177] Compound c6: 3,4-Difluoro-5-methacryl-2-(4-iodo-2-methylaniline)benzoic acid [Chemical 65] 5-vinyl-3,4-difluoro-2-(4-iodo-2-methylaniline)benzoic acid (compound c5, 626 mg, 1.51 mmol) was microencapsulated in anhydrous THF solution (6.3 mL) with 1 M sodium bicarbonate aqueous solution (3.02 mL, 3.02 mmol), sodium periodate (1.29 g, 6.03 mmol), and osmium oxide (VIII) (38.3 mg, 0.015 mmol) and stirred at room temperature for 6 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 1 M hydrochloric acid and 0.2 M sodium thiosulfate aqueous solution. The organic layer was dried with anhydrous sodium sulfate, the desiccant was filtered off, and the mixture was concentrated under reduced pressure. The resulting residue was resuspended and washed with ethyl acetate / hexane (1 / 25, 42 mL), and the solid was filtered off. The solid was washed with hexane to give the title compound as a colorless solid (558 mg, 89%). LCMS m / z: 418 [M + H] + HPLC holding time: 0.86 min (analytical condition B)

[0178] Compound d1: Methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate [Chemical 66] The title compound was synthesized from methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazine]methyl]benzoate (compound a2) under the same conditions as in the preparation example of compound a5. However, (3-amino-2-fluorophenyl)borate salt was used to replace [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4). LCMS m / z: 531 [M+H]+ HPLC holding time: 0.96 min (analytical condition I)

[0179] Compound E-1: 5-[[3-(ethylsulfonylmino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzoylamine [Chemical 67] 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 manufacturing examples of compounds A-25, b2, and a12. However, pyridine was used as the solvent in the sulfonation step. Furthermore, the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the manufacturing example of compound a12. LCMS m / z: 638 [M+H]+ HPLC holding time: 1.68 min (analytical condition H)

[0180] Compound E-7: 3,4-Difluoro-2-(2-fluoro-4-iodoaniline)-5-[[2-fluoro-3-(methylaminesulfonylamino)phenyl]methyl]benzoylamine [Chemical 68] The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoaniline)benzoate (compound d1) under the same conditions as in the manufacturing examples of compounds A-25, b2, and a12. However, pyridine was used as the solvent in the sulfonation step. Furthermore, the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the manufacturing example of compound a12. LCMS m / z: 609 [M+H]+ HPLC holding time: 1.23 min (analytical conditions E)

[0181] Compound e20: Methyl 3,4-difluoro-2-(2-fluoro-4-iodoaniline)-5-[[2-fluoro-3-(methanesulfonylamine)phenyl]methyl]benzoate [Chemical 69] was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoaniline)benzoate (compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation example of compound A-25. However, pyridine was used as the solvent. LCMS m / z: 609 [M+H]+ HPLC holding time: 1.01 min (analytical condition B)

[0182] Compound E-13: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonylamine)phenyl]methyl]benzoylamine [Chemical 70] was prepared by adding lithium hydroxide monohydrate (7.9 mg, 0.19 mmol) to a mixture of methyl benzoate (compound e20, 23.0 mg, 0.038 mmol) in THF (0.7 mL) and water (0.3 mL) and stirring at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure, and 1 M hydrochloric acid (0.76 mL) was added, followed by further concentration under reduced pressure. HOOBt (9.3 mg, 0.057 mmol) and EDC·HCl (10.9 mg, 0.057 mmol) were added to anhydrous DMF solution (0.3 mL) of the resulting mixture, and the mixture was stirred at room temperature for 3 hours. Then, 7 M ammonia MeOH solution (22 μL, 0.15 mmol) was added at 0 °C, and the mixture was stirred for 30 minutes. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) with 10% trifluoroacetic acid aqueous solution (1 mL) to give the title compound as a colorless solid (19.7 mg, 97%). LCMS m / z: 594 [M + H] + HPLC holding time: 1.61 min (analytical condition H)

[0183] Compound h1: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-[3-(2-ethylhexaoxy)-3-sideoxypropyl]hydrothio-2-fluoroaniline]-3,4-difluorobenzoate methyl ester [Chemical 71] 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate methyl ester (compound a6, 500 mg, 0. A 1,4-dimethylacetonide suspension (17 mL) of 941 mmol of 2-ethylhexyl 3-mercaptopropionate (226 mg, 1.04 mmol), Xantphos (109 mg, 0.188 mmol), triphenylacetone (dibenzylacetone)dipalladium(0) (86 mg, 0.094 mmol), and DIPEA (0.492 mL, 2.82 mmol) was stirred at 110 °C for 1 hour. Acetonitrile was added to the reaction mixture, and the mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to obtain the title compound (584 mg, quant.) as a yellow, viscous, oily substance. LCMS m / z: 622 [M+H]+ HPLC holding time: 1.14 min (analytical condition G)

[0184] Compound h2: Methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-(difluoromethylhydrothio)-2-fluoroaniline]-3,4-difluorobenzoate [Chemical 72] A methanol solution (9 mL) of methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-[3-(2-ethylhexaoxy)-3-toxypropyl]hydrothio-2-fluoroaniline]-3,4-difluorobenzoate (compound h1, 584 mg, 0.939 mmol) was cooled to 0 °C, and 1.29 mL (5.64 mmol) of 25% sodium methoxide in methanol was added. The mixture was stirred at room temperature for 3 hours. Then, diethyl (bromodifluoromethyl)phosphonate (1.00 g, 3.76 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0°C, and 25% sodium methoxide in methanol (1.29 mL, 5.64 mmol) and diethyl (bromodifluoromethyl)phosphonate (1.51 g, 5.64 mmol) were added. The mixture was stirred at room temperature for 20 minutes. The reaction mixture was then 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 as a colorless solid (195 mg, 43%). LCMS m / z: 488 [M+H]+ HPLC holding time: 0.81 min (analytical condition G)

[0185] Compound h3: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-(difluoromethylhydrothio)-2-fluoroaniline]-3,4-difluorobenzoic acid [Chem. 73] was prepared by stirring a mixture of methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-(difluoromethylhydrothio)-2-fluoroaniline]-3,4-difluorobenzoate (compound h2, 60.0 mg, 0.123 mmol) and 7M ammonia MeOH solution (1.80 mL, 12.6 mmol) in a sealed tube using a microwave reaction apparatus at 85°C for 6 hours. 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 obtain the title compound (53.2 g, 91%) as a yellow oil. LCMS m / z: 473 [M + H] + HPLC holding time: 0.63 min (analytical condition B)

[0186] Compound H-1: 2-[4-(difluoromethylhydrothio)-2-fluoroaniline]-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzamide [Chemical 74] The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-(difluoromethylhydrothio)-2-fluoroaniline]-3,4-difluorobenzamide (compound h3) under the same conditions as in the preparation example of compound A-1. LCMS m / z: 566 [M+H]+ HPLC holding time: 1.49 min (analytical condition H)

[0187] Compound h4: 2-(1-benzothiophene-5-ylamino)-3,4-difluoro-5-methylbenzoic acid [Chemical 75] A solution of 2,2,6,6-tetramethylpiperidine (2.53 g, 17.9 mmol) in anhydrous THF (30 mL) was cooled to -78 °C. Under nitrogen atmosphere, a solution of 1.6 M n-butyllithium hexane (11.2 mL, 17.9 mmol) was added and stirred for 5 minutes. The reaction mixture was then 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. A 1.3 M lithium bis(trimethylsilyl)amide THF solution (15.1 mL, 19.6 mmol) and the previous reaction mixture were added, and 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 with anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated 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 as a gray solid (609 mg, 21%). LCMS m / z: 334 [M + H] + HPLC holding time: 0.80 min (analytical condition B)

[0188] Compound h5: 2-(1-benzothiophene-5-ylamino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazinyl]methyl]benzoamide [Chem. 76] HOOBt (595 mg, 3.65 mmol) and EDC·HCl (699 mg, 3.65 mmol) were added to an anhydrous DMF suspension (9.1 mL) of 2-(1-benzothiophene-5-ylamino)-3,4-difluoro-5-methylbenzoic acid (compound h4, 608 mg, 1.82 mmol) and stirred at room temperature for 1.5 hours. Next, 7M ammonia-MeOH solution (0.912 mL, 6.38 mmol) was added at 0°C, and the mixture was stirred for 30 minutes. Then, 4-methylbenzenesulfonylhydrazine (340 mg, 1.82 mmol) was added at 0°C, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and acetonitrile (14 mL) and 0.1M hydrochloric acid (100 mL) were added to the filtrate. The solid was filtered and washed with water to obtain the title compound (412 mg, 45%) as a light brown solid. LCMS m / z: 501 [M + H] + HPLC holding time: 0.83 min (analytical condition B)

[0189] Compound h7: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(1-benzothiophene-5-ylamino)-3,4-difluorobenzamide [Chem. 77] The title compound was synthesized from 2-(1-benzothiophene-5-ylamino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazine]methyl]benzamide (compound h5) under the same conditions as in the preparation examples of compounds a5 and a6. LCMS m / z: 429 [M+H]+ HPLC holding time: 0.57 min (analytical condition B)

[0190] Compound h8: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-[(4-fluoro-1-benzothiophene-5-yl)amino]benzamide [Chemical 78] A solution (0.3 mL) of anhydrous acetonitrile of 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(1-benzothiophene-5-ylamino)-3,4-difluorobenzamide (compound h7, 22 mg, 0.051 mmol) was cooled to 0 °C, and N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (9.5 mg, 0.027 mmol) was added, and the mixture was stirred for 2.5 hours. Then, N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (8.0 mg, 0.023 mmol) was added, and the mixture was 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% trifluoroacetic acid aqueous solution / 0.05% trifluoroacetic acid acetonitrile solution) to obtain the title compound as a brown solid (8.0 mg, 35%). LCMS m / z: 447 [M+H]+ HPLC holding time: 0.61 min (analytical condition B)

[0191] Compound H-3: 3,4-Difluoro-2-[(4-fluoro-1-benzothiophene-5-yl)amino]-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzamide [Chem. 79] The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-[(4-fluoro-1-benzothiophene-5-yl)amino]benzamide (compound h8) under the same conditions as in the preparation example of compound A-1. LCMS m / z: 540 [M+H]+ HPLC holding time: 1.10 min (analytical condition E)

[0192] Compound h9: 1,2,3-trifluoro-4-[(4-methoxyphenyl)methoxy]benzene [Chemical 80] Potassium carbonate (9.90 g, 71.6 mmol) and 4-methoxybenzyl chloride (5.55 mL, 40.9 mmol) were added to an anhydrous acetone solution (101 mL) of 2,3,4-trifluorophenol (5.05 g, 34.1 mmol) and stirred at 70 °C for 8 hours. Water (150 mL) was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. DMSO (15 mL) and water (100 mL) were added to the residue, and the resulting solid was washed to obtain the title compound (8.72 g, 95%) as a gray solid. LCMS m / z: 267 [M-H] - HPLC holding time: 0.92 min (analytical condition B)

[0193] Compound h10: 2,3,4-trifluoro-5-[(4-methoxyphenyl)methoxy]benzoic acid [Chemical 81] 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 nitrogen atmosphere, a solution of 1.6 M bis(trimethylsilyl)acetylenehydride lithium hexane (15.4 mL, 24.6 mmol) was added, and the mixture was stirred for 10 minutes. The reaction mixture was then 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 the mixture was stirred for 3 hours, followed by stirring while injecting carbon dioxide gas for 30 minutes. 1 M hydrochloric acid (60 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried with anhydrous sodium sulfate, and the desiccant was removed by filtration. The solution was then concentrated 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 obtain the title compound as a gray solid (1.32 g, 34%). LCMS m / z: 311 [M-H] - HPLC holding time: 0.80 min (analytical condition B)

[0194] Compound h13: Methyl 3,4-difluoro-2-(2-fluoro-4-iodoaniline)-5-hydroxybenzoate [Chemical 82] 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 manufacturing examples of compounds c5, a1, and a6. However, 2-fluoro-4-iodoaniline was used instead of 4-iodo-2-methylaniline used in the manufacturing example of compound c5, and anhydrous THF was used instead of toluene used in the manufacturing example of compound a1. LCMS m / z: 424 [M+H]+ HPLC holding time: 0.91 min (analytical condition B)

[0195] Compound h14: Methyl 5-[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]oxy-3,4-difluoro-2-(2-fluoro-4-iodoaniline)benzoate [Chemical 83] In a DCM solution (15 mL) of methyl 3,4-difluoro-2-(2-fluoro-4-iodoaniline)-5-hydroxybenzoate (compound h13, 375 mg, 0.886 mmol), [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4, 814 mg, 2.66 mmol), molecular sieve 4A (375 mg), tetra(acetonitrile)copper(I)hexafluorophosphate (495 mg, 1.33 mmol) and pyridine (0.287 mL, 3.55 mmol) were added and stirred at room temperature for 2.5 hours. Next, [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-acetycysteine ​​(434 mg, 2.66 mmol) was added to the reaction mixture, and the mixture was stirred for 3 hours. The solids were filtered, 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 aqueous solution / 0.1% formic acid acetonitrile solution) to obtain the title compound (168 mg, 28%) as a bubbly substance. LCMS m / z: 684 [M+H]+ HPLC holding time: 1.07 min (analytical condition B)

[0196] Compound H-4: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]oxybenzoamide [Chemical 84] 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 preparation examples of compounds a6, E-13 and A-1. LCMS m / z: 612 [M+H]+ HPLC holding time: 1.55 min (analytical condition H)

[0197] Compound I-1: 4-fluoro-2-(2-fluoro-4-iodoaniline)-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzamide [Chemical 85] The title compound was synthesized from 2,4-difluoro-5-vinylbenzoic acid under the same conditions as in the manufacturing examples of compounds c5, c6, c1, a5, a6, and A-1. However, 2-fluoro-4-iodoaniline was used instead of 4-iodo-2-methylaniline used in the manufacturing example of compound c5. LCMS m / z: 592 [M+H]+ HPLC holding time: 1.17 min (analytical condition E)

[0198] Compound J1: Methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-sideoxypyridine-3-carboxylic acid ester [Chem. 86] was added to a DCM suspension (91 mL) of (2-amino-3-fluoropyridin-4-yl)methanol (10.3 g, 72.7 mmol) over 10 minutes with thionyl chloride (10.6 mL, 145 mmol) and stirred at room temperature for 65 minutes. The reaction mixture was filtered, and the resulting solid was dissolved in ethyl acetate and washed with an aqueous sodium bicarbonate solution. The organic layer was dried with anhydrous magnesium sulfate, and after filtering off the drying agent, the mixture was concentrated under reduced pressure to obtain a crude product of 2-amino-4-(chloromethyl)-3-fluoropyridine (10.3 g).

[0199] The crude product of 2-amino-4-(chloromethyl)-3-fluoropyridine (3.47 g) and tripotassium phosphate (5.00 g, 23.6 mmol) were added to a 1,3-dimethyl-2-imidazolidine ionomer solution (39 mL) of methyl 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-sideoxy-1,6-dihydropyridine-3-carboxylic acid (7.90 g, 19.7 mmol) and tetrabutylammonium iodide (0.726 g, 1.97 mmol). The mixture was stirred at 50 °C for 4 hours. Water was added to the reaction mixture, and the resulting filtered solid was washed with a mixture of acetonitrile / water to obtain the title compound (10.3 g, 60%). LCMS m / z: 527 [M + H] + HPLC holding time: 0.63 min (analytical condition B)

[0200] Compound J2: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-sideoxypyridin-3-carboxylic acid hydrochloride [Chemical 87] The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-sideoxypyridin-3-carboxylic acid ester (compound J1) under the same conditions as in the preparation example of compound A7. LCMS m / z: 513 [M+H]+ HPLC holding time: 0.76 min (analytical condition D)

[0201] Compound J3: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-sideoxypyridin-3-carboxylic acid hydrochloride [Chemical 88] was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-sideoxypyridin-3-carboxylic acid hydrochloride (compound J2) under the same conditions as in the preparation example of compound A8. LCMS m / z: 512 [M+H]+ HPLC holding time: 0.84 min (analytical condition D)

[0202] Compound J-1: 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]-1-methyl-6-sideoxypyridin-3-methylamine [Chemical 89] The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-sideoxypyridin-3-methylamine (compound j3) under the same conditions as in the preparation example of compound A-25. LCMS m / z: 605 [M+H]+ HPLC holding time: 0.95 min (analytical condition E)

[0203] Compound k1: Methyl 2-(2-fluoro-4-iodoanilino)-5-methoxy-1-methyl-6-sideoxypyridine-3-carboxylic acid ester [Chem. 90] Methyl 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-sideoxy-1,6-dihydropyridine-3-carboxylic acid ester (132 mg, 0.328 mmol) was added to an acetonitrile solution (2.7 mL), and (chloromethylene)dimethylammonium chloride (168 mg, 1.31 mmol) was added. The mixture was stirred at room temperature for 1.5 h. Water was added to the reaction mixture, and after stirring for 30 min, the solid was filtered to give the title compound (108 mg, 76%). LCMS m / z: 431 [M+H]+ HPLC holding time: 0.80 min (analytical condition B)

[0204] Compound k4: Methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-sideoxypyridine-3-carboxylic acid ester [Chemical 91] The title compound was synthesized from methyl 2-(2-fluoro-4-iodoanilino)-5-methoxy-1-methyl-6-sideoxypyridine-3-carboxylic acid ester (compound k1) under the same conditions as in the manufacturing examples of compounds a2, a5, and a6. However, 2-nitrobenzene-1-sulfadiazine was used instead of 4-methylbenzenesulfadiazine used in the manufacturing example of compound a2. Furthermore, [2-fluoro-3-[(2-methylpropane-2-yl)oxycarbonylamino]phenyl]boronic acid and DIPEA were used to replace [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4) and potassium carbonate used in the preparation example of compound a5. LCMS m / z: 526 [M+H]+ HPLC holding time: 0.90 min (analytical condition B)

[0205] Compound k11: The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-sideoxypyridine-3-carboxylic acid ester (compound k4) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of compounds A-25 and b2. However, pyridine was used as the solvent in the sulfonation step. LCMS m / z: 604 [M+H]+ HPLC holding time: 0.77 min (analytical condition B)

[0206] Compound K-10: 5-[[3-(ethylsulfonylmino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-sideoxypyridine-3-carboxylic acid (compound K11, 22.0 mg, 0.036 mmol) in anhydrous DMF solution (0.264 mL) was mixed with HOOBt (8.92 mg, 0.055 mmol) and EDC·HCl (10.5 mg, 0.055 mmol) at room temperature for 3 hours. Then, 7M ammonia MeOH solution (20.8 μL, 0.146 mmol) was added at 0 °C, and the mixture was stirred 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 as a colorless solid (15.8 mg, 72%). LCMS m / z: 603 [M + H] + HPLC holding time: 1.42 min (analytical condition H)

[0207] Compound l2: Methyl 2-bromo-5-(2-fluoro-4-trimethylsilylaniline)pyridine-4-carboxylic acid ester [Chemical 94] The title compound was obtained from 2-bromo-5-fluoropyridine-4-carboxylic acid under the same conditions as in the manufacturing examples of compound c5 and compound a1. However, 2-fluoro-4-trimethylsilylaniline was used instead of 4-iodo-2-methylaniline used in the manufacturing example of compound c5. LCMS m / z: 397 [M+H]+ HPLC holding time: 1.17 min (analytical condition G)

[0208] Compound 13a: Methyl 5-(2-fluoro-4-trimethylsilylaniline)-2-methoxypyridine-4-carboxylic acid ester [Chem. 95] Compound 13b: 5-(2-fluoro-4-trimethylsilylaniline)-4-methoxycarbonylpyridine-2-carboxylic acid [Chem. 96] In methyl 2-bromo-5-(2-fluoro-4-trimethylsilylaniline)pyridine-4-carboxylic acid ester (Compound 12, 2.5 g, 6.29 mmol), 1,1,3-trisyloxy-1,2-benzothiazolium-2-carboxaldehyde (2.66 g, 612.6 mmol) An anhydrous DMF suspension (63 mL) containing Xantphos (728 mg, 1.26 mmol), palladium acetate (141 mg, 0.629 mmol), and sodium carbonate (1.67 g, 15.7 mmol) was mixed with an anhydrous DMF solution (63 mL) containing triethylsilane (2.01 mL, 12.6 mmol). The mixture was stirred at room temperature for 10 minutes, followed by stirring 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 obtain compounds l3a (0.4 g, 18%) and l3b (1.4 g, 61%) as yellow solids. Compound l3a LCMS m / z: 347 [M+H]+ HPLC holding time: 1.06 min (analytical condition G) Compound l3b LCMS m / z: 363 [M+H]+ HPLC holding time: 0.92 min (analytical condition G)

[0209] Compound l4: Methyl 5-(2-fluoro-4-trimethylsilylaniline)-2-(hydroxymethyl)pyridine-4-carboxylic acid ester [Chem. 97] A 1M tetrahydrofuran borane complex THF solution (4.33 mL, 4.33 mmol) was added to anhydrous THF solution (14 mL) of methyl 5-(2-fluoro-4-trimethylsilylaniline)-2-methylpyridine-4-carboxylic acid ester (compound l3a, 500 mg, 1.44 mmol) and stirred at room temperature for 1 hour. Acetic acid (0.496 mL, 8.66 mmol) was added to the reaction mixture and concentrated 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 obtain the title compound as a pale yellow solid (360 mg, 72%). LCMS m / z: 349 [M+H]+ HPLC holding time: 0.91 min (analytical condition G)

[0210] Compound 14: Methyl 5-(2-fluoro-4-trimethylsilylaniline)-2-(hydroxymethyl)pyridine-4-carboxylic acid ester [Chem. 98] A boronane dimethyl sulfide complex (0.747 mL, 7.86 mmol) was added to an anhydrous THF solution (16 mL) of 5-(2-fluoro-4-trimethylsilylaniline)-4-methoxycarbonylpyridine-2-carboxylic acid (compound 13b, 570 mg, 1.57 mmol) and stirred at room temperature for 2 hours. Acetic acid (1.58 mL, 27.6 mmol) was added to the reaction mixture, and the mixture was concentrated 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 (350 mg, 64%) as a pale yellow solid. LCMS m / z: 349 [M+H]+ HPLC holding time: 0.91 min (analytical condition G)

[0211] Compound l5: Methyl 2-(chloromethyl)-5-(2-fluoro-4-trimethylsilylaniline)pyridine-4-carboxylic acid ester [Chem. 99] Thionium chloride (0.168 mL, 2.30 mmol) was added to a DCM solution (12 mL) of methyl 5-(2-fluoro-4-trimethylsilylaniline)-2-(hydroxymethyl)pyridine-4-carboxylic acid ester (compound l4, 400 mg, 1.15 mmol) and stirred at room temperature for 50 min. The reaction mixture was concentrated under reduced pressure to obtain the crude product of the title compound (400 mg). LCMS m / z: 367 [M+H]+ HPLC holding time: 1.11 min (analytical condition G)

[0212] Compound l6: Methyl 2-[[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]methyl]-5-(2-fluoro-4-trimethylsilylaniline)pyridine-4-carboxylic acid ester [Chemical 100] A 1,4-dicarboxylic acid suspension (17 mL) of methyl 2-(chloromethyl)-5-(2-fluoro-4-trimethylsilylaniline)pyridine-4-carboxylic acid ester (compound l5, 584 mg, 1.59 mmol), [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4, 731 mg, 2.39 mmol), tetra-triphenylphosphine palladium (184 mg, 0.159 mmol) and potassium carbonate (660 mg, 4.78 mmol) was stirred at 110 °C for 2 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound as a yellow solid (583 mg, 62%). LCMS m / z: 593 [M + H] + HPLC holding time: 1.13 min (analytical condition G)

[0213] Compound 17: Methyl 2-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-trimethylsilylaniline)pyridine-4-carboxylic acid ester [Chemical 101] The title compound was synthesized from methyl 2-[[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]methyl]-5-(2-fluoro-4-trimethylsilylaniline)pyridine-4-carboxylic acid ester (compound 16) under the same conditions as in the preparation example of compound a6. LCMS m / z: 443 [M+H]+ HPLC holding time: 0.83 min (analytical condition G)

[0214] Compound 18: Methyl 2-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoaniline)pyridine-4-carboxylic acid ester [Chemical 102] An anhydrous DCM solution (14 mL) of methyl 2-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-trimethylsilylaniline)pyridine-4-carboxylic acid ester (Compound 17, 300 mg, 0.678 mmol) 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, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the 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 holding time: 0.69 min (analytical condition G)

[0215] Compound L-1: The title compound was synthesized from methyl 2-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoaniline)pyridine-4-carboxylic acid ester (compound l8) under the same conditions as in the preparation examples of compounds a7, K-10, and A-1. LCMS m / z: 575 [M+H]+ HPLC holding time: 1.36 min (analytical condition H)

[0216] Compound m1: Methyl 2-amino-6-(aminomethyl)pyridine-3-carboxylic acid ester diacetate [Chemical 104] A palladium-supported activated carbon powder catalyst (10% palladium) (933 mg, 0.877 mmol) was added to a mixed solution of methyl 2-amino-6-cyanopyridine-3-carboxylic acid ester (9.14 g, 51.6 mmol) in acetic acid (100 mL) and methanol (100 mL), and stirred at room temperature for 4 hours under hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound (15.3 g). LCMS m / z: 182 [M + H] + HPLC holding time: 0.26 min (analytical condition G)

[0217] Compound m2: Methyl 2-amino-6-(aminomethyl)pyridine-3-carboxylic acid ester [Chemical 105] In a formic acid solution (230 mL) of methyl 2-amino-6-(aminomethyl)pyridine-3-carboxylic acid ester diacetate (compound m1, 14.7 g, 48.8 mmol), acetic anhydride (115 mL, 1.22 mol) was added over 30 minutes, and the mixture was stirred overnight at 70 °C. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate by adding saturated sodium bicarbonate aqueous solution. The organic layer was washed with saturated brine, dried with anhydrous magnesium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was purified by amino silicone column chromatography to give the title compound (8.16 g, 80%) as a yellow solid. LCMS m / z: 210 [M + H] + HPLC holding time: 0.29 min (analytical conditions G)

[0218] Compound m3: Methyl 2-amino-5-bromo-6-(methamidomethyl)pyridine-3-carboxylic acid ester [Chemical 106] In an anhydrous acetonitrile solution (400 mL) of methyl 2-amino-6-(methamidomethyl)pyridine-3-carboxylic acid ester (compound m2, 9.25 g, 44.2 mmol), N-bromosuccinimide (7.87 g, 44.2 mmol) was added in fractions, 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 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 holding time: 0.52 min (analytical condition G)

[0219] Compound m4: Methyl 5-amino-8-bromoimidazolo[1,5-a]pyridine-6-carboxylic acid ester [Chem. 107] Phosphorus trichloride (17.5 mL, 187 mmol) was added to an anhydrous toluene suspension (200 mL) of methyl 2-amino-5-bromo-6-(methamidomethyl)pyridine-3-carboxylic acid ester (compound m3, 12.0 g, 41.7 mmol) and stirred at 95 °C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was treated with a saturated aqueous solution of sodium bicarbonate and water. The resulting solid was washed with water to dissolve it in DCM and dried with anhydrous magnesium sulfate. After filtering off the drying agent, the mixture was concentrated under reduced pressure to give the title compound (10.5 g, 93%) as a light brown solid. LCMS m / z: 270 [M + H] + HPLC holding time: 0.65 min (analytical conditions G)

[0220] Compound m5: Methyl 5-[bis[(2-methylpropane-2-yl)oxycarbonyl]amino]-8-bromoimidazolo[1,5-a]pyridine-6-carboxylic acid ester [Chem. 108] was added to anhydrous DCM solution (50 mL) of methyl 5-amino-8-bromoimidazolo[1,5-a]pyridine-6-carboxylic acid ester (compound m4, 1.58 g, 5.85 mmol) and di-tert-butyl dicarbonate (3.19 g, 14.6 mmol), and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silicone column chromatography to give the title compound (2.5 g, 91%) as a yellow solid. LCMS m / z: 470 [M + H] + HPLC holding time: 0.95 min (analytical condition G)

[0221] Compound m6: Methyl 5-[bis[(2-methylpropane-2-yl)oxycarbonyl]amino]-8-vinylimidazo[1,5-a]pyridine-6-carboxylic acid ester [Chem. 109] A suspension of methyl 5-[bis[(2-methylpropane-2-yl)oxycarbonyl]amino]-8-bromoimidazo[1,5-a]pyridine-6-carboxylic acid ester (compound m5, 2.5 g, 5.32 mmol), potassium vinyl trifluoroborate (1.07 g, 7.97 mmol), tetra-triphenylphosphine palladium (614 mg, 0.532 mmol) and cesium carbonate (5.20 g, 16.0 mmol) in 1,4-dimethylamine (40 mL) and water (10 mL) was stirred at 100 °C for 2 hours. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried with anhydrous magnesium sulfate. After filtering out the desiccant, the mixture was concentrated under reduced pressure. The resulting residue was purified by silicone column chromatography to obtain the title compound as a yellow solid (1.68 g, 76%). LCMS m / z: 418 [M + H] + HPLC holding time: 0.89 min (analytical conditions G)

[0222] Compound m8: Methyl 5-amino-8-methylimidazo[1,5-a]pyridine-6-carboxylic acid ester trifluoroacetate [Chemical 110] The title compound was synthesized from methyl 5-[bis[(2-methylpropane-2-yl)oxycarbonyl]amino]-8-vinylimidazo[1,5-a]pyridine-6-carboxylic acid ester (compound m6) under the same conditions as in the preparation examples of compounds c6 and a6. LCMS m / z: 220 [M+H]+ HPLC holding time: 0.48 min (analytical condition G)

[0223] Compound m9: Methyl 5-amino-8-(5,5-dimethyl-1,3-dialkyl-2-yl)imidazo[1,5-a]pyridine-6-carboxylic acid ester [Chem. 111] A toluene suspension (30 mL) of methyl 5-amino-8-methylimidazo[1,5-a]pyridine-6-carboxylic acid ester 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) was stirred overnight at 110 °C. DIPEA (1 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography to give the title compound (340 mg, 78%) as a red solid. LCMS m / z: 306 [M+H]+ HPLC holding time: 0.66 min (analytical condition G)

[0224] Compound m10: Methyl 5-chloro-8-(5,5-dimethyl-1,3-dicarboxy-2-yl)imidazo[1,5-a]pyridine-6-carboxylate [Chemical 112] An acetonitrile suspension (15 mL) of methyl 5-amino-8-(5,5-dimethyl-1,3-dicarboxy-2-yl)imidazo[1,5-a]pyridine-6-carboxylate (compound m9, 340 mg, 1.11 mmol) was cooled to 0 °C, and copper chloride (I) (165 mg, 1.67 mmol) and copper chloride (II) (225 mg, 1.67 mmol) were added. Then, tert-butyl nitrite (172 mg, 1.67 mmol) was 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 give the title compound as a red solid (237 mg, 66%). LCMS m / z: 325 [M + H] + HPLC holding time: 0.77 min (analytical conditions G)

[0225] Compound m11: Methyl 8-(5,5-dimethyl-1,3-dialkyl-2-yl)-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridine-6-carboxylic acid ester [Chemical 113] A DMA suspension (4 mL) of methyl 5-chloro-8-(5,5-dimethyl-1,3-dialkyl-2-yl)imidazo[1,5-a]pyridine-6-carboxylic acid ester (compound m10, 237 mg, 0.730 mmol), cesium carbonate (713 mg, 2.19 mmol), and 2-fluoro-4-iodoaniline (346 mg, 1.46 mmol) was stirred overnight at 50 °C. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous magnesium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography to obtain the title compound as a yellow solid (210 mg, 55%). LCMS m / z: 526 [M + H] + HPLC holding time: 1.02 min (analytical conditions G)

[0226] Compound m12: Methyl 5-(2-fluoro-4-iodoanilino)-8-methylimidazo[1,5-a]pyridine-6-carboxylic acid ester [Chemical 114] A suspension of methyl 8-(5,5-dimethyl-1,3-dialkyl-2-yl)-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylic acid ester (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 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 (168 mg, 96%) as a yellow solid. LCMS m / z: 440 [M+H] + HPLC holding time: 0.84 min (analytical condition G)

[0227] Compound m15: The title compound was synthesized from methyl 5-(2-fluoro-4-iodoaniline)-8-methylimidazo[1,5-a]pyridine-6-carboxylic acid ester trifluoroacetate [Chemical 115] under the same conditions as in the manufacturing examples of compounds a2, a5, and a6. However, MeOH was used instead of EtOH used in the manufacturing example of compound a2. LCMS m / z: 536 [M+H]+ HPLC holding time: 0.54 min (analytical condition F)

[0228] Compound m16: 8-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylic acid trifluoroacetate [Chemical 116] A suspension of methyl 8-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylic acid 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 overnight at 50 °C. The reaction mixture was concentrated under reduced pressure after adding formic acid to make it acidic. The resulting residue was purified by reverse-phase column chromatography (0.1% TFA aqueous solution / 0.1% TFA acetonitrile solution) to obtain the title compound as a yellow solid (42 mg, 72%). LCMS m / z: 522 [M+H]+ HPLC holding time: 0.45 min (analytical condition F)

[0229] Compound m17: 8-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylic acid trifluoroacetate [Chemical 117] A DMF solution (1.6 mL) 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) 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. The mixture was 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 obtain the title compound as a yellow solid (25 mg, 60%). LCMS m / z: 521 [M+H]+ HPLC holding time: 0.41 min (analytical condition F)

[0230] Compound M-1: The title compound was synthesized from 8-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoaniline)imidazo[1,5-a]pyridin-6-methylamine trifluoroacetate (compound m17) under the same conditions as in the preparation example of compound A-1. LCMS m / z: 614 [M+H]+ HPLC holding time: 1.18 min (analytical condition H)

[0231] Compound n1: 6-chloro-5-fluoro-4-(2-fluoro-4-iodoaniline)pyridine-3-carboxylic acid [Chemical 119] An anhydrous THF solution (8 mL) of 2-fluoro-4-iodoaniline (2.26 g, 9.52 mmol) was cooled to -78 °C, and a 2 M LDA THF / heptane / ethylbenzene solution (7.14 mL, 14.3 mmol) was added and stirred for 30 minutes. Next, an anhydrous THF solution (8 mL) of 4,6-dichloro-5-fluoropyridine-3-carboxylic acid (1.00 g, 4.76 mmol) was added, and the mixture was stirred at -78 °C for 30 minutes. Subsequently, water and 6 M hydrochloric acid were added to the reaction mixture to adjust the pH from 1 to 2, and extraction was performed with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, the desiccant was filtered off, and the mixture was concentrated under reduced pressure. Recrystallization (DCM) of the resulting residue yielded the title compound as a light brown solid (850 mg, 44%). LCMS m / z: 411 [M+H]+ HPLC holding time: 0.85 min (analytical conditions G)

[0232] Compound n2: Methyl 6-chloro-5-fluoro-4-(2-fluoro-4-iodoaniline)pyridine-3-carboxylic acid ester [Chemical 120] The title compound was synthesized from 6-chloro-5-fluoro-4-(2-fluoro-4-iodoaniline)pyridine-3-carboxylic acid (compound n1) under the same conditions as in the preparation example of compound a1. LCMS m / z: 425 [M+H]+ HPLC holding time: 1.04 min (analytical condition G)

[0233] Compound n3: Methyl 5-fluoro-4-(2-fluoro-4-iodoanilino)-6-hydroxypyridine-3-carboxylic acid ester [Chemical 121] 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-carboxylic acid ester (compound n2, 350 mg, 0.824 mmol) and 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 obtain the title compound (281 mg, 84%) as a light brown solid. LCMS m / z: 407 [M+H]+ HPLC holding time: 0.72 min (analytical condition G)

[0234] Compound n4: N-[4-(bromomethyl)-3-fluoropyridin-2-yl]-1,1-diphenylmethaneimine [Chem. 122] was prepared by adding DIPEA (3.93 mL, 22.5 mmol) and methanesulfonic anhydride (2.07 g, 11.3 mmol) to an anhydrous DCM solution (37.5 mL) of [2-(diphenylmethyleneamino)-3-fluoropyridin-4-yl]methanol (2.30 g, 7.51 mmol) and stirring at room temperature for 30 minutes. Then, an anhydrous THF solution (0.5 mL) of lithium bromide (3.26 g, 37.5 mmol) was added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and extraction was performed with DCM. The organic layer was dried with anhydrous sodium sulfate, and after filtering to remove the drying agent, the mixture was concentrated under reduced pressure. The 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 holding time: 0.94 min (analytical condition G)

[0235] Compound n5: Methyl 1-[[2-(diphenylmethyleneamino)-3-fluoropyridin-4-yl]methyl]-5-fluoro-4-(2-fluoro-4-iodoanilino)-6-sideoxypyridine-3-carboxylic acid ester [Chemical 123] Lithium hydride (1.85 mg, 0.222 mmol) was added to an anhydrous DMF solution (0.739 mL) of methyl 5-fluoro-4-(2-fluoro-4-iodoanilino)-6-hydroxypyridine-3-carboxylic acid ester (compound n3, 30 mg, 0.074 mmol) and stirred at room temperature for 30 minutes. Then, an anhydrous THF solution (0.5 mL) of N-[4-(bromomethyl)-3-fluoropyridin-2-yl]-1,1-diphenylmethaneimine (compound n4, 82 mg, 0.222 mmol) was added and stirred at room temperature for 1 hour. Subsequently, an anhydrous THF solution (0.5 mL) of lithium hydride (1 mg, 0.126 mmol) and compound n4 (25 mg, 0.068 mmol) was added, and the mixture was 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 with anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The resulting residue was purified by silicone column chromatography (hexane / ethyl acetate) to give the title compound (19 mg, 37%) as a colorless solid. LCMS m / z: 695 [M + H] + HPLC holding time: 1.05 min (analytical condition G)

[0236] Compound n8: The title compound was synthesized from methyl 1-[[2-(2-amino-3-fluoropyridin-4-yl)methyl]-5-fluoro-4-(2-fluoro-4-iodoaniline)-6-sideoxypyridin-3-carboxylic acid ester (compound n5) under the same conditions as in the manufacturing examples of compounds a6, a7, and K-10. However, in the initial step of the reaction carried out under the same conditions as in the manufacturing example of compound a6, 4M hydrochloric acid was added. LCMS m / z: 516 [M+H]+ HPLC holding time: 0.52 min (analytical condition B)

[0237] Compound N-1: 5-fluoro-4-(2-fluoro-4-iodoaniline)-1-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]-6-sideoxypyridin-3-methylamine [Chemical 125] The title compound was synthesized from 1-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-fluoro-4-(2-fluoro-4-iodoaniline)-6-sideoxypyridin-3-methylamine (compound n8) under the same conditions as in the preparation example of compound A-1. LCMS m / z: 609 [M+H]+ HPLC holding time: 0.94 min (analytical condition E)

[0238] Compound N-2: 5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(propylaminesulfonylamino)pyridin-4-yl]methyl]-6-sideoxypyridin-3-methylamine [Chemical 126] was synthesized from 1-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-fluoro-4-(2-fluoro-4-iodoanilino)-6-sideoxypyridin-3-methylamine (compound n8) and the corresponding 4-nitrobenzene aminesulfonic acid under the same conditions as in the preparation example of compound A-1. LCMS m / z: 637 [M+H]+ HPLC holding time: 1.04 min (analytical condition E)

[0239] Compound p3: Methyl 4-(2-fluoro-4-iodoanilino)-6-hydroxy-5-methylpyridine-3-carboxylic acid ester [Chemical 127] The title compound was synthesized from 4,6-dichloro-5-methylpyridine-3-carboxylic acid under the same conditions as in the manufacturing examples of compounds c5, a1, and n3. However, 2-fluoro-4-iodoaniline was used instead of 4-iodo-2-methylaniline used in the manufacturing example of compound c5. LCMS m / z: 403 [M+H]+ HPLC holding time: 0.76 min (analytical condition G)

[0240] Compound P-1: 4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]-5-methyl-6-sideoxypyridin-3-carboxylic acid ester (compound p3) was synthesized under the same conditions as in the manufacturing examples of compounds n4, b2, m17, a6, and A-1. However, 2M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate used in the manufacturing example of compound b2, and 4M 1,4-dimethylhydrochloride solution was used instead of trifluoroacetic acid used in the manufacturing example of compound a6. LCMS m / z: 605 [M+H]+ HPLC holding time: 0.66 min (analytical condition B)

[0241] [Experimental Examples] In the following experimental examples, the compounds described in the above-mentioned manufacturing examples are represented by the compound numbers used in the above-mentioned manufacturing examples. Also, ref-1 represents compound 34 of Bioorg. Med. Chem. Lett. 2008, vol. 18, no. 24, pp. 6501-6504, which is the compound represented by formula (A) below. Also, ref-2 represents compound 27 of Bioorg. Med. Chem. Lett. 2013, vol. 23, no. 8, pp. 2384-2390, which is the compound represented by formula (B) below. Also, ref-3 and ref-4 represent compounds 9 and 10 of ChemMedChem. 2015, vol. 10, no. 12, pp. 2004-2013, which are the compounds represented by formulas (C) and (D) below. Furthermore, ref-5 represents compound 1 of ACS Medchem. Lett. 2014, vol. 5, no. 4, p. 309–314, which is the compound represented by the following formula (E).

[0242] ref-1: N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoaniline)benzamide (PD0325901) [Chemical 129]

[0243] ref-2: 4-Fluoro-2-(2-Fluoro-4-iodoaniline)-6-[3-(methylaminesulfonylamino)phenoxy]benzamide [Chemical 130]

[0244] ref-3: 3-(2-fluoro-4-iodoaniline)-5-[3-(propane-2-ylsulfonylamino)phenoxy]pyridine-4-methylamine [Chem. 131]

[0245] ref-4: 3-[3-(cyclopropylsulfonylamino)phenoxy]-5-(2-fluoro-4-iodoaniline)pyridine-4-methylamine [Chemical 132]

[0246] ref-5: 3-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]-4-methyl-7-pyrimidin-2-yloxybenzopiperanone (CH5126766) [Chem. 133]

[0247] (Experimental Example 1) The effect of the interaction between RAF1 and MEK1 was investigated using Biacore 8K (GE Healthcare) as follows: the effect of the compounds described in Figures 4-7 on the interaction between RAF1 and MEK1 was investigated.

[0248] Using an anti-GST antibody (GE Healthcare), RAF1 fused with a GST tag (Carna Biosciences) was immobilized on the surface of a Sensor Chip CM5 (GE Healthcare). Subsequently, the surface of the sensor chip was flushed for 120 seconds with electrophoresis buffer (blank), 40 nM MEK1 solution, or a mixture of 40 nM MEK1 and 3 μM of the test compound, followed by flushing with the electrophoresis buffer. MEK1 used was recombinant human protein, inactive (Thermo Fisher Scientific). The electrophoresis buffer was PBS (Sigma-Aldrich) supplemented with 1 mM DTT (Wako), 10 mM MgCl2 (Wako), 500 μM ATP (Wako), 0.01% Tween20 (Junsei-Kagaku), and 1% DMSO (Sigma-Aldrich). The electrophoresis buffer was also used in the preparation of the sample solution. Measurements were performed at 15°C. Both RAF1 and MEK1 were dephosphorylated using Lambda protein phosphatase (New England Biolabs) before use, while MEK1 was purified by size exclusion chromatography.

[0249] The obtained sensing maps (charts showing the amount of MEK1 bound to immobilized RAF1 over time) were double-referencing using Biacore Insight Evaluation Software. Furthermore, the sensing maps were normalized using TIBCO Spotfire to account for the amount of RAF1 immobilization. The normalized sensing maps are shown in Figures 4-7. On each sensing map, the experiment ID, Biacore channel number, and compound number are sequentially displayed (however, "no compound" indicates that the tested compound was not present). In each sensing map, the horizontal axis (X-axis) represents the time (in seconds) since the start of sample solution addition, and the vertical axis (Y-axis) represents the normalized amount of MEK1 bound.

[0250] (Experimental Example 2) The effects of the compounds (ref-5 and compound A-1) shown in Figure 8 on the phosphorylation of MEK and ERK in cells were investigated by Western ink dot method as follows.

[0251] A549 cells were seeded in 12-well trays at a density of 400,000 cells per well and cultured in a 37°C incubator with 5% carbon dioxide using Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum (SIGMA). The following day, the test compound (0.3 μM Ref-5 or 0.05 μM compound A-1) or DMSO was added to the medium, and the cells were cultured for 30 minutes or 2 hours. Cells were then collected using a cell scraper and soluble. The 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 manufactured by Cell Signaling Technology). After washing with the primary antibody, the membrane was treated with HRP-labeled secondary antibody (manufactured by Cell Signaling Technology). After washing, the signal was detected using chemiluminescence immunoassay with Chemi-Lumi One Super (manufactured by Nacalai). Figure 8 shows the electrophoresis results of the Western spectrophotometric method. In Figure 8, "p-MEK" and "p-ERK" represent phosphorylated MEK and phosphorylated ERK, respectively.

[0252] (Experimental Example 3) MEK1 inhibitory activity was evaluated by fluorescence polarization method for the compounds listed in Table 6 below.

[0253] The test compound, CRAF (Thermo Fisher Scientific), MEK1 (Thermo Fisher Scientific), 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 reaction was carried out at 30°C for 45 minutes. Then, IMAP (registered trademark) Progressive Binding Reagent (Molecular Devices) was added, and the reaction was carried out at room temperature for 15 minutes. After the reaction, the fluorescence polarization was measured using a plate reader, and the 50% inhibition concentration (IC50) was calculated based on the inhibition rate relative to the control group without the test compound. The results are shown in Table 6.

[0254] (Experimental Example 4) The BRAF inhibitory activity of the compounds listed in Table 6 below was evaluated by time-decomposition fluorescence-fluorescence resonance energy transfer method as follows.

[0255] The test compound, BRAF (manufactured by Eurofins), and MEK1 (manufactured by 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 (manufactured by PerkinElmer) was added, and the reaction was carried out at room temperature for 60 minutes. After the reaction, the fluorescence resonance energy shift was measured using a fluorescent optical disc reader, and the 50% inhibition concentration (IC50) was calculated based on the inhibition rate relative to the control group without the test compound. The results are shown in Table 6.

[0256] (Experimental Example 5) Cell proliferation inhibitory activity was evaluated by measuring the ATP levels of surviving cells as follows. The cell proliferation inhibitory activity of the compounds listed in Table 6 below was evaluated as follows.

[0257] The test compound was serially diluted with DMSO and then diluted 25-fold with phosphate-buffered saline (C2+ and Mg2+-free). This solution was aliquoted into 96-well plates at 5 μL per well. Human lung cancer cell lines A549, Calu-6, or NCI-H2122 (all obtained from ATCC) were prepared using the culture medium supplemented with 10% fetal bovine serum (SIGMA) to achieve the following cell numbers. This cell suspension was aliquoted into culture plates containing the test compound at 95 μL per well and cultured at 37°C in a 5% carbon dioxide incubator. After 4 days, 80 μL of CellTiter-Glo (registered trademark) (Promega) was added to each well, and bioluminescence was measured using a fluorescent disc reader. The 50% inhibition concentration (IC50) was calculated based on the inhibition rate relative to the control group without the test compound. The results are shown in Table 6. A549: Dalberg modified Eagle's medium (SIGMA); 2000 cells / 95μL Calu-6: Eagle's minimal essential medium (SIGMA); 4000 cells / 95μL NCI-H2122: RPMI-1640 medium (SIGMA); 2000 cells / 95μL

[0258] (Experimental Example 6) Metabolic stability of human liver microsomes For the compounds listed in Table 6 below, metabolic stability in human liver microsomes was tested using Biomek 3000 (Beckman Coulter) as follows.

[0259] 1 mg / mL human liver microsomes (XENOTECH) / 0.1 M potassium phosphate buffer (pH 7.4) was dispensed into a 96-well plate at 400 μL per well. Next, 4 μL of 200 μM DMSO solution of the test compound was added, and the mixture was incubated at 37°C. To this reaction solution (200 μL), 200 μL of a solution prepared by incubating at 37°C with 2 mM NADPH (ORIENTAL YEAST) / 0.1 M potassium phosphate buffer (pH 7.4) was added. After 0, 5, 15, or 30 minutes, 50 μL of the reaction solution was added to 100 μL of acetonitrile to stop the metabolic reaction. As an internal standard, 50 μL of 1 μM warfarin aqueous solution was added to each reaction solution where the metabolic reaction had been stopped. The reaction solution was filtered and analyzed by LC / MS / MS (LC: SHIMADZU NEXERA; MS: ABSciex 4000Qtrap; column: Ascentis Express C18 HPLC column (5cm × 2.1mm, 2.7μm); ionization: electro-ionization). The residue rate relative to the amount of the test compound at 0 minutes was calculated from the peak area ratio of the obtained test compound / internal standard. The disappearance rate constant (ke) was calculated from the culture time and residue rate using the rate formula for a single disappearance process. The intrinsic liver clearance (CLint) was calculated using the following formula. The results are shown in Table 6. CLint (μL / min / mg) = ke (min - 1) / human liver microsomal concentration (mg protein / μL)

[0260] [Table 6] Table 6 compound serial number MEK1 IC 50 (nM) BRAF IC 50 (nM) A549 IC 50 (nM) Calu-6 IC 50 (nM) NCI-H2122 IC 50 (nM) CLint (μL / min / mg) A-1 17 1 26 64 5 1 A-2 5 3 1 2 0.1 25 A-8 3 4 0.4 2 0.1 33 A-18 8 4 5 7 2 53 A-20 23 2 7 ND 6 14 A-25 5 2 0.5 2 0.2 7 A-27 32 7 24 ND 10 4 A-33 10 2 27 68 8 6 B-1 2 5 6 11 2 15 E-1 40 12 2 6 0.4 17 E-7 334 6 1 8 0.4 5 E-13 290 1 30 84 6 25 H-1 7 2 9 21 5 39 H-3 2 4 5 ND 1 149 H-4 8 12 9 6 1 11 I-1 25 3 5 15 3 19 J-1 58 4 38 29 8 11 K-10 128 8 25 81 16 69 L-1 6 2 21 41 17 10 M-1 5 4 27 28 13 59 N-1 1 2 20 ND 28 8 N-2 1 1 193 ND 60 11 P-1 2 ND ND twenty two 6 15 ref-1 7 17 7 91 7 20 ref-2 364 12 8 35 3 12 ref-3 5 12 2 10 1 11 ref-4 11 9 2 18 2 32 ref-5 292 11 113 418 27 <1 ND: Not measured

[0261] (Experimental Example 7) In vivo antitumor effect: Using cancer-bearing mice, the effect of compound A-1 on cancer cells with KRAS mutation was evaluated as follows.

[0262] The human lung cancer cell line Calu-6 with KRAS mutations was transplanted into nude mice (CAnN.Cg-Foxn1nu / CrlCrlj, female, 5 weeks old, Charles River) by subcutaneous injection of cell suspension into the ventral part of the mice using a 26G injection needle. Seventeen days post-transplantation, when the tumor volume reached approximately 200 mm³, the mice were divided into five groups (n=8 per group) according to the dosage of the test compound administered. For four groups (A-1 administration group), compound A-1 was orally administered at doses of 0.0625 mg / kg, 0.25 mg / kg, 1 mg / kg, or 4 mg / kg using 10% DMSO / 10% Cremophor EL / 15% PEG400 / 15% HPCD as the vehicle solvent. For the remaining group (the solvent control group), the same solvent was administered orally only. The tested compound or solvent was administered once a day for 10 days.

[0263] Tumor volume was measured at 20, 24, and 27 days post-transplantation. Tumor volume was calculated using the following formula after measuring the major and minor diameters of the tumor with a diaphragm. 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 post-transplantation, and the vertical axis (Y-axis) represents the tumor volume. Tumor volume (mm³) = 1 / 2 × major diameter (mm) × minor diameter (mm) × minor diameter (mm) [Simplified Explanation of the Diagram]

[0043] 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. Figure 4 shows a sensor gram over time of the binding amount of the tested compound (ref-2, ref-3, ref-4, A-1, ref-1, ref-5, or B-1) and the added MEK1 on the surface of the RAF1-immobilized sensor chip. Figure 5 shows a sensor gram over time of the binding amount of the tested compound (A-2, A-25, J-1, E-1, M-1, N-1, or H-3) and the added MEK1 on the surface of the RAF1-immobilized sensor chip. Figure 6 is a sensing graph showing the time-varying binding amount of the tested compounds (I-1, H-4, L-1, P-1, E-7, or A-27) to the added MEK1 on the surface of a RAF1-immobilized sensing chip. Figure 7 is a sensing graph showing the time-varying binding amount of the tested compounds (A-33, A-18, N-2, A-20, A-8, E-13, or H-1) to the added MEK1 on the surface of a RAF1-immobilized sensing chip. Figure 8 is an electrophoretic image showing the Western blot results of proteins (p-MEK, MEK, p-ERK, and ERK) extracted from cultured A549 cells in the presence of the tested compounds (ref-5 or compound A-1). Figure 9 is a graph showing the time-varying tumor volume (mean ± standard deviation) in nude mice subcutaneously transplanted with the human lung cancer cell line Calu-6.

Claims

1. A method for producing a compound represented by general formula (1) or a pharmaceutically permissible salt thereof or a pharmaceutically permissible solvate of the aforementioned compound or salt, comprising: (I) reacting a compound represented by general formula (2) in a solvent with a compound represented by X1-R9 and a base to obtain a compound represented by general formula (4); (II) reacting a compound represented by general formula (4) in a solvent and in the presence of a catalyst with a compound represented by general formula (10) to obtain a compound represented by general formula (5); and (III) reacting a compound represented by general formula (5) with a compound represented by X2-S(=O)2-NH-R11 or X2-S(=O)2-R11 to obtain a compound represented by general formula (1) or a salt thereof or a solvate of the aforementioned compound or salt, [wherein, R1 is -S(=O)2-NH-R11 or -S(=O)2-R11, where R11 is a hydrogen atom, a C1-6 alkyl group (which may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), or a C3-6 cycloalkyl group (which 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 (which may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), a C3-6 cycloalkyl group (which may be substituted with a halogen atom or a C1-6 alkyl group), or a C1-6 alkoxy group (which may be substituted with a halogen atom, a hydroxyl 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)-R12, -C(=O)-O-R12, or -P(=O)(-O-R12)2; R12 is a C1-6 alkyl group or an aryl group; R13 is -B(-OR14)(-OR15) or -BF3K. R14 and R15 are each independent and are either hydrogen atoms or C1-6 alkyl groups (which may be substituted by C1-6 alkoxy or aryl groups), or R14 and R15 together with the oxygen and boron atoms in between form a 5-8 member saturated or unsaturated ring (which may be substituted by C1-6 alkyl groups, C1-6 alkoxy groups, or aryl groups, and may also condense with a benzene ring), and X2 is a halogen atom.

2. As in request item 1, where, The base used in step (I) is at least one selected from the group consisting of N,N-dimethylaminopyridine and 1-methylimidazole.

3. As in request item 1, where, The solvent used in step (I) is at least one selected from the group consisting of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropiperanone, cyclopentyl methyl ether, and tert-butyl methyl ether.

4. As in request item 2, wherein, The solvent used in step (I) is at least one selected from the group consisting of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropiperanone, cyclopentyl methyl ether, and tert-butyl methyl ether.

5. As in request item 1, where, The catalyst used in step (II) is selected from a combination of bis(allyl palladium chloride) and 2',6'-dimethoxy-2-(dicyclohexylphosphino)biphenyl, a combination of bis(allyl palladium chloride) and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, a combination of bis(allyl palladium chloride) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, and (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate. At least one of the group consisting of 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.

6. As in request item 5, wherein, The solvent used in step (II) comprises C1-6 alcohols.

7. As in request item 1, wherein, R9 is -C(=O)-O-R12, and R12 is a C1-6 alkyl or aryl group.

8. As in request item 7, wherein, R2 is a fluorine atom, R1 is -S(=O)2-NH-R11, R11 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, and X1 is a chlorine atom.

9. The method described in any of requests 1 to 8, wherein, The compound represented by general formula (1) is 2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzamide.

10. The method of claim 9, which is a method for manufacturing the sodium salt of 2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzoamide.

11. A composition comprising a sodium salt of 2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzoamide and a compound of formula (X) or a sodium salt thereof, wherein the amount of the compound of formula (X) or its sodium salt contained in the composition is 3.0 w / w or less relative to the weight of the sodium salt of 2-(4-cyclopropyl-2-fluoroaniline)-3,4-difluoro-5-[[3-fluoro-2-(methylaminesulfonylamino)pyridin-4-yl]methyl]benzoamide contained in the composition.

12. A method for manufacturing a compound represented by the following general formula (4), comprising: (I) reacting a compound represented by the following general formula (2) in a solvent with a compound represented by X1-R9 and a base to obtain a compound represented by the general formula (4), [wherein, 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)-R12, -C(=O)-O-R12 or -P(=O)(-O-R12)2, and R12 is a C1-6 alkyl group or an aryl group].

13. As in request item 12, wherein, The base used in step (I) is at least one selected from the group consisting of N,N-dimethylaminopyridine and 1-methylimidazole.

14. As in request item 12, wherein, The solvent used in step (I) is at least one selected from the group consisting of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropiperanone, cyclopentyl methyl ether, and tert-butyl methyl ether.

15. As in request item 13, wherein, The solvent used in step (I) is at least one selected from the group consisting of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropiperanone, cyclopentyl methyl ether, and tert-butyl methyl ether.

16. The method of any one of requests 12 to 15, wherein, R9 is -C(=O)-O-R12, and R12 is a C1-6 alkyl or aryl group.

17. (2-amino-3-fluoropyridin-4-yl)methyl methyl carbonate.

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