Composition containing arylamide derivatives

Abstract

To provide a composition comprising a specific arylamide derivative having RAF / MEK complex stabilizing activity and / or MEK inhibitory activity, which is useful for the treatment or prevention of cell proliferation disorders, particularly cancer, and which has good properties with respect to the elution and / or stability of the arylamide derivative in the composition. [Solution] A composition comprising, for example, 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the said compound or salt, and a dispersant (e.g., methylcellulose) and / or a basic compound (e.g., meglumine).

Description

[Technical Field]

[0001] This disclosure relates to compositions comprising arylamide derivatives. [Background technology]

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

[0003] On the other hand, it is known that some MEK inhibitors do not always have sufficient 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 poor efficacy in clinical trials of non-small cell lung cancer with KRAS mutations (see Non-Patent Documents 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 against non-small cell lung cancer with RAS mutations (see Non-Patent Document 9). Furthermore, it has been reported that CH5126766 stabilizes the RAF / MEK complex and suppresses the enhancement 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 thought to be one of the reasons why the clinical efficacy of MEK inhibitors against cancer with RAS mutations is not always sufficient (see Non-Patent Document 10). [Prior art documents]

Patent Document

[0005]

Patent Document 1

Patent Document 2

Non-Patent Document

[0006]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Summary of the Invention

Problems to be Solved by the Invention

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

[0008] Under these circumstances, it was newly discovered that certain arylamide derivatives (compounds, salts, or solvates described in (A1) to (A16) and (B1) to (B3) below) possess RAF / MEK complex stabilizing activity and / or MEK inhibitory activity, and are useful for the treatment or prevention of cell proliferation disorders, particularly cancer, and the inventors intended to formulate them.

[0009] However, regarding compositions comprising such arylamide derivatives and, for example, lactose monohydrate, the inventors have found that treatment with an acidic solution significantly reduces the elution of the arylamide derivative into artificial intestinal fluid, meaning that when administered orally to a living organism, the arylamide derivative may not be well absorbed in the body. Furthermore, regarding compositions comprising such arylamide derivatives and, for example, mannitol, the inventors have found that the arylamide derivative in the composition is easily degraded.

[0010] Therefore, the object of this disclosure is to provide a composition comprising the above-mentioned arylamide derivative that has good properties with respect to the elution and / or stability of the arylamide derivative in the composition. [Means for solving the problem]

[0011] As a result of diligent research to achieve the above objective, the inventors have discovered that the elution properties of the arylamide derivative in the composition can be improved by coexisting a dispersant in the composition, and that the stability of the arylamide derivative in the composition can be improved by coexisting a basic compound in the composition, thereby completing the invention of this disclosure.

[0012] This disclosure provides a composition comprising an arylamide derivative described in any of (A1) to (A16) and (B1) to (B3) below, and a dispersant.

[0013] The disclosure also provides compositions comprising an arylamide derivative described in any of (A1) to (A16) and (B1) to (B3) below, and a basic compound.

[0014] The disclosure also provides compositions comprising an arylamide derivative as described in any of (A1) to (A16) and (B1) to (B3) below, a dispersant, and a basic compound.

[0015] When a dispersant is included, the compositions of this disclosure have good properties with respect to the elution of arylamide derivatives in the composition. Specifically, for example, even after treatment with an acidic solution (e.g., Japanese Pharmacopoeia Dissolution Test Solution No. 1, FaSSGF (Simulated Gastric Juice under Fasting Condition)) for 60 minutes, they exhibit high performance in eluting arylamide derivatives into artificial intestinal fluid (e.g., FaSSIF (Simulated Small Intestinal Fluid under Fasting Condition), FeSSIF (Simulated Small Intestinal Fluid under Feeding Condition)). In other words, when the above compositions are administered orally to a living organism, the arylamide derivatives in the composition are expected to be well absorbed in the body.

[0016] When a basic compound is included, the compositions of this disclosure have good properties with respect to the stability of the arylamide derivative in the composition. Specifically, for example, when stored in a tightly sealed state at 80°C for two weeks or at 40°C for three months, the arylamide derivative in the composition is not easily decomposed and exhibits high shelf life. For example, in the case of the arylamide derivative described in (A14) below, even after being stored at 80°C for two weeks, the content of its hydrolysate (the compound of formula (X) described in Test Example 12 below) is, for example, 3.0% by weight or less relative to the content of the arylamide derivative.

[0017] Examples of dispersants in the compositions of this disclosure include methylcellulose, polyvinyl alcohol, hydroxypropylcellulose, copolyvidone, hydroxypropylmethylcellulose, methacrylate copolymer, polyvinylpyrrolidone, and hypromellose acetate succinate, with methylcellulose, polyvinyl alcohol, and hydroxypropylcellulose being preferred, and methylcellulose being particularly preferred.

[0018] The content of the dispersant in the composition of this disclosure is, for example, 0.1 to 20 parts by weight, preferably 0.2 to 10 parts by weight, and more preferably 1 to 10 parts by weight, per 1 part by weight of the arylamide derivative.

[0019] Examples of basic compounds in the compositions of this disclosure include meglumine, arginine, histidine, magnesium oxide, calcium silicate, and magnesium stearate, with meglumine and arginine being preferred, and meglumine being particularly preferred.

[0020] The content of the basic compound in the composition of this disclosure is, for example, 0.2 to 40 parts by weight, preferably 0.5 to 20 parts by weight, and more preferably 1 to 10 parts by weight, per 1 part by weight of the arylamide derivative.

[0021] The following describes the arylamide derivatives included in the compositions of this disclosure.

[0022] In one embodiment, the arylamide derivative of the present disclosure is a compound, salt, or solvate described in any of (A1) to (A6) below. (A1) A compound represented by the following general formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the said compound or salt. [ka] [In the formula, Ring A is a group represented by the following general formulas (2), (3), (4), or (5) (where the bonds marked with *, **, and *** are bonded to -NH-, -CONH-, and -CH2-, respectively), [ka] X1, X2, X3, X4, X5, and X6 are each independently -CR2= or -N=, R2 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group. R1 is -S(=O)2-NH-R8 or -S(=O)2-R8, R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, or a C3-6 heterocycloalkyl group), a monocyclic or bicyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group or a C1-6 alkoxy group), or a monocyclic or bicyclic C3-6 heterocycloalkyl group. R3 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group), or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy 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, and 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, or R6 and R4 together with the carbon atoms to which they are bonded form an unsaturated hetero 5-membered ring. R7 is a hydrogen atom or a C1-6 alkyl group. R9 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group.

[0023] (A2) Ring A is a group represented by general formula (2) or (4), R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group). R3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxyl group). R6 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group, and R4 is a halogen atom or a cyclopropyl group. R7 is a hydrogen atom or a methyl group. The compounds, salts, or solvates described in (A1).

[0024] (A3) The compound represented by general formula (1) is the compound represented by general formula (6) below, the compound, salt or solvate described in (A1). [ka] [In the formula, X1, X2, X3, and X4 are each independently -CR2= or -N=, R2 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group. R1 is -S(=O)2-NH-R8 or -S(=O)2-R8, R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group). R3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxyl 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, and R4 is a halogen atom or a cyclopropyl group.

[0025] (A4) R2 is a hydrogen atom or a halogen atom. R8 is a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom or a C1-6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), R3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxyl group). R5 is a halogen atom, R6 is a hydrogen atom, and R4 is a halogen atom or a cyclopropyl group. A compound, salt, or solvate described in any of (A1) to (A3).

[0026] (A5) R2 is a hydrogen atom or a fluorine atom. R8 is a C1-4 alkyl group (the C1-4 alkyl group may be substituted with a fluorine atom or a C1-4 alkoxy group) or a cyclopropyl group (the cyclopropyl group may be substituted with a C1-4 alkyl group), R3 is a hydrogen atom, a C1-4 alkyl group, a cyclopropyl group, or a C1-4 alkoxy group (the C1-4 alkoxy group may be substituted with a hydroxyl group). R5 is a fluorine atom, R6 is a hydrogen atom, and R4 is an iodine atom or a cyclopropyl group. A compound, salt, or solvate described in any of (A1) to (A3).

[0027] (A6) R2 is a fluorine atom, R1 is -S(=O)2-NH-R8, R8 is a C1-C4 alkyl group. R3 is a hydrogen atom or a cyclopropyl group. R5 is a fluorine atom, R6 is a hydrogen atom, and R4 is an iodine atom or a cyclopropyl group. A compound, salt, or solvate described in any of (A1) to (A3).

[0028] In another embodiment, the arylamide derivative of the present disclosure is a compound, salt, or solvate described in any of (A7) to (A10) below. The compound, salt, or solvate described in (A7) below includes the compounds, salts, or solvates described in (A1) to (A6). (A7) A compound represented by the following general formula (11), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the said compound or salt. [ka] [In the formula, Ring A is a group represented by the following general formulas (2), (3), (4), or (5) (where the bonds marked with *, **, and *** are bonded to -NH-, -CONH-, and -X7-, respectively), [ka] X1, X2, X3, X4, X5, and X6 are each independently -CR2= or -N=, R2 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group. X7 is -(CH2) m - or -O-, where m is 1, 2, or 3. R1 is -S(=O)2-NH-R8 or -S(=O)2-R8, R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, or a C3-6 heterocycloalkyl group), a monocyclic or bicyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group or a C1-6 alkoxy group), or a monocyclic or bicyclic C3-6 heterocycloalkyl group. R3 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group), or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group). R5 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group. R6 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group, and 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, or R6 and R4 together with the carbon atoms to which they are bonded form an unsaturated hetero 5-membered ring. R7 is a hydrogen atom or a C1-6 alkyl group. R9 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group.

[0029] (A8) Ring A is a group represented by general formula (2) or (4), X7 is -CH2-, R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group). R3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxyl 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, and R4 is a halogen atom or a cyclopropyl group. R7 is a hydrogen atom or a methyl group. The compounds, salts, or solvates described in (A7).

[0030] (A9) The compound represented by general formula (11) is the compound represented by general formula (6) below, the compound, salt or solvate described in (A7). [ka] [In the formula, X1, X2, X3, and X4 are each independently -CR2= or -N=, R2 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group. R1 is -S(=O)2-NH-R8 or -S(=O)2-R8, R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group). R3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxyl 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, and R4 is a halogen atom or a cyclopropyl group.

[0031] (A10) R2 is a hydrogen atom or a halogen atom. R8 is a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom or a C1-6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), R3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxyl group). R5 is a halogen atom, R6 is a hydrogen atom, and R4 is a halogen atom or a cyclopropyl group. A compound, salt, or solvate listed in any of (A7) to (A9).

[0032] In another embodiment, the arylamide derivative of the present disclosure is a compound, salt, or solvate described in any of (A11) to (A16) below. The compound, salt, or solvate described in (A7) includes the compounds, salts, or solvates described in (A11) to (A16) below. (A11) N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (compound J-1), 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-1), N-Cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound A-4), N-Cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (compound A-6), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide (compound A-8), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-methoxybenzamide (compound A-13), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-25), 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound A-30), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-31), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-33), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-34), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridine-4-yl]methyl]benzamide (compound A-35), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-41), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide (compound B-1), 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound D-4), 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (compound E-1), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide (compound E-7), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide (compound E-13), 4-Fluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound I-1), N-Cyclopropyl-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (Compound J-5), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridine-4-yl]methyl]-N-methoxybenzamide (compound A-15), 3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-methylsulfanylanilino)benzamide (compound A-18), 2-(4-ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-20), 2-(4-bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-27), 2-(2-chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-methoxybenzamide (compound E-9), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxan-4-ylsulfonylamino)phenyl]methyl]benzamide (compound E-23), 2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound H-1), 3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound H-3), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]oxybenzamide (compound H-4), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine-3-carboxamide (compound J-8), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide (compound J-10), 5-[[2-(ethylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide (compound J-14), 5-(2-fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]pyridine-4-carboxamide (compound L-1), 5-(2-fluoro-4-iodoanilino)-8-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]imidazo[1,5-a]pyridine-6-carboxamide (compound M-1), 5-Fluoro-4-(2-Fluoro-4-iodoanilino)-1-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-6-oxopyridine-3-carboxamide (compound N-1), 5-Fluoro-4-(2-Fluoro-4-iodoanilino)-1-[[3-Fluoro-2-(Propylsulfamoylamino)pyridine-4-yl]methyl]-6-oxopyridine-3-carboxamide (compound N-2), 4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (compound P-1), and 1-[[2-(ethylsulfonylamino)-3-fluoropyridine-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide (compound P-2) A compound selected from or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

[0033] (A12) N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (compound J-1), 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-1), N-Cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound A-4), N-Cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (compound A-6), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide (compound A-8), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-methoxybenzamide (compound A-13), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-25), 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound A-30), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-31), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-33), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-34), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridine-4-yl]methyl]benzamide (compound A-35), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-41), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide (compound B-1), 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound D-4), 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (compound E-1), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide (compound E-7), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide (compound E-13), 4-Fluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound I-1), and N-Cyclopropyl-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (Compound J-5) A compound selected from or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

[0034] (A13) N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (compound J-1), and 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-1) A compound selected from or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

[0035] (A14) 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the said compound or salt.

[0036] (A15) 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-1) or its sodium or potassium salt, or a pharmaceutically acceptable solvate of the said compound or salt.

[0037] (A16) Sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-1).

[0038] The compounds, salts, or solvates described in (A1) to (A16) have high RAF / MEK complex stabilizing activity and can be used as active ingredients in therapeutic or prophylactic agents for cell proliferation disorders, particularly cancer (more specifically, for example, cancer with RAS mutations). That is, a composition containing a compound, salt, or solvate described in any of (A1) to (A16) and a dispersant and / or a basic compound can be used as a pharmaceutical composition. Furthermore, a composition containing a compound, salt, or solvate described in any of (A1) to (A16) and a dispersant and / or a basic compound can be used as a pharmaceutical composition for the therapeutic or prophylactic treatment of cell proliferation disorders, particularly cancer.

[0039] In another embodiment, the arylamide derivative of the present disclosure is a compound, salt, or solvate described in any of (B1) to (B3) below. (B1) A compound represented by the following general formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the said compound or salt. [ka] [In the formula, Ring A is a group represented by the following general formula (2), (3), or (4) (where the bonds marked with *, **, and *** are bonded to -NH-, -CONH-, and -CH2-, respectively), [ka] X1, X2, X3, X4, and X5 are each independently -CR2= or -N=, R2 is a hydrogen atom, a halogen atom, or a C1-4 alkyl group. R1 is -S(=O)2-NH-R8 or -S(=O)2-R8, R8 is a C1-4 alkyl group (the C1-4 alkyl group may be substituted with a halogen atom, a hydroxyl group, a C1-4 alkoxy group, a C3-6 cycloalkyl group, or a C3-6 heterocycloalkyl group) or a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-4 alkyl group), R3 is a hydrogen atom, a C3-6 cycloalkyl group, or a C1-6 alkoxy group. R5 is a halogen atom, R6 is a hydrogen atom, and R4 is a halogen atom or a C3-6 cycloalkyl group. R7 is a C1-4 alkyl group. R9 is a hydrogen atom.

[0040] (B2) 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-1), (+ / -)-3,4-difluoro-5-[[3-fluoro-2-(2-hydroxypropylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (compound A-17), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(oxetan-3-ylmethylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-21), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-25), 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound A-30), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-33), 5-[[2-(ethylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound A-40), 3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (compound A-42), 5-[[2-(ethylsulfonylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (compound B-16), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound C-3), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide (compound J-10), 5-(2-fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]pyridine-4-carboxamide (compound L-1), 5-Fluoro-4-(2-Fluoro-4-iodoanilino)-1-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-6-oxopyridine-3-carboxamide (compound N-1), 1-[[2-(ethylsulfonylamino)-3-fluoropyridine-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide (compound P-2), 1-[[2-(ethylsulfonylamino)-3-fluoropyridine-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-N-methoxy-5-methyl-6-oxopyridine-3-carboxamide (compound P-5), and N-Cyclopropyl-4-(2-Fluoro-4-iodoanilino)-1-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (Compound P-6) A compound selected from or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

[0041] (B3) (+ / -)-3,4-difluoro-5-[[3-fluoro-2-(2-hydroxypropylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (compound A-17), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(oxetan-3-ylmethylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-21), 5-[[2-(ethylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound A-40), 3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (compound A-42), 5-[[2-(ethylsulfonylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (compound B-16), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound C-3), 1-[[2-(ethylsulfonylamino)-3-fluoropyridine-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-N-methoxy-5-methyl-6-oxopyridine-3-carboxamide (compound P-5), and N-Cyclopropyl-4-(2-Fluoro-4-iodoanilino)-1-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (Compound P-6) A compound selected from or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

[0042] The compounds, salts, or solvates described in (B1) to (B3) have high MEK inhibitory activity and can be used as active ingredients in therapeutic or prophylactic agents for cell proliferation disorders, particularly cancer (more specifically, for example, cancer with RAF mutations). That is, a composition containing a compound, salt, or solvate described in any of (B1) to (B3) and a dispersant and / or a basic compound can be used as a pharmaceutical composition. Furthermore, a composition containing a compound, salt, or solvate described in any of (B1) to (B3) and a dispersant and / or a basic compound can be used as a pharmaceutical composition for the therapeutic or prophylactic treatment of cell proliferation disorders, particularly cancer.

[0043] The inventions provided by this disclosure include, for example, the compositions or methods described in D1 to D19 below. D1: A composition comprising a compound represented by general formula (1) as described in (A1) above, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, and a dispersant. D2: The composition according to D1, wherein the dispersant is at least one selected from the group consisting of methylcellulose, polyvinyl alcohol, hydroxypropylcellulose, copolyvidone, hydroxypropylmethylcellulose, methacrylate copolymer, polyvinylpyrrolidone, and hypromellose acetate succinate. D3: The composition according to D1 or D2, wherein the dispersant is methylcellulose. D4: The composition according to any one of D1 to D3, wherein the content of the dispersant is 0.1 to 20 parts by weight per 1 part by weight of the compound of general formula (1), the salt, or the solvate. D5: The composition according to any one of D1 to D4, wherein the elution of the compound of general formula (1), the salt, or the solvate into FaSSIF after treating the composition with Japanese Pharmacopoeia elution test solution No. 1 for 60 minutes is improved compared to the case without the dispersant. D6: A composition according to any one of D1 to D5, further comprising a basic compound. D7: A composition comprising a compound represented by general formula (1) as described in (A1) above, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, and a basic compound. D8: The composition according to D6 or D7, wherein the basic compound is at least one selected from the group consisting of meglumine, arginine, histidine, magnesium oxide, calcium silicate, and magnesium stearate. D9: The composition according to any one of D6 to D8, wherein the basic compound is meglumine. D10: The composition according to any one of D6 to D9, wherein the content of the basic compound is 0.2 to 40 parts by weight per 1 part by weight of the compound of general formula (1), the salt, or the solvate. D11: The composition according to any one of D6 to D10, wherein when the composition is stored at 80°C in a tightly sealed state for two weeks, the stability shown by the compound of general formula (1), the salt, or the solvate during storage is improved compared to the case in which the basic compound is not included. D12: Ring A is a group represented by the general formula (2) or (4) described in (A1) above, R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group). R3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxyl group). R6 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group, and R4 is a halogen atom or a cyclopropyl group. R7 is a hydrogen atom or a methyl group. A composition as described in any of D1 to D11. D13: The composition according to any one of D1 to D12, wherein the compound of general formula (1) is 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide. D14: A composition according to any one of D1 to D13, comprising a pharmaceutically acceptable excipient. D15: The composition according to any one of D1 to D14, wherein the content of the compound of general formula (1), the salt, or the solvate is 10% by weight or less relative to the weight of the composition. D16: The composition according to any one of D1 to D15, wherein the content of the compound of general formula (1), the salt, or the solvate is 7% by weight or less relative to the weight of the composition. D17: The composition according to any one of D1 to D16, wherein the content of the compound of general formula (1), the salt, or the solvate is 5% by weight or less relative to the weight of the composition. D18: A composition according to any one of D1 to D17, in the form of a capsule or a tablet. D19: A method for producing any of the compositions described in D1 to D18, A method comprising the step of providing a mixture comprising the compound of general formula (1), the salt or solvate of the compound, and the dispersant and / or the basic compound.

[0044] The inventions provided by this disclosure also include, for example, the compositions described in E1 to E7 below. E1: A composition comprising 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, together with a compound represented by formula (X) as described in Test Example 12 below, A composition in which the content of the compound of formula (X) is 3.0% by weight or less relative to the content of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, the salt, or the solvate. E2: A composition comprising 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, together with a compound represented by formula (X) as described in Test Example 12 below, A composition wherein the peak area of ​​the compound of formula (X) obtained by high-performance liquid chromatography (HPLC) analysis of the composition is 3.0% or less of the peak area of ​​2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, the salt, or the solvate obtained by the HPLC analysis. E3: A composition comprising 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, and a basic compound together with a compound represented by formula (X) as described in Test Example 12 below, A composition in which the content of the compound of formula (X) is 3.0% by weight or less relative to the content of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, the salt, or the solvate. E4: A composition comprising 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, and a basic compound together with a compound represented by formula (X) as described in Test Example 12 below, A composition wherein the peak area of ​​the compound of formula (X) obtained by high-performance liquid chromatography (HPLC) analysis of the composition is 3.0% or less of the peak area of ​​2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, the salt, or the solvate obtained by the HPLC analysis. E5: The composition according to E3 or E4, wherein the basic compound is at least one selected from the group consisting of meglumine, arginine, histidine, magnesium oxide, calcium silicate, and magnesium stearate. E6: The composition according to any one of E3 to E5, wherein the basic compound is meglumine. E7: The composition according to any one of E3 to E6, wherein the content of the basic compound is 0.2 to 40 parts by weight per 1 part by weight of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, the salt, or the solvate.

[0045] The inventions provided by this disclosure also include, for example, the compositions described in Q1 to Q24 below. Q1: A composition comprising 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, and a dispersant. Q2: A composition comprising the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide and a dispersant. Q3: The composition according to Q1 or Q2, wherein the dispersant is at least one selected from the group consisting of methylcellulose, polyvinyl alcohol, and hydroxypropylcellulose. Q4: The composition according to any one of Q1 to Q3, wherein the dispersant is methylcellulose. Q5: The composition according to any one of Q1 to Q4, wherein the content of the dispersant is 0.1 to 20 parts by weight per 1 part by weight of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, the salt, or the solvate. Q6: The composition according to any one of Q1 to Q5, wherein the content of the dispersant is 0.2 to 10 parts by weight per 1 part by weight of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, the salt, or the solvate. Q7: The composition according to any one of Q1 to Q6, wherein the content of the dispersant is 1 to 10 parts by weight per 1 part by weight of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, the salt, or the solvate. Q8: A composition according to any one of Q1 to Q7, further comprising a basic compound. Q9: A composition comprising 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, and a basic compound. Q10: A composition comprising the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide and a basic compound. Q11: The composition according to any one of Q8 to Q10, wherein the basic compound is at least one selected from the group consisting of meglumine and arginine. Q12: The composition according to any one of Q8 to Q11, wherein the basic compound is meglumine. Q13: The composition according to any one of Q8 to Q12, wherein the content of the basic compound is 0.2 to 40 parts by weight per 1 part by weight of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, the salt, or the solvate. Q14: The composition according to any one of Q8 to Q13, wherein the content of the basic compound is 0.5 to 20 parts by weight per 1 part by weight of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, the salt, or the solvate. Q15: The composition according to any one of Q8 to Q14, wherein the content of the basic compound is 1 to 10 parts by weight per 1 part by weight of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, the salt, or the solvate. Q16: A composition according to any one of Q1 to Q15, further comprising an excipient. Q17: The composition according to Q16, wherein the excipient is mannitol. Q18: A composition according to any one of Q1 to Q17, further comprising a lubricant. Q19: The composition according to Q18, wherein the lubricant is magnesium stearate. Q20: The composition according to any one of Q1 to Q19, wherein the content of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, the salt, or the solvate is 10% by weight or less relative to the weight of the composition. Q21: The composition according to any one of Q1 to Q20, wherein the content of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, the salt, or the solvate is 7% by weight or less relative to the weight of the composition. Q22: The composition according to any one of Q1 to Q21, wherein the content of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, the salt, or the solvate is 5% by weight or less relative to the weight of the composition. Q23: A composition according to any one of Q1 to Q22, in the form of a capsule or a tablet. Q24: A pharmaceutical formulation, the composition described in any of Q1 to Q23.

[0046] The inventions provided by this disclosure also include, for example, the uses or methods described in F1 to F6 below. F1: Use of any of the compositions described in D1 to D18, E1 to E7 and Q1 to Q24 in the manufacture of a pharmaceutical product for treating a patient who requires treatment with the compound of general formula (1) or the 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, the salt, or the solvate. F2: A method for treating a patient who requires treatment with the compound of general formula (1) or the 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, the salt, or the solvate, comprising administering to the patient any of the compositions described in D1 to D18, E1 to E7, and Q1 to Q24. F3: Use of any of the compositions described in D1-D18, E1-E7, and Q1-Q24 in the manufacture of pharmaceuticals for the treatment or prevention of cell proliferation disorders. F4: Use as described in F3, wherein the aforementioned cell proliferation disorder is cancer. F5: A method for treating or preventing a cell proliferation disorder in a patient, comprising administering to the patient any of the compositions described in D1-D18, E1-E7, and Q1-Q24. F6: The method according to F5, wherein the cell proliferation disorder is cancer.

[0047] The inventions provided in this disclosure also include, for example, the uses described in G1 to G8 below. G1: Use of a dispersant for the preparation of a composition comprising a compound represented by general formula (1) as described in (A1) above, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt. G2: Use of a basic compound for the preparation of a composition comprising a compound represented by general formula (1) as described in (A1) above, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt. G3: Use of dispersants and basic compounds for the preparation of a composition comprising a compound represented by general formula (1) as described in (A1) above, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt. G4: The use described in G1 or G3, wherein the dispersant is at least one selected from the group consisting of methylcellulose, polyvinyl alcohol, hydroxypropylcellulose, copolyvidone, hydroxypropylmethylcellulose, methacrylate copolymer, polyvinylpyrrolidone, and hypromellose acetate succinate. G5: The dispersant is methylcellulose, as described in G4. G6: The use described in G2 or G3, wherein the basic compound is at least one selected from the group consisting of meglumine, arginine, histidine, magnesium oxide, calcium silicate, and magnesium stearate. G7: The basic compound is meglumine, as described in G6. G8: The compound of general formula (1) is 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, as described in any of G1 to G7.

[0048] The inventions provided by this disclosure also include, for example, the methods described in K1 to K10 below. K1: A method for improving the elution properties of a compound represented by general formula (1) as described in (A1) above, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt in a composition, the method comprising coexisting a dispersant in the composition. K2: The method according to K1, wherein the elution property is the elution property of the compound of general formula (1), the salt, or the solvate of the composition into FaSSIF after treating the composition with Japanese Pharmacopoeia Dissolution Test Solution No. 1 for 60 minutes. K3: The method according to K1 or K2, wherein the dispersant is at least one selected from the group consisting of methylcellulose, polyvinyl alcohol, hydroxypropylcellulose, copolyvidone, hydroxypropylmethylcellulose, methacrylic acid copolymer, polyvinylpyrrolidone, and hypromellose acetate succinate. K4: The method according to any one of K1 to K3, wherein the dispersant is methylcellulose. K5: The method according to any one of K1 to K4, wherein the composition further comprises a basic compound. K6: The method according to K5, wherein the basic compound is at least one selected from the group consisting of meglumine, arginine, histidine, magnesium oxide, calcium silicate, and magnesium stearate. K7: The method according to K5 or K6, wherein the basic compound is meglumine. K8: The method according to any one of K1 to K7, wherein the composition further comprises an excipient. K9: The method according to K8, wherein the excipient is mannitol. K10: The method according to any one of K1 to K9, wherein the compound of general formula (1) is 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide.

[0049] The inventions provided by this disclosure also include, for example, the methods described in L1 to L10 below. L1: A method for improving the stability of a compound represented by general formula (1) as described in (A1) above, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt in a composition, the method comprising coexisting a basic compound in the composition. L2: The method according to L1, wherein the stability is the stability shown by the compound of general formula (1), the salt, or the solvate during storage when the composition is stored at 80°C in a tightly sealed state for two weeks. L3: The method according to L1 or L2, wherein the basic compound is at least one selected from the group consisting of meglumine, arginine, histidine, magnesium oxide, calcium silicate, and magnesium stearate. L4: The basic compound is meglumine, according to any one of L1 to L3. L5: The method according to any one of L1 to L4, wherein the composition further comprises a dispersant. L6: The dispersant is at least one selected from the group consisting of methylcellulose, polyvinyl alcohol, hydroxypropylcellulose, copovidone, hydroxypropylmethylcellulose, methacrylic acid copolymer, polyvinylpyrrolidone, and hypromellose acetate succinate, according to the method described in L5. L7: The dispersant is methylcellulose, according to the method described in L5 or L6. L8: The composition further contains an excipient, according to the method described in any one of L1 to L7. L9: The excipient is mannitol, according to the method described in L8. L10: The compound of the general formula (1) is 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide, according to the method described in any one of L1 to L9.

Advantages of the Invention

[0050] According to the present disclosure, there is provided a composition containing a specific arylamide derivative having RAF / MEK complex stabilization activity and / or MEK inhibitory activity and being useful for the treatment or prevention of cell proliferative diseases, particularly cancer, and having good characteristics regarding the elution property and / or stability of the arylamide derivative in the composition.

Brief Description of the Drawings

[0051] [Figure 1] Figure 1 shows the powder X-ray diffraction pattern of Sample A-1a (Form I). [Figure 2] Figure 2 shows the powder X-ray diffraction pattern of Sample A-1b. [Figure 3] Figure 3 shows the powder X-ray diffraction pattern of Sample A-1c. [Figure 4]Figure 4 is a sensorgram showing the time course of MEK1 binding to a sensor chip surface immobilized with RAF1, along with the test compound (ref-2, ref-3, ref-4, A-1, ref-1, ref-5, or B-1). [Figure 5] Figure 5 is a sensorgram showing the time course of MEK1 binding to a sensor chip surface immobilized with RAF1, when the test compound (A-2, A-25, J-1, E-1, M-1, N-1, or H-3) is added together. [Figure 6] Figure 6 is a sensorgram showing the time course of MEK1 binding to a sensor chip surface immobilized with RAF1, when the test compound (I-1, H-4, L-1, P-1, E-7, or A-27) is added together. [Figure 7] Figure 7 is a sensorgram showing the time course of MEK1 binding to a sensor chip surface immobilized with RAF1, when the test compound (A-33, A-18, N-2, A-20, A-8, E-13, or H-1) was added. [Figure 8] Figure 8 is a sensorgram showing the time course of MEK1 binding to the surface of a sensor chip immobilized with RAF1, along with the test compound (P-2, A-41, E-9, A-6, J-14, A-31, or A-34). [Figure 9] Figure 9 is a sensorgram showing the time course of MEK1 binding to a sensor chip surface immobilized with RAF1, when the test compound (A-35, A-30, D-4, A-15, J-8, J-5, or A-4) was added together. [Figure 10] Figure 10 is a sensorgram showing the time course of MEK1 binding to the surface of a sensor chip immobilized with RAF1, along with the test compound (A-13, E-23, or J-10). [Figure 11] Figure 11 is a sensorgram showing the time course of MEK1 binding to a sensor chip surface immobilized with RAF1, along with the test compound (ref-4, A-1, P-2, or A-6). [Figure 12]Figure 12 shows electrophoretic images of the results of Western blotting of proteins (p-MEK, MEK, p-ERK, and ERK) extracted from A549 cells cultured in the presence of the test compound (ref-5 or compound A-1). [Figure 13] Figure 13 is a graph showing the time course of tumor volume (mean ± standard deviation) in nude mice subcutaneously transplanted with the human lung cancer cell line Calu-6. [Figure 14] Figure 14 is a graph showing the time course of the concentration (mean ± standard deviation) of compound A-1 in the solution after treating a composition containing the sodium salt of compound A-1 (Samples 1, 2, 3, 4, or 5) with Japanese Pharmacopoeia Elution Test Solution No. 1, followed by the addition of FaSSIF and stirring. [Figure 15] Figure 15 is a graph showing the time course of the concentration (mean ± standard deviation) of compound A-1 in the solution after treating a composition containing the sodium salt of compound A-1 (samples 6, 7, 8, or 9) with Japanese Pharmacopoeia elution test solution No. 1, followed by the addition of FaSSIF and stirring. [Figure 16] Figure 16 is a graph showing the time course of the concentration (mean ± standard deviation) of compound A-1 in the solution after treating a composition containing the sodium salt of compound A-1 (sample 10 or 11) with the Japanese Pharmacopoeia elution test solution No. 1, followed by the addition of FaSSIF and stirring. [Figure 17] Figure 17 is a graph showing the time course of the concentration (mean ± standard deviation) of compound A-1 in the solution after treating a composition containing the sodium salt of compound A-1 (sample 12 or 13) with Japanese Pharmacopoeia elution test solution No. 1, followed by the addition of FaSSIF and stirring. [Figure 18] Figure 18 is a graph showing the time course of the concentration (mean ± standard deviation) of compound A-1 in the solution after treating a composition containing the sodium salt of compound A-1 (Sample 14 or 15) with Japanese Pharmacopoeia Elution Test Solution No. 1, followed by the addition of FaSSIF and stirring. [Figure 19]Figure 19 is a graph showing the time course of the concentration (mean ± standard deviation) of compound A-1 in the solution after treating a composition containing the sodium salt of compound A-1 (sample 16 or 17) with the Japanese Pharmacopoeia elution test solution No. 1, followed by the addition of FaSSIF and stirring. [Figure 20] Figure 20 is a graph showing the time course of the concentration (mean ± standard deviation) of compound A-1 in the solution after treating a composition containing the sodium salt of compound A-1 (sample 18 or 19) with Japanese Pharmacopoeia elution test solution No. 1, followed by the addition of FaSSIF and stirring. [Figure 21] Figure 21 is a graph showing the time course of the concentration (mean ± standard deviation) of compound A-1 in the solution after treating a composition containing the sodium salt of compound A-1 (sample 20 or 21) with Japanese Pharmacopoeia elution test solution No. 1, followed by the addition of FaSSIF and stirring. [Figure 22] Figure 22 is a graph showing the time course of the concentration (mean ± standard deviation) of compound A-1 in the solution after treating a composition containing the sodium salt of compound A-1 (sample 22 or 23) with Japanese Pharmacopoeia elution test solution No. 1, followed by the addition of FaSSIF and stirring. [Modes for carrying out the invention]

[0052] The following describes exemplary embodiments of this disclosure.

[0053] In this disclosure, halogen atoms mean fluorine atoms, chlorine atoms, bromine atoms, or iodine atoms.

[0054] In the present disclosure, the C1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, 1-methylpropyl group, n-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1,1-dimethylpropyl group, 2,2-dimethylpropyl group, 1,2-dimethylpropyl group, 1-ethylpropyl group, n-hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group and 2-ethylbutyl group may be mentioned.

[0055] In the present disclosure, the C2-7 alkenyl group means a linear or branched alkenyl group having 2 to 7 carbon atoms. For example, vinyl group, allyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, pentenyl group, pentadienyl group, hexenyl group, hexadienyl group, heptenyl group, heptadienyl group and heptatriene group may be mentioned.

[0056] In the present disclosure, the C2-7 alkynyl group means a linear or branched alkynyl group having 2 to 7 carbon atoms. For example, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, pentynyl group, pentadiynyl group, hexynyl group, hexadiynyl group, heptynyl group, heptadiynyl group and heptatriynyl group may be mentioned.

[0057] In the present disclosure, the C1-6 alkoxy group means an alkyloxy group having a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group and n-hexyloxy group may be mentioned.

[0058] In this disclosure, C1-6 alkylthio group means an alkylthio group having a linear or branched alkyl group having 1 to 6 carbon atoms. Examples include methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, sec-butylthio group, tert-butylthio group, n-pentylthio group, and n-hexylthio group.

[0059] In this disclosure, C3-6 cycloalkyl groups refer to cyclic alkyl groups having 3 to 6 atoms constituting the ring. They may be monocyclic or bicyclic, but unless otherwise specified, monocyclic groups are referred to. Examples of monocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. Examples of bicyclic groups include bicyclo[1.1.1]pentanyl and bicyclo[2.1.1]hexyl groups.

[0060] In this disclosure, a C3-6 heterocycloalkyl group means a C3-6 cycloalkyl group in which at least one of the carbon atoms constituting the ring is replaced by a nitrogen atom, an oxygen atom, or a sulfur atom. It may be monocyclic or bicyclic, but unless otherwise specified, it means monocyclic. Examples of monocyclic groups include the tetrahydrofuranyl group, tetrahydropyranyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, and morpholinyl group. Examples of bicyclic groups include the oxabicyclo[3.1.0]hexane-6-yl group and the azabicyclo[2.1.1]hexanyl group.

[0061] In this disclosure, an unsaturated hetero 5-membered ring means an unsaturated 5-membered ring containing at least one heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom. Examples include furan, thiophene, pyrrole, imidazole, and thiazole.

[0062] In this disclosure, examples of pharmaceutically acceptable salts include inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate; sulfonates such as methanesulfonate, benzenesulfonic acid, and toluenesulfonate; carboxylates such as formate, acetate, oxalate, maleate, fumarate, citrate, malate, succinate, malonate, gluconate, mandelate, benzoate, salicylate, fluoroacetate, trifluoroacetate, tartrate, propionate, and glutarate; alkali metal salts such as lithium salt, sodium salt, potassium salt, cesium salt, and rubidium salt; alkaline earth metal salts such as magnesium salt and calcium salt; and ammonium salts such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, and tetraalkylammonium salt. Among these, alkali metal salts such as lithium salt, sodium salt, potassium salt, cesium salt, and rubidium salt are preferred, and sodium salt and potassium salt are more preferred.

[0063] In this disclosure, a pharmaceutically acceptable solvate is, for example, a solvate with water, an alcohol (e.g., methanol, ethanol, 1-propanol, or 2-propanol), acetone, dimethylformamide, or dimethylacetamide. It may be a solvate with a single solvent or with multiple solvents. A preferred solvate is, for example, a hydrate.

[0064] A first aspect of this disclosure provides a composition comprising a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, and a dispersant and / or a basic compound. [ka] [In the formula, Ring A is a group represented by the following general formulas (2), (3), (4), or (5) (where the bonds marked with *, **, and *** are bonded to -NH-, -CONH-, and -CH2-, respectively), [ka] X1, X2, X3, X4, X5, and X6 are each independently -CR2= or -N=, R2 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group. R1 is -S(=O)2-NH-R8 or -S(=O)2-R8, R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, or a C3-6 heterocycloalkyl group), a monocyclic or bicyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group or a C1-6 alkoxy group), or a monocyclic or bicyclic C3-6 heterocycloalkyl group. R3 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group), or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy 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, and 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, or R6 and R4 together with the carbon atoms to which they are bonded form an unsaturated hetero 5-membered ring. R7 is a hydrogen atom or a C1-6 alkyl group. R9 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group.

[0065] Compounds, salts, or solvates of the first embodiment have high RAF / MEK complex stabilizing activity and can be used for the treatment or prevention of cell proliferation disorders, particularly cancer (more specifically, for example, cancer with RAS mutations). Many also have high MEK inhibitory activity, and such compounds, salts, or solvates are suitable for cancer with RAF mutations, for example.

[0066] Ring A is preferably a group represented by general formula (2) or (4), and more preferably a group represented by general formula (2). R2 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. R1 is preferably -S(=O)2-NH-R8. R8 is preferably a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), more preferably a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom or a C1-6 alkoxy group), even more preferably a C1-4 alkyl group (the C1-4 alkyl group may be substituted with a fluorine atom or a C1-4 alkoxy group), or a cyclopropyl group (the cyclopropyl group may be substituted with a C1-4 alkyl group), and even more preferably a C1-4 alkyl group. R3 is preferably a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxyl group), more preferably a hydrogen atom, a C1-4 alkyl group, a cyclopropyl group, or a C1-4 alkoxy group (the C1-4 alkoxy group may be substituted with a hydroxyl group), and even more preferably a hydrogen atom or a cyclopropyl group. R5 is preferably a halogen atom, and more preferably a fluorine atom. R6 is preferably a hydrogen atom, a halogen atom, or a C1-6 alkyl group, and more preferably a hydrogen atom. R4 is preferably a halogen atom or a cyclopropyl group, and more preferably an iodine atom or a cyclopropyl group. R7 is preferably a hydrogen atom or a methyl group.

[0067] The compound represented by general formula (1) is preferably, for example, the compound represented by general formula (6) below. [ka] [In the formula, X1, X2, X3, and X4 are each independently -CR2= or -N=, R2 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group. R1 is -S(=O)2-NH-R8 or -S(=O)2-R8, R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group). R3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxyl 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, and R4 is a halogen atom or a cyclopropyl group.

[0068] Examples of compounds represented by general formula (1) include: N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (compound J-1), 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-1), N-Cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound A-4), N-Cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (compound A-6), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide (compound A-8), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-methoxybenzamide (compound A-13), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-25), 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound A-30), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-31), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-33), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-34), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridine-4-yl]methyl]benzamide (compound A-35), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-41), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide (compound B-1), 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound D-4), 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (compound E-1), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide (compound E-7), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide (compound E-13), 4-Fluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound I-1), N-Cyclopropyl-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (Compound J-5), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridine-4-yl]methyl]-N-methoxybenzamide (compound A-15), 3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-methylsulfanylanilino)benzamide (compound A-18), 2-(4-ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-20), 2-(4-bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-27), 2-(2-chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-methoxybenzamide (compound E-9), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxan-4-ylsulfonylamino)phenyl]methyl]benzamide (compound E-23), 2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound H-1), 3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound H-3), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine-3-carboxamide (compound J-8), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide (compound J-10), 5-[[2-(ethylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide (compound J-14), 5-(2-fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]pyridine-4-carboxamide (compound L-1), 5-(2-fluoro-4-iodoanilino)-8-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]imidazo[1,5-a]pyridine-6-carboxamide (compound M-1), 5-Fluoro-4-(2-Fluoro-4-iodoanilino)-1-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-6-oxopyridine-3-carboxamide (compound N-1), 5-Fluoro-4-(2-Fluoro-4-iodoanilino)-1-[[3-Fluoro-2-(Propylsulfamoylamino)pyridine-4-yl]methyl]-6-oxopyridine-3-carboxamide (compound N-2), 4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (compound P-1), and 1-[[2-(ethylsulfonylamino)-3-fluoropyridine-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide (compound P-2) These are some examples.

[0069] Among those compounds, for example, in terms of MEK inhibitory activity, RAF inhibitory activity, cell proliferation inhibitory activity and / or metabolic stability, N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (compound J-1), 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-1), N-Cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound A-4), N-Cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (compound A-6), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide (compound A-8), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-methoxybenzamide (compound A-13), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-25), 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound A-30), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-31), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-33), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-34), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridine-4-yl]methyl]benzamide (compound A-35), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-41), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide (compound B-1), 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound D-4), 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (compound E-1), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide (compound E-7), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide (compound E-13), 4-Fluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound I-1), and N-Cyclopropyl-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (Compound J-5) This is preferable, N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (compound J-1), and 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-1) More preferable, 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-1) That is particularly preferable. Pharmacologically acceptable salts of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-1) are preferably sodium salts or potassium salts, with sodium salts being particularly preferred.

[0070] A second aspect of the present disclosure provides a composition comprising a compound represented by the following general formula (11) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, and a dispersant and / or a basic compound. [ka] [In the formula, Ring A is a group represented by the following general formulas (2), (3), (4), or (5) (where the bonds marked with *, **, and *** are bonded to -NH-, -CONH-, and -X7-, respectively), [ka] X1, X2, X3, X4, X5, and X6 are each independently -CR2= or -N=, R2 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group. X7 is -(CH2) m - or -O-, where m is 1, 2, or 3. R1 is -S(=O)2-NH-R8 or -S(=O)2-R8, R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, or a C3-6 heterocycloalkyl group), a monocyclic or bicyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group or a C1-6 alkoxy group), or a monocyclic or bicyclic C3-6 heterocycloalkyl group. R3 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group), or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group). R5 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group. R6 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group, and 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, or R6 and R4 together with the carbon atoms to which they are bonded form an unsaturated hetero 5-membered ring. R7 is a hydrogen atom or a C1-6 alkyl group. R9 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group.

[0071] Compounds, salts, or solvates of the second embodiment have high RAF / MEK complex stabilizing activity and can be used for the treatment or prevention of cell proliferation disorders, particularly cancer (more specifically, for example, cancer with RAS mutations). Many also have high MEK inhibitory activity, and such compounds, salts, or solvates are suitable for cancer with RAF mutations, for example.

[0072] Ring A is preferably a group represented by general formula (2) or (4), and more preferably a group represented by general formula (2). R2 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. X7 is preferably -CH2-. R1 is preferably -S(=O)2-NH-R8. R8 is preferably a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), more preferably a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom or a C1-6 alkoxy group), even more preferably a C1-4 alkyl group (the C1-4 alkyl group may be substituted with a fluorine atom or a C1-4 alkoxy group), or a cyclopropyl group (the cyclopropyl group may be substituted with a C1-4 alkyl group), and even more preferably a C1-4 alkyl group. R3 is preferably a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxyl group), more preferably a hydrogen atom, a C1-4 alkyl group, a cyclopropyl group, or a C1-4 alkoxy group (the C1-4 alkoxy group may be substituted with a hydroxyl group), and even more preferably a hydrogen atom or a cyclopropyl group. R5 is preferably a halogen atom or a C1-6 alkyl group, more preferably a halogen atom, and even more preferably a fluorine atom. R6 is preferably a hydrogen atom, a halogen atom, or a C1-6 alkyl group, and more preferably a hydrogen atom. R4 is preferably a halogen atom or a cyclopropyl group, and more preferably an iodine atom or a cyclopropyl group. R7 is preferably a hydrogen atom or a methyl group.

[0073] The compound represented by general formula (11) is preferably, for example, the compound represented by general formula (6) below. [ka] [In the formula, X1, X2, X3, and X4 are each independently -CR2= or -N=, R2 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group. R1 is -S(=O)2-NH-R8 or -S(=O)2-R8, R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group). R3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxyl 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, and R4 is a halogen atom or a cyclopropyl group.

[0074] Examples of compounds represented by general formula (11) include: N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (compound J-1), 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-1), N-Cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound A-4), N-Cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (compound A-6), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide (compound A-8), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-methoxybenzamide (compound A-13), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-25), 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound A-30), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-31), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-33), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-34), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridine-4-yl]methyl]benzamide (compound A-35), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-41), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide (compound B-1), 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound D-4), 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (compound E-1), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide (compound E-7), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide (compound E-13), 4-Fluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound I-1), N-Cyclopropyl-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (Compound J-5), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridine-4-yl]methyl]-N-methoxybenzamide (compound A-15), 3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-methylsulfanylanilino)benzamide (compound A-18), 2-(4-ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-20), 2-(4-bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-27), 2-(2-chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-methoxybenzamide (compound E-9), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxan-4-ylsulfonylamino)phenyl]methyl]benzamide (compound E-23), 2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound H-1), 3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound H-3), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]oxybenzamide (compound H-4), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine-3-carboxamide (compound J-8), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide (compound J-10), 5-[[2-(ethylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide (compound J-14), 5-(2-fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]pyridine-4-carboxamide (compound L-1), 5-(2-fluoro-4-iodoanilino)-8-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]imidazo[1,5-a]pyridine-6-carboxamide (compound M-1), 5-Fluoro-4-(2-Fluoro-4-iodoanilino)-1-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-6-oxopyridine-3-carboxamide (compound N-1), 5-Fluoro-4-(2-Fluoro-4-iodoanilino)-1-[[3-Fluoro-2-(Propylsulfamoylamino)pyridine-4-yl]methyl]-6-oxopyridine-3-carboxamide (compound N-2), 4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (compound P-1), and 1-[[2-(ethylsulfonylamino)-3-fluoropyridine-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide (compound P-2) These are some examples.

[0075] Among those compounds, for example, in terms of MEK inhibitory activity, RAF inhibitory activity, cell proliferation inhibitory activity and / or metabolic stability, N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (compound J-1), 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-1), N-Cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound A-4), N-Cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (compound A-6), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide (compound A-8), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-methoxybenzamide (compound A-13), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-25), 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound A-30), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-31), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-33), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-34), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridine-4-yl]methyl]benzamide (compound A-35), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-41), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide (compound B-1), 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound D-4), 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (compound E-1), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide (compound E-7), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide (compound E-13), 4-Fluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound I-1), and N-Cyclopropyl-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (Compound J-5) This is preferable, N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (compound J-1), and 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-1) More preferable, 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-1) That is particularly preferable. Pharmacologically acceptable salts of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-1) are preferably sodium salts or potassium salts, with sodium salts being particularly preferred.

[0076] A third aspect of this disclosure provides a composition comprising a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, and a dispersant and / or a basic compound. [ka] [In the formula, Ring A is a group represented by the following general formula (2), (3), or (4) (where the bonds marked with *, **, and *** are bonded to -NH-, -CONH-, and -CH2-, respectively), [ka] X1, X2, X3, X4, and X5 are each independently -CR2= or -N=, R2 is a hydrogen atom, a halogen atom, or a C1-4 alkyl group. R1 is -S(=O)2-NH-R8 or -S(=O)2-R8, R8 is a C1-4 alkyl group (the C1-4 alkyl group may be substituted with a halogen atom, a hydroxyl group, a C1-4 alkoxy group, a C3-6 cycloalkyl group, or a C3-6 heterocycloalkyl group) or a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-4 alkyl group), R3 is a hydrogen atom, a C3-6 cycloalkyl group, or a C1-6 alkoxy group. R5 is a halogen atom, R6 is a hydrogen atom, and R4 is a halogen atom or a C3-6 cycloalkyl group. R7 is a C1-4 alkyl group. R9 is a hydrogen atom.

[0077] Compounds, salts, or solvates of the third embodiment have high MEK inhibitory activity and can be used for the treatment or prevention of cell proliferation disorders, particularly cancer (more specifically, for example, cancer with RAF mutations).

[0078] Examples of compounds in the third embodiment include those with MEK inhibitory activity and metabolic stability, for example, 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-1), (+ / -)-3,4-difluoro-5-[[3-fluoro-2-(2-hydroxypropylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (compound A-17), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(oxetan-3-ylmethylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-21), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-25), 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound A-30), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-33), 5-[[2-(ethylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound A-40), 3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (compound A-42), 5-[[2-(ethylsulfonylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (compound B-16), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound C-3), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide (compound J-10), 5-(2-fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]pyridine-4-carboxamide (compound L-1), 5-Fluoro-4-(2-Fluoro-4-iodoanilino)-1-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-6-oxopyridine-3-carboxamide (compound N-1), 1-[[2-(ethylsulfonylamino)-3-fluoropyridine-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide (compound P-2), 1-[[2-(ethylsulfonylamino)-3-fluoropyridine-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-N-methoxy-5-methyl-6-oxopyridine-3-carboxamide (compound P-5), and N-Cyclopropyl-4-(2-Fluoro-4-iodoanilino)-1-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (Compound P-6) It is preferable.

[0079] In this specification, "Japanese Pharmacopoeia" means the 17th edition of the Japanese Pharmacopoeia. Furthermore, "Japanese Pharmacopoeia Dissolution Test Solution No. 1" means the Dissolution Test Solution No. 1 described in the 17th edition of the Japanese Pharmacopoeia. Examples of abbreviations used in this specification, along with their meanings, are listed below. Boc: tert-butoxycarbonyl COMU: (1-Cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate DBU: Diazabicycloundecene DCC: N,N'-Dicyclohexylcarbodiimide DCM: Dichloromethane DIPEA: N,N-diisopropylethylamine DMA: N,N-dimethylacetamide DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide EDC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EDC·HCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EtOH: Ethanol HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HOAt: 1-Hydroxy-7-Azabenzotriazole HOOBt: 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine LDA: Lithium diisopropylamide MeOH: methanol NMP: N-methyl-2-pyrrolidone TBS: tert-butyldimethylsilyl TFA: Trifluoroacetic acid THF: Tetrahydrofuran Xantphos: 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene

[0080] Next, an example of a preferred method for producing the compounds of this disclosure will be described. In the following, the definitions of X1, R1, R2, R3, R4, R5 and R7 are as described above unless otherwise understood in context. a R represents, for example, a 4-methylphenyl group or a 2-nitrophenyl group. b This represents, for example, a Boc group or a 2,4-dimethoxybenzyl group.

[0081] (General manufacturing method-1) General method-1 is a preferred method for producing compounds represented by general formula (6) in which X2, X3, and X4 (X2, X3, and X4 may be the same or different) are -CR2= and R6 is a hydrogen atom.

[0082] [ka] [ka]

[0083] Process 1-1: S between aniline derivative 1b and fluorobenzene derivative 1a N Ar reaction In the presence of a base, aniline derivative 1b is reacted with fluorobenzene derivative 1a. Examples of bases include organolithium reagents, with lithium bis(trimethylsilyl)amide and lithium diisopropylamide being preferred. Examples of solvents include polar aproton solvents such as THF, 1,4-dioxane, and NMP, with THF being preferred.

[0084] Step 1-2: Methylation of benzoic acid derivative 1c The benzoic acid derivative 1c is reacted with a methylation reagent. Examples of methylation reagents include diazomethane derivatives, with diazomethyltrimethylsilane being preferred. Examples of solvents include alcohols, nonpolar solvents, and mixtures thereof, with a mixture of toluene and methanol and a mixture of THF and methanol being preferred.

[0085] Step 1-3: Hydrazone formation of aldehyde derivative 1d The aldehyde derivative 1d is reacted with an arylsulfonyl hydrazide. Examples of arylsulfonyl hydrazides include methylbenzenesulfonyl hydrazide and nitrobenzenesulfonyl hydrazide, with 4-methylbenzenesulfonyl hydrazide and 2-nitrobenzenesulfonyl hydrazide being preferred. Examples of solvents include polar solvents such as alcohols, with methanol and ethanol being preferred.

[0086] Step 1-4: Coupling of hydrazone derivative 1e and arylboronic acid derivative 1f In the presence of a base, the hydrazone derivative 1e is reacted with the arylboronic acid derivative 1f. Examples of bases include carbonates and amines, with potassium carbonate and DIPEA being preferred. Examples of solvents include polar solvents such as 1,4-dioxane, DMF, NMP, and THF, with 1,4-dioxane being preferred. The reaction temperature is preferably 80°C or higher.

[0087] Step 1-5: Deprotection of 1 g of methyl benzoate derivative By placing 1 g of methyl benzoate derivative under acidic conditions, the protecting group R b The acid is removed. Examples of acids include sulfuric acid, hydrochloric acid, methanesulfonic acid, and trifluoroacetic acid, with trifluoroacetic acid being preferred. Examples of solvents include alcohols and nonpolar solvents such as DCM, with DCM being preferred.

[0088] Step 1-6: Hydrolysis of ester derivative 1h The ester derivative 1h is reacted with a hydroxide. Examples of hydroxides include lithium hydroxide, potassium hydroxide, and sodium hydroxide, with lithium hydroxide being preferred. Examples of solvents include alcohols, polar solvents such as THF, water, and mixed solvents thereof, with aqueous THF being preferred.

[0089] Step 1-7: Amidation of benzoic acid derivative 1i In the presence of a condensing agent, a benzoic acid derivative 1i is reacted with the corresponding amine or amine hydrochloride. The corresponding amine or amine hydrochloride may have a Boc group. Examples of condensing agents include DCC, EDC or EDC·HCl, HATU, COMU, and propylphosphonic anhydride (cyclic trimer), and optionally, HOOBt or HOAt may be further added. Preferably, for example, a combination of EDC or EDC·HCl and HOOBt, or HATU is used. In addition, a base such as DIPEA or triethylamine may be used in addition to the condensing agent, with DIPEA being preferred as the base. Examples of solvents include polar solvents such as DMF, DMA, NMP, methanol, and ethanol, and mixed solvents thereof, with DMF being preferred.

[0090] Step 1-8: Sulfamidation or sulfonamidation of amine derivatives 1j, 1ja, or 1jb Sulfamide conversion: In the presence of a base, the amine derivative 1j, 1ja, or 1jb is reacted with the corresponding sulfamoyl chloride or 4-nitrophenyl sulfamic acid. The corresponding sulfamoyl chloride or 4-nitrophenyl sulfamic acid may have a Boc group. Examples of bases include amines, with pyridine, triethylamine, DIPEA, and imidazole being preferred. Examples of solvents include polar solvents such as DMF, DMA, NMP, THF, 1,4-dioxane, acetonitrile, and pyridine; nonpolar solvents such as dichloromethane and dichloroethane; and mixed solvents thereof, with DMF, DMA, THF, and dichloromethane being preferred.

[0091] Sulfonamidation: In the presence of a base, the amine derivative 1j, 1ja, or 1jb is reacted with the corresponding sulfonyl chloride. Examples of bases include amines, with pyridine, triethylamine, DIPEA, and imidazole being preferred. Examples of solvents include polar solvents such as DMF, DMA, NMP, THF, 1,4-dioxane, acetonitrile, and pyridine; nonpolar solvents such as dichloromethane and dichloroethane; and mixed solvents thereof, with dichloromethane and pyridine being preferred.

[0092] Process 1-9-1: De-Bocization of sulfamide or sulfonamide derivative 1k1 If R1 or R3 of the sulfamide or sulfonamide derivative 1k1 has a Boc group, the Boc group is removed by placing compound 1k1 under acidic conditions. Examples of acids include sulfuric acid, hydrochloric acid, methanesulfonic acid, and trifluoroacetic acid. Alternatively, Boc removal may be carried out by generating an acid in an alcohol, for example, with chlorotrimethylsilane (TMSCl). Examples of solvents include alcohols and nonpolar solvents such as DCM. Preferred acid-solvent combinations include, for example, TMSCl and 2,2,2-trifluoroethanol, or trifluoroacetic acid and DCM.

[0093] Process 1-9-2: Alkylation, alkenylation, alkynylation, or thioetherification of sulfamide or sulfonamide derivative 1k1 If R4 or R5 of sulfamide or sulfonamide derivative 1k1 is a halogen, alkylation, alkenylation, alkynylation, or thioetheration can be carried out, for example, by the following method.

[0094] Method 1 (Alkylation or alkenylation by Suzuki-Miyaura cross-coupling): Compound 1k1 is reacted with the corresponding boronic acid, boronic acid ester, or borate in the presence of Pd. For example, this can be carried out by the method described in Chem. Rev. 1995, vol. 95, no. 7, p. 2457 or ACC. Chem. Res., vol. 40, p. 275. Examples of bases include inorganic salts such as carbonates and hydroxides, and amines such as triethylamine and DIPEA, with sodium carbonate, potassium carbonate, and triethylamine being preferred. Examples of solvents include polar solvents such as THF, 1,4-dioxane, DMF, DMA, NMP, methanol, ethanol, 2-propanol, and water, and mixed solvents thereof, with mixed solvents of THF and 2-propanol and mixed solvents of THF and water being preferred. Examples of Pd and ligands include those described in Chem. Rev. 1995, vol. 95, no. 7, p. 2457, ACC. Chem. Res., vol. 40, p. 275, and ACC. Chem. Res., vol. 41, p. 1461, with PdCl2(PPh3)2, Pd(PPh3)4, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride being preferred. The reaction temperature is preferably 80°C or higher.

[0095] Method 2 (Alkylation or alkenylation by Negishi cross-coupling): Compound 1k1 is reacted with the corresponding organozinc reagent in the presence of Pd or Ni. This can be carried out, for example, by the method described in Tetrahedron. 1992, vol. 48, no. 44, p. 9577 or Aldrichimica Acta. 2005, vol. 38, p. 71. Suitable solvents include polar solvents such as THF, 1,4-dioxane, DMF, DMA, NMP, and mixtures thereof, with THF being preferred. Examples of Pd and Ni include those described in Tetrahedron.1992,vol.48,no.44,p.9577 and Aldrichimica Acta.2005,vol.38,p.71, as well as PdCl2(PPh3)2, Pd(PPh3)4, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, with PdCl2(PPh3)2, Pd(PPh3)4, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride being preferred.

[0096] Method 3 (Alkynylation by Sonogashira Cross-Coupling): Compound 1k1 is reacted with the corresponding alkyne in the presence of Pd and Cu. For example, this can be carried out by the method described in Chem. Soc. Rev. 2011, vol. 40, p. 5048. The corresponding alkyne may have a silyl group and may be, for example, trimethylsilylacetylene. Examples of bases include amines such as triethylamine, DIPEA, DBU, and piperidine, and inorganic bases such as NaOAc, with triethylamine and DIPEA being preferred. Examples of Pd catalysts include PdCl2(PPh3)2, Pd(PPh3)4, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, Pd(OAc)2, and Pd2(dba)3, with PdCl2(PPh3)2, Pd(PPh3)4, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride being preferred. Examples of copper include copper iodide, copper bromide, and copper chloride, with copper iodide being preferred. Examples of solvents include polar solvents such as THF, 1,4-dioxane, DMF, DMA, NMP, DMSO, methanol, ethanol, and 2-propanol, as well as mixed solvents thereof, with THF being preferred.

[0097] Method 4 (thioetherification): Compound 1k1 is reacted with the corresponding mercaptan or mercaptan salt in the presence of Pd. Examples of bases include amines such as triethylamine, DIPEA, DBU, and piperidine, with triethylamine and DIPEA being preferred. Examples of Pd catalysts include zero-valent Pd complexes such as Pd(PPh3)4, with [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate being preferred. Examples of solvents include polar solvents such as THF, 1,4-dioxane, DMF, DMA, NMP, DMSO, methanol, ethanol, and 2-propanol, and mixed solvents thereof, with 1,4-dioxane being preferred.

[0098] Process 1-10: Bromination or chlorination of amine derivative 1j If R4 or R5 of the amine derivative 1j is a halogen, bromination or chlorination can be performed by reacting compound 1j with copper bromide or copper chloride. Examples of solvents include polar solvents such as THF, 1,4-dioxane, DMF, DMA, and NMP, with DMF being preferred.

[0099] Step 1-11: TBS conversion of amine derivative 1j If the R3 of the amine derivative 1j has a hydroxyl group, TBS conversion can be performed by reacting compound 1j with tert-butyldimethylchlorosilane (TBSCl) in the presence of a base. Examples of bases include triethylamine, DIPEA, and imidazole, with triethylamine being preferred. Examples of solvents include polar solvents such as THF, 1,4-dioxane, DMF, DMA, and NMP, with DMF being preferred.

[0100] Process 1-12-1: De-TBS treatment of sulfamide or sulfonamide derivative 1k2 If R3 of the sulfamide or sulfonamide derivative 1k2 has a TBS group, the TBS group is removed by reacting compound 1k2 with tetrabutylammonium fluoride. Examples of solvents include polar solvents such as THF, 1,4-dioxane, and DMF, with THF being preferred.

[0101] Process 1-12-2: Desilylation of sulfamide or sulfonamide derivative 1k2 If R4 or R5 of the sulfamide or sulfonamide derivative 1k2 has a silyl group, the silyl group is removed by reacting compound 1k2 with a base. Examples of bases include carbonates, with potassium carbonate being preferred. Examples of solvents include alcohols such as methanol and ethanol, with methanol being preferred.

[0102] (General manufacturing method-2) General method-2 is another preferred method for producing compound 1k1. [ka]

[0103] Process 2-1: The amine derivative 1h is sulfamidated or sulfonamidated in the same manner as in step 1-8. Process 2-2: Hydrolysis of ester derivative 2a is carried out in the same manner as in steps 1-6. Step 2-3: The benzoic acid derivative 2b is amidated in the same manner as in step 1-7. Before amidation, if necessary, the benzoic acid derivative 2b may be debocated, alkylated, alkenylated, alkynylated, thioetherified, brominated, or chlorinated in the same manner as in steps 1-9-1, 1-9-2, or 1-10.

[0104] (General manufacturing method-3) General method-3 is another preferred method for producing compound 1k1. [ka]

[0105] Step 3-1: Hydrazone conversion of aldehyde derivative 1c is carried out in the same manner as in step 1-3. Step 3-2: The benzoic acid derivative 3a is amidated in the same manner as in step 1-7. Step 3-3: Coupling of hydrazone derivative 3b and arylboronic acid derivative 1f, protecting group R b The elimination of and the sulfamidation or sulfonamidation of the amine derivative are carried out in this order in the same manner as in steps 1-4, 1-5, and 1-8, respectively.

[0106] (General manufacturing method-4) General method-4 is a preferred method for constructing the skeleton of a compound represented by general formula (1) in which ring A is a group represented by general formula (4), X1 is -N=, X2 is -CF=, and R6 and R9 are hydrogen atoms. [ka]

[0107] Step 4-1: Alkylation of compound 4a Compound 4a is reacted with compound 4b in the presence of a base. Examples of bases include phosphates and metal alkoxides such as sodium tert-butoxide, with tripotassium phosphate being preferred. Potassium iodide or tetrabutylammonium iodide may also be added to accelerate the reaction, with tetrabutylammonium iodide being preferred as such an additive. Examples of solvents include polar solvents such as NMP and 1,3-dimethyl-2-imidazolidinone, with 1,3-dimethyl-2-imidazolidinone being preferred. The reaction temperature is preferably 40°C or higher.

[0108] In the preparation of the compounds of this disclosure, the starting compound or reagent may form a salt or solvate, provided that the desired reaction is not inhibited.

[0109] If the compounds of this disclosure are obtained in free form, they can be converted to pharmaceutically acceptable salts or solvates by conventional methods. Furthermore, if the compounds of this disclosure are obtained in pharmaceutically acceptable salts or solvates, they can be converted to free forms by conventional methods.

[0110] The compounds, salts, or solvates of this disclosure can be isolated or purified, for example, by distillation, recrystallization, or chromatography. Furthermore, if isomers (e.g., enantiomers, diastereomers, or conformational isomers) are present, their isolation or purification can be carried out, for example, by recrystallization, diastereomer salting, enzymatic resolution, or chromatography (e.g., thin-layer chromatography, column chromatography, high-performance liquid chromatography, or gas chromatography).

[0111] Examples of dispersants in the compositions of the present disclosure include methylcellulose, polyvinyl alcohol, hydroxypropylcellulose, copolyvidone, hydroxypropylmethylcellulose, methacrylic acid copolymer, polyvinylpyrrolidone, and hypromellose acetate succinate, with methylcellulose, polyvinyl alcohol, and hydroxypropylcellulose being preferred, and methylcellulose being particularly preferred. In one embodiment, the composition of the present disclosure comprises at least one dispersant selected from the group consisting of methylcellulose, polyvinyl alcohol, hydroxypropylcellulose, copolyvidone, hydroxypropylmethylcellulose, methacrylic acid copolymer, polyvinylpyrrolidone, and hypromellose acetate succinate.

[0112] The amount of dispersant in the composition of the present disclosure is, for example, 0.1 to 20 parts by weight, preferably 0.2 to 10 parts by weight, and more preferably 1 to 10 parts by weight, per 1 part by weight of the compound, salt, or solvate of any of the first to third embodiments.

[0113] Examples of basic compounds in the compositions of this disclosure include meglumine, arginine, histidine, magnesium oxide, calcium silicate, and magnesium stearate, with meglumine and arginine being preferred, and meglumine being particularly preferred. In one embodiment, the composition of this disclosure comprises at least one basic compound selected from the group consisting of meglumine, arginine, histidine, magnesium oxide, calcium silicate, and magnesium stearate.

[0114] The content of the basic compound in the composition of the present disclosure is, for example, 0.2 to 40 parts by weight, preferably 0.5 to 20 parts by weight, and more preferably 1 to 10 parts by weight, per 1 part by weight of the compound, salt, or solvate of any of the first to third embodiments.

[0115] The compositions of the present disclosure may consist of a compound, salt, or solvate of any of the first to third embodiments and a dispersant and / or a basic compound, or they may contain other pharmaceutically acceptable components, such as at least one component selected from the group consisting of excipients, lubricants (coating agents), binders, disintegrants, flavoring agents, bases, diluents, surfactants, and emulsifiers.

[0116] Examples of excipients include starch (such as starch, potato starch, and corn starch), lactose monohydrate, crystalline cellulose, mannitol, and calcium hydrogen phosphate.

[0117] Examples of lubricants (coating agents) include ethylcellulose, shellac, talc, magnesium stearate, carnauba wax, and paraffin.

[0118] Examples of binders include macrogol and compounds similar to those used as excipients.

[0119] Examples of disintegrants include croscarmellose sodium and carboxymethyl starch sodium, as well as compounds similar to those used as excipients.

[0120] Examples of flavoring and odor-modifying agents include commonly used sweeteners, acidulants, and flavorings.

[0121] Examples of base materials include fats such as lard; vegetable oils such as olive oil and sesame oil; higher alcohols such as stearyl alcohol and cetanol; animal oils; lanolinic acid; petrolatum; paraffin; bentonite; glycerin; and glycol oil.

[0122] Examples of solvents or diluents used in liquid formulations include phenol, chlorocresol, purified water, and distilled water.

[0123] Examples of surfactants or emulsifiers include polysorbate 80, polyoxyl stearate 40, and lauromacrogol.

[0124] The compositions of the present disclosure can be produced, for example, by mixing a compound, salt, or solvate of any of the first to third embodiments with a dispersant and / or a basic compound, or by mixing a compound, salt, or solvate of any of the first to third embodiments with a dispersant and / or a basic compound with other pharmaceutically acceptable components (e.g., the aforementioned excipients, lubricants (coating agents), binders, disintegrants, flavoring agents, bases, diluents, surfactants, or emulsifiers). That is, in one embodiment, a method is provided for producing a composition comprising a compound represented by general formula (1) described above or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of the said compound or salt, and a dispersant and / or a basic compound, the method comprising the step of providing a mixture comprising the compound of general formula (1), the said salt, or the said solvate, and the said dispersant and / or the said basic compound.

[0125] In a preferred embodiment, the composition of the present disclosure comprises 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of said compound or salt, and a dispersant and / or a basic compound. In a more preferred embodiment, the composition of the present disclosure comprises a sodium salt or potassium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, and a dispersant and / or a basic compound. In a more preferred embodiment, the composition of the present disclosure comprises a sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide and a dispersant and / or a basic compound.

[0126] In one embodiment, the composition of the present disclosure comprises 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, together with a compound represented by formula (X) as described in Test Example 12 below. In one embodiment, the content of the compound of formula (X) is, for example, 3.0% by weight or less relative to the content of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, said salt, or said solvate. In one embodiment, the content of the compound of formula (X) is, for example, 0.02% by weight or more relative to the content of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, the salt, or the solvate.

[0127] In one embodiment, a composition of the present disclosure comprising a compound, salt, or solvate of any of the first to third embodiments and a dispersant and / or a basic compound is a pharmaceutical composition containing the compound, salt, or solvate as an active ingredient.

[0128] In another embodiment, a composition of the present disclosure comprising a compound, salt, or solvate of any of the first to third embodiments and a dispersant and / or a basic compound is a pharmaceutical composition for the treatment or prevention of cell proliferation disorders, particularly cancer, containing the compound, salt, or solvate as an active ingredient.

[0129] The subjects to whom the compounds, salts, or solvates of this disclosure are administered are animals, preferably mammals (e.g., mice, rats, rabbits, dogs, monkeys (e.g., cynomolgus macaques), or humans), and particularly preferably humans. Humans may be adults (18 years of age or older) or children (under 18 years of age). Children are preferably, for example, 6 months of age or older.

[0130] When the compounds, salts, or solvates of this disclosure are used for the treatment or prevention of cell proliferative disorders, the dosage and administration interval can be appropriately determined depending on the severity of the symptoms, the age and weight of the recipient, the presence or absence of concomitant drugs, and the method of administration. For example, when the recipient is a human, the usual dose is 0.00001 to 5000 mg per kg of body weight, preferably 0.01 to 100 mg, administered once every 1 to 3 weeks. If administered daily, the above amount may be divided into 2 to 4 doses.

[0131] Methods of administration to the target include systemic administration such as oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneous administration, intracisional administration, vaginal administration, intraperitoneal administration, intravesical administration, and inhalation administration, as well as local administration using ointments, gels, or creams, but oral administration is preferred.

[0132] The compounds, salts, or solvates of the present disclosure are typically used in the form of a specific formulation (dosage form). In one embodiment, the compositions of the present disclosure are formulations, such as pharmaceutical formulations. Such formulations include, for example, tablets, capsules, granules, powders, fine granules, pills, and aqueous or non-aqueous solutions and suspensions. Solutions and suspensions can be stored in containers suitable for dispensing into individual doses.

[0133] The various formulations described above can be prepared by known methods by mixing the compounds, salts, or solvates of the present disclosure with a dispersant and / or a basic compound and other pharmaceutically acceptable additives. Examples of such additives include the aforementioned excipients, lubricants (coating agents), binders, disintegrants, flavoring agents, bases, diluents, surfactants, and emulsifiers.

[0134] The preferred content of the compound, salt, or solvate of this disclosure in the formulation varies depending on the dosage form, but is usually 0.01 to 100% by weight of the total weight of the formulation.

[0135] Cellular proliferative disorders that can be treated or prevented with the compounds, salts, or solvates of the present disclosure include cancer, rheumatism, and inflammation, preferably cancer.

[0136] Cancers include, for example, blood and lymphatic cancers such as leukemia (acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, etc.), malignant lymphoma (Hodgkin's disease, non-Hodgkin's lymphoma, etc.), multiple myeloma, myelodysplastic syndrome; central nervous system cancers such as brain tumors and gliomas; and head and neck cancers (pharyngeal cancer, laryngeal cancer, tongue cancer, etc.), esophageal cancer, gastric cancer, colorectal cancer (cecal cancer, colon cancer, rectal cancer, etc.). Examples of solid cancers include lung cancer (small cell carcinoma, non-small cell carcinoma, etc.), thyroid cancer, breast cancer, gallbladder cancer, pancreatic cancer, liver cancer, prostate cancer, ovarian cancer, uterine cancer (endometrial cancer, cervical cancer, etc.), testicular cancer, renal cell carcinoma, bladder cancer, renal pelvis and ureteral cancer, malignant melanoma, and skin cancer (basal cell carcinoma, squamous cell carcinoma, extramammary Paget's disease, Merkel cell carcinoma, sweat gland carcinoma (e.g., apocrine gland carcinoma or eccrine gland carcinoma), sebaceous gland carcinoma, follicular epithelioma, etc.).

[0137] Cancer may have a gene mutation, may not have a gene mutation, or it may be unclear whether it has a gene mutation or not. Examples of genes that can undergo mutations include EGFR, FGFR, ALK, ROS1, PI3K, BRAF, HRAS, KRAS, and NRAS.

[0138] When using the compound, salt, or solvate of the first or second embodiment, the cancer is preferably one having a RAS mutation, and more preferably a solid tumor (particularly non-small cell lung cancer) having a KRAS mutation. In one embodiment, it is also used for cancer having a RAF mutation, and particularly for cancer having both RAF and RAS mutations. When using the compound, salt, or solvate of the third embodiment, the cancer is preferably one having an RAF mutation, and more preferably a solid tumor (especially malignant melanoma) having a BRAF mutation. [Examples]

[0139] The present disclosure will be described in more detail below based on examples (manufacturing examples and test examples), but the present disclosure is not limited to the following examples.

[0140] [Manufacturing example] NMR analysis was performed using a BRUKER AVANCE III HD400 (400 MHz). NMR data are shown in ppm (parts per million) (δ), and the deuterium-locked signal from the sample solvent was referenced.

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

[0142] High-performance liquid chromatography was performed using one of the analytical conditions A to G listed in Table 1 below. In Table 1 below, "TFA" means trifluoroacetic acid, "FA" means formic acid, and "AA" means ammonium acetate. [Table 1-1] [Table 1-2]

[0143] The microwave reaction was carried out using a Biotage Initiator. A snap-cap reaction vial was also used for the microwave reaction.

[0144] Commercially available reagents were used without further purification. All non-aqueous reactions were carried out in anhydrous solvent. Vacuum concentration or solvent removal was performed using a rotary evaporator.

[0145] In this specification, "room temperature" means a temperature of approximately 20°C to approximately 25°C.

[0146] In the following manufacturing examples, "manufacturing example of compound A-1" refers to manufacturing example A-1-1, and "manufacturing example of compound a9" refers to manufacturing example a9-1.

[0147] Compound a1: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-formylmethyl benzoate [ka] A suspension of 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-formylbenzoic acid (5.50 g, 13.1 mmol) in toluene (44 mL) and MeOH (11 mL) was cooled to 0 °C, and a 10% diazomethyltrimethylsilane hexane solution (21.8 mL, 13.1 mmol) was added. The mixture was stirred at room temperature for 64 h. Acetic acid (0.748 mL) was added to the reaction mixture, and it was concentrated under reduced pressure. The resulting residue was purified by trituration (hexane / ethyl acetate) to give the title compound (5.01 g, 88%) as a colorless solid. LCMS m / z: 436 [M+H] + HPLC retention time: 1.00 min (analysis condition D)

[0148] Compound a2: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]methyl benzoate

Chemical formula

[0149] Compound a3: N-(2,4-dimethoxybenzyl)-3-fluoro-4-iodopyridine-2-amine

Chemical formula

[0150] Compound a4: [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridine-4-yl]boronic acid [ka] A 1,4-dioxane solution (27 mL) containing N-(2,4-dimethoxybenzyl)-3-fluoro-4-iodopyridine-2-amine (compound a3, 2.70 g, 6.96 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (568 mg, 0.696 mmol), potassium acetate (2.05 g, 20.9 mmol), and bis(pinacorato)diborone (2.65 g, 10.4 mmol) was stirred under a nitrogen atmosphere at 90°C for 5 hours, and then 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 retention time: 0.44 minutes (analysis condition C)

[0151] Compound a5: 5-[[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate [ka] A 1,4-dioxane suspension (59 mL) containing 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]methyl benzoate (compound a2, 1.30 g, 2.16 mmol), [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridine-4-yl]boronic acid (compound a4, 1.98 g, 6.46 mmol), and potassium carbonate (357 mg, 2.59 mmol) was stirred under a nitrogen atmosphere at 100°C for 2.5 hours, then at 110°C for 3 hours. Ethyl acetate was added to the reaction mixture and washed with water and 13% saline solution. The organic layer was dried over anhydrous sodium sulfate, and after filtering off the drying agent, it was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (524 mg, 36%) as a foamy substance. LCMS m / z: 682[M+H] + HPLC retention time: 1.03 minutes (analysis condition D)

[0152] Compound a6: 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate [ka] A 16 mL DCM solution of 5-[[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound a5, 523 mg, 0.768 mmol) was cooled to 0°C, trifluoroacetic acid (15.7 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.05% trifluoroacetic acid aqueous solution / 0.05% trifluoroacetic acid acetonitrile solution) to obtain the title compound (321 mg, 79%) as an oily substance. LCMS m / z: 532[M+H] + HPLC retention time: 0.55 minutes (analysis condition D)

[0153] Compound a7: 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate [ka] A mixed solution of 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound a6, 4.00 g, 7.53 mmol) in THF (64 mL) and water (32 mL) was cooled to 0°C, lithium hydroxide monohydrate (948 mg, 22.6 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. After cooling to 0°C, 5 M hydrochloric acid (15.1 mL) was added to the reaction mixture and concentrated under reduced pressure. The resulting residue was washed with water and TBME to obtain the title compound (4.20 g, quant.) as a purple solid. LCMS m / z: 518[M+H] + HPLC retention time: 0.68 min (analysis condition C)

[0154] Compound a8: 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide [ka] A 3.6 mL solution of anhydrous DMF containing 5-((2-amino-3-fluoropyridine-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. Further addition of HOOBt (8.8 mg, 0.054 mmol) and EDC·HCl (10.4 mg, 0.054 mmol) was added. The mixture was stirred at room temperature for 1 hour, and then 7 M ammonia MeOH solution (0.103 mL, 0.722 mmol) and DIPEA (0.189 mL, 1.08 mmol) were added at 0°C. The mixture was stirred at room temperature for 30 minutes. Water and saturated sodium bicarbonate aqueous solution were added to the reaction mixture in a 1:1 ratio, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the drying agent was filtered off, and the mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (1 mL) and hexane (10 mL) was added. The resulting solid was filtered and washed with hexane to obtain the title compound (162 mg, 87%) as a colorless solid. LCMS m / z: 517[M+H] + HPLC retention time: 0.64 min (analysis condition C)

[0155] Compound a9: 5-((2-amino-3-fluoropyridine-4-yl)methyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluorobenzamide [ka] Manufacturing example a9-1: To a 1.9 mL anhydrous THF solution (5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (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 the mixture was stirred at room temperature under a nitrogen atmosphere for 2.5 hours. Ethyl acetate (5 mL) was added to the reaction mixture, and after Celite filtration, the mixture was washed with ethyl acetate (3 mL). The filtrate was washed with water and saturated brine, the organic layer was dried over anhydrous sodium sulfate, the drying agent was filtered off, and the mixture was concentrated under reduced pressure. Dichloromethane / hexane (1 / 10, 11 mL) was added to the resulting residue, 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 retention time: 0.61 min (analysis condition C)

[0156] Compound r1: 4-nitrophenyl methylsulfamic acid [ka] A 60 mL dichloromethane solution of 4-nitrophenol (5.00 g, 35.9 mmol) and triethylamine (11.3 mL, 81.0 mmol) was cooled to -78°C, and a 15 mL dichloromethane solution of methylsulfamoyl 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 resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) and reversed-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 retention time: 0.63 minutes (analysis condition C) 1H-NMR(400MHz,CDCl3) δ: 8.31(2H,m),7.46(2H,m),4.68(1H,m),3.00(3H,d,J=5.4Hz).

[0157] Compound A-1: 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] Manufacturing example A-1-1: 5-((2-amino-3-fluoropyridine-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 methylsulfamic acid 4-nitrophenyl (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. Acetonitrile (3 mL) and water (19.8 mL) were added, and the mixture was stirred for 10 minutes, after which the solid was filtered off. The obtained solid was washed with water / acetonitrile (1 / 1, 49.4 mL) to obtain compound A-1 (2.56 g, 85%) as a colorless solid. LCMS m / z: 524[M+H] + HPLC retention time: 1.13 minutes (analysis condition A)

[0158] Compound a10: 5-((2-amino-3-fluoropyridine-4-yl)methyl)-N-cyclopropyl-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide [ka] 5-((2-amino-3-fluoropyridine-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 obtain the title compound (103 mg, 96%) as a brown solid. LCMS m / z: 557[M+H] + HPLC retention time: 0.73 minutes (analysis condition C)

[0159] Compound A-2: N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-((2-amino-3-fluoropyridine-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 retention time: 1.65 minutes (analysis condition B)

[0160] Compound r2: 1-Chlorosulfonyloxy-4-nitrobenzene [ka] A 96 mL Et2O suspension of 4-nitrophenol (12.0 g, 86 mmol) and pyridine (6.98 mL, 86 mmol) was cooled to -78°C, and a 96 mL Et2O solution of sulfuryl chloride (6.98 mL, 86 mmol) was added over 10 minutes. The mixture was stirred at room temperature for 6.5 hours. The reaction mixture was filtered, washed with Et2O (15 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / DCM) to obtain the title compound (19.8 g, 97%) as a yellow oily substance. HPLC retention time: 0.77 min (analysis condition C) 1 H-NMR(400MHz,CDCl3) δ: 8.41(2H,m),7.61(2H,m).

[0161] Compound r3: N-[(2,4-dimethoxyphenyl)methyl]sulfamic acid 4-nitrophenyl [ka] A DCM solution (36 mL) of 1-chlorosulfonyloxy-4-nitrobenzene (compound r2, 1.78 g, 7.48 mmol) was cooled to -78°C, and DCM solutions (53 mL) of 2,4-dimethoxybenzylamine (1.00 g, 5.98 mmol), 4-nitrophenol (1.04 g, 7.48 mmol), and triethylamine (5.00 mL, 35.9 mmol) were added over 10 minutes, and the mixture was stirred at room temperature for 4 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) and silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.28 g, 58%) as a colorless solid. LCMS m / z: 367[MH] - HPLC retention time: 0.81 min (analysis condition C)

[0162] Compound r4: 4-nitrophenyl sulfamic acid [ka] The title compound was synthesized from N-[(2,4-dimethoxyphenyl)methyl]sulfamic acid 4-nitrophenyl (compound r3) under the same conditions as in the preparation example of compound a6. LCMS m / z: 217[MH] - HPLC retention time: 0.53 minutes (analysis condition C)

[0163] Compound r5: N-ethylsulfamic acid 4-nitrophenyl [ka] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the preparation example of compound r3. LCMS m / z: 245[MH] - HPLC retention time: 0.68 min (analysis condition C)

[0164] Compound r6: N-cyclopropylsulfamic acid 4-nitrophenyl [ka] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the preparation example of compound r3. LCMS m / z: 257[MH] - HPLC retention time: 0.70 min (analysis condition C)

[0165] Compound r7: N-(2-fluoroethyl)sulfamic acid 4-nitrophenyl [ka] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the preparation example of compound r3. LCMS m / z: 263[MH] - HPLC retention time: 0.65 min (analysis condition C)

[0166] Compound r11: N-[2-[tert-butyl(dimethyl)silyl]oxypropyl]sulfamic acid 4-nitrophenyl [ka] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the preparation example of compound r3. LCMS m / z: 389[MH] - HPLC retention time: 1.03 minutes (analysis condition C)

[0167] Compound r8: N-(2-methoxyethyl)sulfamic acid 4-nitrophenyl [ka] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the preparation example of compound r3. LCMS m / z: 277[M+H] + HPLC retention time: 0.64 min (analysis condition C)

[0168] Compound r9: N-(1-methylcyclobutyl)sulfamic acid 4-nitrophenyl [ka] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the preparation example of compound r3. LCMS m / z: 287[M+H] + HPLC retention time: 0.78 min (analysis condition C)

[0169] Compound r10: N-[1-(methoxymethyl)cyclopropyl]sulfamic acid 4-nitrophenyl [ka] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the preparation example of compound r3. LCMS m / z: 303[M+H] + HPLC retention time: 0.67 min (analysis condition C)

[0170] Compound r12: N-propylsulfamic acid 4-nitrophenyl [ka] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the preparation example of compound r3. LCMS m / z: 261[M+H] + HPLC retention time: 0.72 minutes (analysis condition C)

[0171] Compound r13: N-(oxetane-3-ylmethyl)sulfamic acid 4-nitrophenyl [ka] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the preparation example of compound r3. LCMS m / z: 289[M+H] + HPLC retention time: 0.59 minutes (analysis condition C)

[0172] Compound r14: N-(3-oxabicyclo[3.1.0]hexane-6-yl)sulfamic acid 4-nitrophenyl [ka] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the preparation example of compound r3. LCMS m / z: 301[M+H]+ HPLC retention time: 0.63 minutes (analysis condition C)

[0173] Compound r15: N-(1-methylcyclopropyl)sulfamic acid 4-nitrophenyl [ka] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the preparation example of compound r3. LCMS m / z: 273[M+H] + HPLC retention time: 0.73 minutes (analysis condition C)

[0174] Compound r16: N-[[(2R)-oxolan-2-yl]methyl]sulfamic acid 4-nitrophenyl [ka] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the preparation example of compound r3. LCMS m / z: 303[M+H] + HPLC retention time: 0.67 min (analysis condition C)

[0175] Compound r17: N-(1-methoxy-2-methylpropan-2-yl)sulfamic acid 4-nitrophenyl [ka] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the preparation example of compound r3. HPLC retention time: 0.76 minutes (analysis condition C) 1 H-NMR(400MHz,DMSO-d6) δ: 8.59(1H,s),8.34(2H,m),7.58(2H,m),3.30(2H,s),3.27(3H,s),1.28(6H,s).

[0176] Compound A-3: N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(sulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-((2-amino-3-fluoropyridine-4-yl)methyl)-N-cyclopropyl-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (compound a10) and the corresponding sulfamic acid 4-nitrophenyl under the same conditions as in the preparation example of compound A-1. LCMS m / z: 636[M+H] + HPLC retention time: 1.58 minutes (analysis condition B)

[0177] Compound A-4: N-Cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 5-((2-amino-3-fluoropyridine-4-yl)methyl)-N-cyclopropyl-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (compound a10) and the corresponding sulfamic acid 4-nitrophenyl under the same conditions as in the preparation example of compound A-1. LCMS m / z: 664[M+H] + HPLC retention time: 1.70 minutes (analysis condition B)

[0178] Compound A-5: N-Cyclopropyl-5-[[2-(Cyclopropylsulfamoylamino)-3-Fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 5-((2-amino-3-fluoropyridine-4-yl)methyl)-N-cyclopropyl-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (compound a10) and the corresponding sulfamic acid 4-nitrophenyl under the same conditions as in the preparation example of compound A-1. LCMS m / z: 676[M+H] + HPLC retention time: 1.70 minutes (analysis condition B)

[0179] Compound A-6: N-Cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 5-((2-amino-3-fluoropyridine-4-yl)methyl)-N-cyclopropyl-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (compound a10) and the corresponding sulfamic acid 4-nitrophenyl under the same conditions as in the preparation example of compound A-1. LCMS m / z: 682[M+H] + HPLC retention time: 1.66 minutes (analysis condition B)

[0180] Compound A-7: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-methylbenzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (compound a7) under the same conditions as in the preparation examples of compound a10 and compound A-1. However, 2M methylamine THF solution was used instead of aminocyclopropane, as used in the preparation example of compound a10. LCMS m / z: 624[M+H] + HPLC retention time: 1.62 minutes (analysis condition B)

[0181] Compound a12: 5-((2-amino-3-fluoropyridine-4-yl)methyl)-N-(tert-butoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide [ka] 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (compound a7, 100 mg, 0.181 mmol) was dissolved in anhydrous DMF (0.9 mL), and 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. Then, 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 obtain the title compound (89 mg, 84%) as a colorless solid. LCMS m / z: 589[M+H] + HPLC retention time: 0.77 min (analysis condition C)

[0182] Compound A-8: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide [ka] The title compound was synthesized from 5-((2-amino-3-fluoropyridine-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 retention time: 1.69 minutes (analysis condition B)

[0183] Compound A-9: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(2-methoxyethylsulfamoylamino)pyridine-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide [ka] The title compound was synthesized from 5-((2-amino-3-fluoropyridine-4-yl)methyl)-N-(tert-butoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (compound a12) and the corresponding sulfamic acid 4-nitrophenyl under the same conditions as in the preparation example of compound A-1. LCMS m / z: 726[M+H] + HPLC retention time: 1.71 minutes (analysis condition B)

[0184] Compound A-10: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-propane-2-yloxybenzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (compound a7) and the corresponding amine under the same conditions as in the preparation examples of compound a12 and compound A-1. LCMS m / z: 668[M+H] + HPLC retention time: 1.24 minutes (Analysis conditions A)

[0185] Compound A-11: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(2-methoxyethylsulfamoylamino)pyridine-4-yl]methyl]-N-propan-2-yloxybenzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (compound a7) and the corresponding amine under the same conditions as in the preparation examples of compound a12 and compound A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 712[M+H] + HPLC retention time: 1.26 minutes (analysis condition A)

[0186] Compound A-12: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridine-4-yl]methyl]-N-propane-2-yloxybenzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (compound a7) and the corresponding amine under the same conditions as in the preparation examples of compound a12 and compound A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 722[M+H] + HPLC retention time: 1.81 minutes (analysis condition B)

[0187] Compound A-13: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-methoxybenzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (compound a7) and the corresponding amine under the same conditions as in the preparation examples of compound a12 and compound A-1. LCMS m / z: 640[M+H] + HPLC retention time: 1.16 minutes (analysis condition A)

[0188] Compound A-14: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(2-methoxyethylsulfamoylamino)pyridine-4-yl]methyl]-N-methoxybenzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (compound a7) and the corresponding amine under the same conditions as in the preparation examples of compound a12 and compound A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 684[M+H] + HPLC retention time: 1.18 minutes (analysis condition A)

[0189] Compound A-15: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridine-4-yl]methyl]-N-methoxybenzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (compound a7) and the corresponding amine under the same conditions as in the preparation examples of compound a12 and compound A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 694[M+H] + HPLC retention time: 1.72 minutes (analysis condition B)

[0190] Compound A-16: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-[[1-(Methoxymethyl)cyclopropyl]sulfamoylamino]pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (compound a7) and the corresponding amine under the same conditions as in the preparation examples of compound a12 and compound A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 680[M+H] + HPLC retention time: 1.20 minutes (Analysis conditions A)

[0191] Compound a15: 5-[[2-[2-[tert-butyl(dimethyl)silyl]oxypropylsulfamoylamino]-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (compound a7) and the corresponding amine under the same conditions as in the preparation examples of compound a12 and compound A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 768[M+H] + HPLC retention time: 1.12 minutes (analysis condition C)

[0192] Compound A-17: (+ / -)-3,4-difluoro-5-[[3-fluoro-2-(2-hydroxypropylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide(racemic) [ka] 5-[[2-[2-[tert-butyl(dimethyl)silyl]oxypropylsulfamoylamino]-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a15, 60.0 mg, 0.78 mmol) was dissolved in MeOH (0.4 mL), (-)-10-camphorsulfonic acid (27.2 mg, 0.117 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to obtain the title compound (38 mg, 74%) as a colorless solid. LCMS m / z: 654[M+H] + HPLC retention time: 1.10 minutes (Analysis conditions A)

[0193] Compound a16: 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-methylsulfanylanilino)benzamide [ka] 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8, 30.0 mg, 0.058 mmol) was dissolved in anhydrous 1,4-dioxane (0.3 mL), and methyl mercaptan sodium (12.2 mg, 0.174 mmol), DIPEA (30.4 μL, 0.174 mmol), and [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (11.2 mg, 0.012 mmol) were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to obtain the title compound (15 mg, 59%) as a colorless solid. LCMS m / z: 437[M+H] + HPLC retention time: 0.60 min (analysis condition C)

[0194] Compound A-18: 3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-methylsulfanylanilino)benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-methylsulfanylanilino)benzamide (compound a16) under the same conditions as in the preparation example of compound A-1. LCMS m / z: 530[M+H] + HPLC retention time: 1.09 minutes (Analysis conditions A)

[0195] Compound a17: 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzamide [ka] 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8, 500 mg, 0.969 mmol) was dissolved in degassed 2-propanol (12 mL) and anhydrous THF (2 mL). Potassium vinyl trifluoroborate (143 mg, 1.07 mmol), triethylamine (0.405 mL, 2.91 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (79.0 mg, 0.097 mmol) were added, and the mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The reaction mixture was filtered through Celite, and the solids were washed with ethyl acetate and MeOH. The filtrate 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 (343 mg, 85%) as a colorless solid. LCMS m / z: 417[M+H] + HPLC retention time: 0.60 min (analysis condition C)

[0196] Compound A-19: 2-(4-ethenyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzamide (compound a17) under the same conditions as in the preparation example of compound A-1. LCMS m / z: 510[M+H] + HPLC retention time: 1.11 minutes (analysis condition A)

[0197] Compound a18: 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-[2-fluoro-4-(2-trimethylsilylethynyl)anilino]benzamide [ka] To a 26 mL solution of 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8, 2.67 g, 5.17 mmol) in anhydrous THF, triethylamine (31.7 mL, 228 mmol), trimethylsilylacetylene (1.43 mL, 10.3 mmol), bis(triphenylphosphine)palladium(II) dichloride (363 mg, 0.517 mmol), and copper(I) iodide (296 mg, 1.55 mmol) were added, and the mixture was 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 (2.57 g, 83%) as a colorless solid. LCMS m / z: 487[M+H] + HPLC retention time: 0.84 minutes (analysis condition G)

[0198] Compound a19: 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(4-ethynyl-2-fluoroanilino)-3,4-difluorobenzamide [ka] Potassium carbonate (17.0 mg, 0.123 mmol) was added to a MeOH solution (0.411 mL) of 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-[2-fluoro-4-(2-trimethylsilylethynyl)anilino]benzamide (compound a18, 20.0 mg, 0.041 mmol) and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to obtain the title compound (14 mg, 82%) as a colorless solid. LCMS m / z: 415[M+H] + HPLC retention time: 0.60 minutes (analysis condition G)

[0199] Compound A-20: 2-(4-ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(4-ethynyl-2-fluoroanilino)-3,4-difluorobenzamide (compound a19) and the corresponding sulfamic acid 4-nitrophenyl under the same conditions as in the preparation example of compound A-1. LCMS m / z: 536[M+H] + HPLC retention time: 1.18 minutes (analysis condition A)

[0200] Compound A-21: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(Oxetan-3-ylmethylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8) and the corresponding sulfamic acid 4-nitrophenyl under the same conditions as in the preparation example of compound A-1. However, imidazole was used instead of pyridine. LCMS m / z: 666[M+H] + HPLC retention time: 1.11 minutes (analysis condition A)

[0201] Compound A-22: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(3-oxabicyclo[3.1.0]hexane-6-ylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8) and the corresponding sulfamic acid 4-nitrophenyl under the same conditions as in the preparation example of compound A-1. However, imidazole was used instead of pyridine. LCMS m / z: 678[M+H] + HPLC retention time: 1.16 minutes (analysis condition A)

[0202] Compound A-23: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-[(1-methylcyclopropyl)sulfamoylamino]pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8) and the corresponding sulfamic acid 4-nitrophenyl under the same conditions as in the preparation example of compound A-1. However, imidazole was used instead of pyridine, and anhydrous THF was used instead of anhydrous DMF. LCMS m / z: 650[M+H] + HPLC retention time: 1.25 minutes (Analysis conditions A)

[0203] Compound A-24: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-[(1-Methoxy-2-methylpropan-2-yl)sulfamoylamino]pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8) and the corresponding sulfamic acid 4-nitrophenyl under the same conditions as in the preparation example of compound A-1. However, imidazole was used instead of pyridine, and anhydrous THF was used instead of anhydrous DMF. LCMS m / z: 682[M+H] + HPLC retention time: 1.27 minutes (Analysis conditions A)

[0204] Compound A-25: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8, 10.0 mg, 0.019 mmol) was dissolved in anhydrous DMA (0.1 mL), and pyridine (2.3 μL, 0.029 mmol) and methylsulfamoyl chloride (2.5 μL, 0.029 mmol) were added at 0°C. 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 obtain the title compound (10.2 mg, 86%) as a colorless solid. LCMS m / z: 610[M+H] + HPLC retention time: 1.15 minutes (Analysis conditions A)

[0205] Compound s2: N-(1-Bicyclo[1.1.1]pentanyl)sulfamoyl chloride [ka] Sulfuryl chloride (0.102 mL, 1.25 mmol) was dissolved in anhydrous acetonitrile (1.5 mL), and bicyclo[1.1.1]pentane-1-amine hydrochloride (50.0 mg, 0.418 mmol) was added at 0°C. The mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to obtain the crude product of the title compound.

[0206] Compound s3: N-(oxan-4-yl)sulfamoyl chloride [ka] The title compound was synthesized from the corresponding amine under the same conditions as in the preparation example of compound s2, except that triethylamine was also added.

[0207] Compound A-28: 5-[[2-(1-bicyclo[1.1.1]pentanylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8) and the corresponding sulfamoyl chloride under the same conditions as the preparation example for compound A-25. LCMS m / z: 662[M+H] + HPLC retention time: 1.27 minutes (Analysis conditions A)

[0208] Compound A-29: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(oxan-4-ylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8) and the corresponding sulfamoyl chloride under the same conditions as the preparation example for compound A-25. LCMS m / z: 680[M+H] + HPLC retention time: 1.16 minutes (analysis condition A)

[0209] Compound A-30: 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8) and the corresponding sulfamoyl chloride under the same conditions as the preparation example for compound A-25. LCMS m / z: 636[M+H] + HPLC retention time: 1.21 minutes (Analysis conditions A)

[0210] Compound A-31: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(Propan-2-ylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8) and the corresponding sulfamoyl chloride under the same conditions as the preparation example for compound A-25. LCMS m / z: 638[M+H] + HPLC retention time: 1.24 minutes (Analysis conditions A)

[0211] Compound A-32: 5-[[2-(cyclobutylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8) and the corresponding sulfamoyl chloride under the same conditions as the preparation example for compound A-25. LCMS m / z: 650[M+H] + HPLC retention time: 1.26 minutes (analysis condition A)

[0212] Compound A-33: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(2-methoxyethylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8) and the corresponding sulfamoyl chloride under the same conditions as the preparation example for compound A-25. LCMS m / z: 654[M+H] + HPLC retention time: 1.17 minutes (Analysis conditions A)

[0213] Compound A-34: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8) and the corresponding sulfamoyl chloride under the same conditions as the preparation example for compound A-25. LCMS m / z: 652[M+H] + HPLC retention time: 1.31 minutes (analysis condition A)

[0214] Compound A-35: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8) and the corresponding sulfamoyl chloride under the same conditions as in the preparation example of compound A-25. However, the reaction was carried out at 0°C. LCMS m / z: 664[M+H] + HPLC retention time: 1.30 minutes (analysis condition A)

[0215] Compound A-36: 5-[[2-(cyclopropylmethylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8) and the corresponding sulfamoyl chloride under the same conditions as in the preparation example of compound A-25. However, the reaction was carried out at 0°C. LCMS m / z: 650[M+H] + HPLC retention time: 1.26 minutes (analysis condition A)

[0216] Compound A-37: 5-[[2-(tert-butylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8) and the corresponding sulfamoyl chloride under the same conditions as in the preparation example of compound A-25. However, the reaction was carried out at 0°C. LCMS m / z: 652[M+H] + HPLC retention time: 1.28 minutes (analysis condition A)

[0217] Compound A-38: 5-[[2-(ethylsulfonylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8) 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 retention time: 1.20 minutes (Analysis conditions A)

[0218] Compound A-39: N-Cyclopropyl-5-[[2-(ethylsulfonylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a10) 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: 649[M+H] + HPLC retention time: 1.68 minutes (analysis condition B)

[0219] Compound A-40: 5-[[2-(ethylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8) and the corresponding sulfamoyl chloride under the same conditions as the preparation example for compound A-25. LCMS m / z: 624[M+H] + HPLC retention time: 1.20 minutes (Analysis conditions A)

[0220] Compound A-41: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8) and the corresponding sulfamoyl chloride under the same conditions as the preparation example for compound A-25. LCMS m / z: 638[M+H] + HPLC retention time: 1.25 minutes (Analysis conditions A)

[0221] Compound A-42: 3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8) and the corresponding sulfamoyl chloride under the same conditions as the preparation example for compound A-25. LCMS m / z: 642[M+H] + HPLC retention time: 1.17 minutes (Analysis conditions A)

[0222] Compound a20: 3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-2-[2-fluoro-4-(2-trimethylsilylethynyl)anilino]benzamide [ka] 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-25, 10.0 mg, 0.016 mmol) was dissolved in anhydrous THF (0.1 mL), and triethylamine (0.100 mL, 0.717 mmol), trimethylsilylacetylene (4.1 μL, 0.033 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (1.2 mg, 1.6 μmol) and copper(I) iodide (0.9 mg, 5 μmol) were added, and the mixture was stirred at room temperature for 24 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 the title compound (12.4 mg) as an oily substance. LCMS m / z: 580[M+H] + HPLC retention time: 0.95 minutes (analysis condition C)

[0223] Compound A-26: 2-(4-ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] 3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-2-[2-fluoro-4-(2-trimethylsilylethynyl)anilino]benzamide (compound a20, 11.0 mg, 0.019 mmol) was dissolved in MeOH (0.2 mL), potassium carbonate (7.9 mg, 0.057 mmol) was 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 obtain the title compound (5.0 mg, 52%) as a solid. LCMS m / z: 508[M+H] + HPLC retention time: 1.05 minutes (Analysis conditions A)

[0224] Compound a21: 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(4-bromo-2-fluoroanilino)-3,4-difluorobenzamide [ka] 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8, 60.0 mg, 0.116 mmol) was dissolved in anhydrous DMF (1.2 mL), copper(I) bromide (83.0 mg, 0.581 mmol) was added, and the mixture was stirred at 100°C for 24 hours. The reaction mixture was purified by preparative HPLC (TSK-gel ODS 80TS 5 μm, 20 × 250 mm column (TOSOH), 0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to obtain the title compound (35.6 mg) as a solid. LCMS m / z: 469[M+H] + HPLC retention time: 0.61 min (analysis condition C)

[0225] Compound A-27: 2-(4-bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(4-bromo-2-fluoroanilino)-3,4-difluorobenzamide (compound a21) under the same conditions as the preparation example for compound A-25. LCMS m / z: 562[M+H] + HPLC retention time: 1.13 minutes (analysis condition A)

[0226] Compound A-43: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-[[Methyl-(methylamino)-oxo-λ6-sulfanylidene]amino]pyridine-4-yl]methyl]benzamide [ka] 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8, 102 mg, 0.198 mmol) was dissolved in anhydrous THF (2 mL), and pyridine (0.160 mL, 1.98 mmol) and methanesulfinate chloride (0.100 mL, 0.717 mmol) were added under a nitrogen atmosphere at 0°C. To this solution, tert-butyl hypochlorite (44.6 μL, 0.395 mmol) was added at 0°C, and after stirring for 1 minute, another tert-butyl hypochlorite (44.6 μL, 0.395 mmol) was added. After adding 1.98 mL (3.95 mmol) of 2 M methylamine THF solution and stirring, the reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to obtain the title compound (45.9 mg, 38%) as a colorless solid. LCMS m / z: 608[M+H] + HPLC retention time: 1.00 minutes (Analysis conditions A)

[0227] Compound a22: 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate trifluoroacetate [ka] 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound a6, 1.05 g, 1.97 mmol) was dissolved in THF (16.8 mL) and water (8.4 mL), and lithium hydroxide monohydrate (415 mg, 9.88 mmol) was added at 0°C. The mixture was stirred at room temperature for 2 hours. Trifluoroacetic acid (305 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was washed with water to obtain the title compound (1.06 g, 85%) as a colorless solid. LCMS m / z: 518[M+H] + HPLC retention time: 0.68 min (analysis condition C)

[0228] Compound a23: 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid trifluoroacetate (compound a22) and the corresponding amine under the same conditions as in the preparation example of compound a12. LCMS m / z: 577[M+H] + HPLC retention time: 0.58 min (analysis condition C)

[0229] Compound a24: 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-N-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [ka] 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)benzamide (compound a23, 320 mg, 0.555 mmol) was dissolved in anhydrous DMF (3 mL), and triethylamine (0.116 mL, 0.833 mmol) and tert-butyldimethylchlorosilane (0.100 mL, 0.717 mmol) were added at 0°C, and the mixture was stirred at room temperature for 16 hours. Subsequently, triethylamine (0.116 mL, 0.833 mmol) and tert-butyldimethylchlorosilane (0.100 mL, 0.717 mmol) were added, and the mixture was stirred for 7 hours. The reaction mixture was purified by reverse-phase column chromatography (10 mM ammonium acetate aqueous solution / methanol) to obtain the title compound (302 mg, 79%) as a yellow solid. LCMS m / z: 691[M+H] + HPLC retention time: 0.98 min (analysis condition C)

[0230] Compound a25: N-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-5-[[2-(ethylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [ka] Under the same conditions as in the production example of Compound A-25, the title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-N-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a24) and the corresponding sulfamoyl chloride. LCMS m / z: 798[M+H] + HPLC retention time: 1.11 minutes (Analysis condition C)

[0231] Compound A-44: 5-[[2-(ethylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)benzamide

Chemical formula

[0232] Compound A-45: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(Propylsulfamoylamino)pyridine-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide

Chemical formula

[0233] Compound A-46: 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (compound a9) and the corresponding sulfamic acid 4-nitrophenyl under the same conditions as in the preparation example of compound A-1. LCMS m / z: 578[M+H] + HPLC retention time: 0.89 minutes (analysis condition C)

[0234] Compound A-47: N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a10) and the corresponding sulfamic acid 4-nitrophenyl under the same conditions as in the preparation example of compound A-1. LCMS m / z: 704[M+H] + HPLC retention time: 0.97 min (analysis condition C)

[0235] Compound a26: 5-Bromo-2,3,4-trifluorobenzoic acid [ka] A reaction vessel containing water (81 mL) was cooled to ambient temperature (0°C), and concentrated sulfuric acid (162 mL) was added. Subsequently, 2,3,4-trifluorobenzoic acid (27.0 g, 153 mmol) and potassium sulfate (401 mg, 2.30 mmol) were added, and the mixture was heated to ambient temperature (55°C). An aqueous solution prepared from sodium bromate (25.4 g, 169 mmol) and water (108 mL) was added dropwise over 2.5 hours, and the mixture was stirred for 2.5 hours. After the reaction mixture was cooled to 0°C, an aqueous solution prepared from sodium sulfite (24.3 g, 161 mmol) and water (324 mL) was added. The crystals were filtered, washed with water (162 mL), and air-dried to obtain the title compound (27.9 g, 71%) as a colorless solid. LCMS m / z: 253[MH] - HPLC retention time: 0.66 min (analysis condition C)

[0236] Compound a27: 5-Bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzoic acid [ka] A reaction vessel containing 1M lithium bis(trimethylsilyl)amide THF solution (206 mL, 206 mmol) was cooled to ambient temperature -15°C, and a THF solution (30 mL) of 4-cyclopropyl-2-fluoroaniline (11.6 g, 76.5 mmol) was added dropwise. Furthermore, a THF solution (120 mL) of 5-bromo-2,3,4-trifluorobenzoic acid (compound a26, 15.0 g, 58.8 mmol) was added dropwise over 30 minutes, and the mixture was stirred for 30 minutes. 5M hydrochloric acid (118 mL) was added to the reaction mixture, the temperature was raised to room temperature, and the mixture was extracted with isopropyl acetate (75 mL). The organic layer was sequentially washed twice with water (75 mL) and once with 15% sodium chloride aqueous solution (75 mL), and then concentrated under reduced pressure. To the obtained concentrated residue, acetone (120 mL) was added and heated to dissolve it. Then, water (45 mL) and seed crystal (150 mg) were added to precipitate crystals. Water (45 mL) was added to the obtained slurry and the crystals were filtered off. The slurry was washed with a mixture of acetone / water (1 / 2) and dried under reduced pressure at an ambient temperature of 40°C to obtain the title compound (19.4 g, 85%). LCMS m / z: 386[M+H] + HPLC retention time: 0.62 minutes (analysis condition C)

[0237] Compound a28: 5-Bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide [ka] 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzoic acid (compound a27, 13.0 g, 33.7 mmol) was placed in a reaction vessel, to which acetonitrile (104 mL), THF (26 mL), and 1,1'-carbonyldiimidazole (8.2 g, 50.5 mmol) were added, and the mixture was stirred at room temperature for 2 hours. 28% aqueous 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, washed with water, and dried under reduced pressure at ambient temperature of 40°C to obtain the title compound (12.0 g, 93%). LCMS m / z: 385[M+H] + HPLC retention time: 0.52 minutes (analysis condition C)

[0238] Compound a30: N-[3-fluoro-4-(hydroxymethyl)pyridine-2-yl]acetamidomethanesulfonate

Chem.

[0239] (2) Synthesis of Compound a30 To the reaction vessel, a toluene solution of the obtained N-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-fluoropyridine-2-yl]acetamide, toluene (175 mL), and methanol (195 mL) were added, the mixture was degassed under reduced pressure, and the vessel was purged with nitrogen. Methanesulfonic acid (188 g, 1.96 mol) was added dropwise at ambient temperature of 10°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to ambient temperature of 0°C and stirred for 3 hours. The precipitate was filtered and washed with a mixture of cooled toluene (312 mL) and methanol (78 mL). To the reaction vessel, the filtered solid and a mixture of toluene (1.1 L) and ethanol (492 mL) were added, and the mixture was stirred at ambient temperature of 0°C for 1 hour. The solid was filtered and washed with a mixture of toluene (281 mL) and ethanol (117 mL), and dried under reduced pressure at ambient temperature of 40°C to obtain compound a30 (149 g, 81%). LCMS m / z: 185[M+H] + HPLC retention time: 0.30 minutes (analysis condition E)

[0240] Compound a31: (2-Acetamido-3-Fluoropyridine-4-yl)methyl methyl carbonate [ka] N-[3-fluoro-4-(hydroxymethyl)pyridine-2-yl]acetamidomethanesulfonate (compound a30, 50.0 g, 178 mmol) and 2-methyltetrahydrofuran (750 mL) were added to a reaction vessel, to which 4-dimethylaminopyridine (52.3 g, 428 mmol) was added at room temperature. The ambient 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 ambient temperature of 40°C. Ethyl acetate (300 mL) was added to the concentrated residue and dissolved at room temperature, after which 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. After cooling the slurry to ambient temperature of 0°C, the crystals were filtered off and washed with a mixture of ethyl acetate / heptane (2 / 7). The title compound (31.3 g, 72%) was dried under reduced pressure at an ambient temperature of 40°C to obtain a colorless solid. LCMS m / z: 243 [M+H] + HPLC holding time: 0.37 minutes (analytical condition C)

[0241] Compound a32: 5-[(2-acetamido-3-fluoropyridine-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide

change

[0242] Compound a9: 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide [ka] Manufacturing example a9-2: 5-[(2-acetamido-3-fluoropyridine-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (compound a32, 100 mg, 0.21 mmol) was placed in a reaction vessel, and methanol (3 mL) and 5M hydrochloric acid (0.42 mL, 2.1 mmol) were added. The mixture was stirred at an ambient temperature of 50°C for 6 hours. The reaction mixture was cooled to room temperature, and 2M aqueous sodium hydroxide solution (1.1 mL, 2.1 mmol) was added. Water (0.5 mL) was added to the resulting slurry, and the crystals were filtered off. The slurry was washed with a methanol / water (3 / 2) mixture and dried under reduced pressure at an ambient temperature of 40°C to obtain compound a9 (77.7 mg, 85%) as a colorless solid. LCMS m / z: 431[M+H] + HPLC retention time: 0.61 min (analysis condition C)

[0243] Compound A-1: 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] Manufacturing example A-1-2: 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (compound a9, 100 mg, 0.232 mmol) was dissolved in anhydrous DMA (1 mL), and pyridine (56.4 μL, 0.697 mmol) was added. After cooling to 0°C, methylsulfamoyl chloride (30.2 μL, 0.349 mmol) was added, and the mixture was stirred for 1 hour. Acetonitrile (0.6 mL), water (0.3 mL), and seed crystal (1 mg) were added to the reaction mixture, and the temperature was raised to room temperature. Water (0.7 mL) and acetonitrile (0.4 mL) were added, and the mixture was stirred for 20 hours. The precipitate was filtered off and washed with a mixture of acetonitrile / water (1 / 1) to obtain compound A-1 (93.1 mg, 77%) as a colorless solid. LCMS m / z: 524[M+H] + HPLC retention time: 1.13 minutes (analysis condition A)

[0244] Sodium salt of compound A-1: 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide sodium salt [ka] (1) Preparation of sample A-1a (Form I) 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (compound A-1, 3.03 g) was dissolved in acetone (10.6 mL) and DMSO (1.51 mL) at room temperature. To this solution, 20% sodium ethoxide ethanol solution (3.03 mL) and a seed crystal of the sodium salt of compound A-1 (sample A-1b described below) were added and the mixture was stirred at room temperature for 1 hour. Then, ethanol (15.1 mL) was added and the mixture was stirred at room temperature for 4 hours. Subsequently, another ethanol (15.1 mL) was added and the mixture was stirred at room temperature for 4 hours to obtain the sodium salt of compound A-1 (2.74 g) as a powder crystal (sample A-1a (Form I)).

[0245] (2) Preparation of sample A-1b Compound A-1 (53.6 mg) was mixed with 20% sodium ethoxide ethanol solution (0.054 mL) and methyl isobutyl ketone (0.161 mL), and the mixture was 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 the sodium salt of compound A-1 (25.6 mg) as powdered crystals (Sample A-1b).

[0246] (3) Preparation of sample A-1c Compound A-1 (1.02 g) was mixed with DMSO (4.26 mL) and 2 M sodium hydroxide aqueous solution (1.07 mL). This solution was freeze-dried at -20°C for 4 days, and then dried under reduced pressure at room temperature for 3 days. 1-Pentanol (10.0 mL) was added to the resulting solid, and the mixture was stirred at 80°C for 10 minutes. The mixture was then stirred at room temperature for 6 hours to obtain the sodium salt of compound A-1 (0.966 g) as a powdered crystal (Sample A-1c).

[0247] (4) Powder X-ray diffraction measurement Samples A-1a (Form I), A-1b, and A-1c were subjected to powder X-ray diffraction measurements under the following conditions. Measurement equipment: SmartLab, D / Tex Ultra detector (manufactured by Rigaku Corporation) Cathode: Cu Tube voltage: 45kV Tube current: 200mA Sampling width: 0.02°

[0248] The results of powder X-ray diffraction measurements are shown in Figures 1 to 3. Figure 1 shows the powder X-ray diffraction pattern of sample A-1a (Form I). Figure 2 shows the powder X-ray diffraction pattern of sample A-1b. Figure 3 shows the powder X-ray diffraction pattern of sample A-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.

[0249] (5) Ion chromatography Ion chromatography was used to measure the proportion of sodium ions in the crystal of sample A-1a (Form I). The molar ratio of sodium ions to compound A-1 was found to be 0.99. This confirmed that sample A-1a is a monosodium salt. Ion chromatography was performed under the following conditions. Measurement equipment: Dionex ICS-1600, AS-AP (manufactured by Thermo Fisher Scientific) Columns: Dionex IonPac CG16 (5 x 50 mm) / CS16 (5 x 250 mm) (manufactured by Thermo Fisher Scientific) Eluent: 30 mmol / L methanesulfonic acid solution Suppressor: Dionex CERS-500 4mm, 88mA (manufactured by Thermo Fisher Scientific) Column temperature: 40℃ Eluent flow rate: 1.00mL / min Sample injection volume: 10 μL Detector: Electrical conductivity detector Sample preparation: Sample A-1a was suspended in a 20 mmol / L methanesulfonic acid solution at a concentration of 0.5 mg / mL, and the mixture was shaken for 17 hours to extract sodium ions. The supernatant was then measured.

[0250] Compound b1: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]methyl benzoate [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound a6) under the same conditions as the preparation example for compound A-25. However, anhydrous NMP was used instead of anhydrous DMA. LCMS m / z: 436[M+H] + HPLC retention time: 1.00 minutes (Analysis condition D)

[0251] Compound b2: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzoic acid [ka] A mixed solution of 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]methyl benzoate (compound b1, 158 mg, 0.253 mmol) in THF (4.8 mL) and water (2.4 mL) was cooled to 0°C, lithium hydroxide monohydrate (60.6 mg, 2.53 mmol) was added, and the mixture was stirred at room temperature for 2 hours. 2 M hydrochloric acid was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the mixture was concentrated under reduced pressure to obtain the title compound (161 mg) as a foamy substance. LCMS m / z: 611[M+H] + HPLC retention time: 0.67 minutes (analysis condition D)

[0252] Compound B-1: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide [ka] The title compound was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-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 retention time: 1.07 minutes (Analysis conditions A)

[0253] Compound B-2: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-(2-methoxyethoxy)benzamide [ka] The title compound was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-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: 684[M+H] + HPLC retention time: 1.56 minutes (analysis condition B)

[0254] Compound B-3: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-(2-methylcyclopropyl)benzamide (composite of 4 isomers) [ka] The title compound was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-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: 664[M+H] + HPLC retention time: 1.70 minutes and 1.72 minutes (Analysis Condition B)

[0255] Compound B-6: (+ / -)-N-(2,2-difluorocyclopropyl)-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide (racemic mixture) [ka] The title compound was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzoic acid (compound b2) and the corresponding amine under the same conditions as in the preparation example of compound a12. LCMS m / z: 686[M+H] + HPLC retention time: 1.69 minutes (analysis condition B)

[0256] Compound B-4: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-[(1S,2R)-(+ / -)-2-methylcyclopropyl]benzamide (racemic mixture) [ka] Compound B-5: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-[(1R,2R)-(+ / -)-2-methylcyclopropyl]benzamide (racemic mixture) [ka] 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-(2-methylcyclopropyl)benzamide (a mixture of four isomers, compound B-3, 57 mg) was purified by preparative HPLC (YMC Triart C18 plus 5 μm, 4.6 × 150 mm column, 0.1% TFA aqueous solution / 0.1% TFA acetonitrile solution) to obtain compound B-4 (14.7 mg) and compound B-5 (41 mg) as solids. Compound B-4 LCMS m / z: 664[M+H] + HPLC retention time: 1.70 minutes (analysis condition B) Compound B-5 LCMS m / z: 664[M+H] + HPLC retention time: 1.72 minutes (analysis condition B)

[0257] Compound B-8: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfonylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound a6) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of compounds A-25, b2, and a8. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, as used in the preparation example of compound A-25. LCMS m / z: 623[M+H] + HPLC retention time: 1.63 minutes (analysis condition B)

[0258] Compound B-9: 3,4-difluoro-5-[[3-fluoro-2-(2-hydroxyethylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate methyl (compound a6) and the corresponding sulfamoyl chloride under the same conditions as in the preparation examples of compounds A-25, b2, and a8. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, as used in the preparation example of compound A-25. LCMS m / z: 640[M+H] + HPLC retention time: 1.06 minutes (Analysis conditions A)

[0259] Compound b8: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-[(2-methylpropan-2-yl)oxycarbonylsulfamoylamino]pyridine-4-yl]methyl]benzoic acid [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound a6) and the corresponding sulfamoyl chloride under the same conditions as in the preparation examples of compound A-25 and compound b2. However, anhydrous NMP was used instead of anhydrous DMA, which was used in the preparation example of compound A-25. LCMS m / z: 697[M+H] + HPLC retention time: 0.71 min (analysis condition D)

[0260] Compound b9: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(Sulfamoylamino)pyridine-4-yl]methyl]benzoic acid [ka] Chlorotrimethylsilane (71.5 μL, 0.564 mmol) was added to a 2,2,2-trifluoroethanol solution (2.6 mL) of 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(2-methylpropan-2-yl)oxycarbonylsulfamoylamino]pyridine-4-yl]methyl]benzoic acid (compound b8, 131 mg, 0.188 mmol) and 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 obtain the title compound (75.0 mg, 67%) as a foamy substance. LCMS m / z: 597[M+H] + HPLC retention time: 0.60 min (analysis condition D)

[0261] Compound B-10: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(sulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(sulfamoylamino)pyridine-4-yl]methyl]benzoic acid (compound b9) and the corresponding amine under the same conditions as in the preparation example of compound a12. LCMS m / z: 596[M+H] + HPLC retention time: 1.11 minutes (analysis condition A)

[0262] Compound b10: 2-(2-chloro-4-iodoanilino)-3,4-difluoro-5-formylbenzoic acid [ka] A 2M LDA THF solution (6.53 mL, 13.1 mmol) was cooled to -78°C, and under a nitrogen atmosphere, a THF solution of 2,3,4-trifluorobenzoic acid (1.00 g, 5.68 mmol) (6 mL) was slowly added. After stirring at -78°C for 50 minutes, DMF (0.484 mL, 6.25 mmol) was slowly added, and the mixture was stirred at -10°C for 2 hours. In a separate flask, a THF solution of 2-chloro-4-iodoaniline (1.44 g, 5.68 mmol) (15 mL) was cooled to -78°C, and a 1M lithium bis(trimethylsilyl)amide THF solution (13.6 mL, 13.6 mmol) was added dropwise, and the mixture was stirred for 30 minutes. After stirring, the reaction mixture was added, and the mixture was stirred at room temperature for 20 hours. Water and 2M hydrochloric acid were added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the drying agent was filtered off, and the mixture was concentrated under reduced pressure to obtain the crude product (1.2 g) of the title compound. LCMS m / z: 438[M+H] + HPLC retention time: 0.91 min (analysis condition G)

[0263] Compound b12: 2-(2-chloro-4-iodoanilino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]methyl benzoate [ka] The title compound was synthesized from 2-(2-chloro-4-iodoanilino)-3,4-difluoro-5-formylbenzoic acid (compound b10) under the same conditions as in the preparation examples of compounds a1 and a2. LCMS m / z: 620[M+H] + HPLC retention time: 1.09 minutes (analysis condition G)

[0264] Compound b14: 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate methyl [ka] The title compound was synthesized from 2-(2-chloro-4-iodoanilino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]methyl benzoate (compound b12) under the same conditions as in the preparation examples of compounds a5 and a6. However, DIPEA was used instead of potassium carbonate as in the preparation example of compound a5. LCMS m / z: 548[M+H] + HPLC retention time: 0.89 minutes (analysis condition C)

[0265] Compound B-11: 2-(2-chloro-4-iodoanilino)-5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluorobenzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate methyl (compound b14) and the corresponding sulfamic acid 4-nitrophenyl under the same conditions as in the preparation examples of compounds A-1, b2, and a8. LCMS m / z: 652[M+H] + HPLC retention time: 1.67 minutes (analysis condition B)

[0266] Compound B-12: 2-(2-chloro-4-iodoanilino)-N-cyclopropyl-5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluorobenzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate methyl (compound b14) and the corresponding sulfamic acid 4-nitrophenyl under the same conditions as in the preparation examples of compounds A-1, b2, and a8. However, the corresponding amine was used instead of the 7M ammonia MeOH solution used in the preparation example of compound a8. LCMS m / z: 692[M+H] + HPLC retention time: 1.78 minutes (analysis condition B)

[0267] Compound B-13: 2-(2-chloro-4-iodoanilino)-5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-N-[(2-methylpropan-2-yl)oxy]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate methyl (compound b14) and the corresponding sulfamic acid 4-nitrophenyl under the same conditions as in the preparation examples of compounds A-1, b2, and a8. However, the corresponding amine was used instead of the 7M ammonia MeOH solution used in the preparation example of compound a8. LCMS m / z: 724[M+H] + HPLC retention time: 1.81 minutes (analysis condition B)

[0268] Compound B-14: N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methanesulfonamide)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound a6) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for compounds A-25, b2, and a12. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, in the preparation example for compound A-25; 1M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate, in the preparation example for compound b2; and the corresponding amine was used instead of tert-butoxyamine hydrochloride, in the preparation example for compound a12. LCMS m / z: 635[M+H] + HPLC retention time: 0.87 min (analysis condition C)

[0269] Compound B-15: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methanesulfonamide)pyridine-4-yl]methyl]-N-methoxybenzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound a6) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for compounds A-25, b2, and a12. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, in the preparation example for compound A-25; 1M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate, in the preparation example for compound b2; and the corresponding amine was used instead of tert-butoxyamine hydrochloride, in the preparation example for compound a12. LCMS m / z: 625[M+H] + HPLC retention time: 0.80 min (analysis condition C)

[0270] Compound B-16: 5-[[2-(ethylsulfonylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound a6) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for compounds A-25, b2, and a12. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, in the preparation example for compound A-25; 1M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate, in the preparation example for compound b2; and the corresponding amine was used instead of tert-butoxyamine hydrochloride, in the preparation example for compound a12. LCMS m / z: 639[M+H] + HPLC retention time: 0.83 minutes (analysis condition C)

[0271] Compound c1: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzamide [ka] 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-formylbenzoic acid (5.00 g, 11.9 mmol) was added to an anhydrous DMF solution (59 mL) with 4-methylbenzenesulfonyl hydrazide (2.21 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. 7 M ammonia MeOH solution (3.39 mL, 23.8 mmol) was added to the reaction mixture and stirred at room temperature for 30 minutes. The solid was then filtered off and washed with DMF (30 mL). Acetonitrile (90 mL) and 0.1 M hydrochloric acid (90 mL) were added to the filtrate, and the resulting solid was washed with an acetonitrile / water mixture to obtain the title compound (6.27 g, 90%) as a colorless solid. LCMS m / z: 589[M+H] + HPLC retention time: 0.90 minutes (analysis condition C)

[0272] Compound c2: [2-[(2,4-dimethoxyphenyl)methylamino]pyridine-4-yl]boronic acid [ka] The title compound was synthesized from 4-bromo-2-fluoropyridine under the same conditions as those used for the preparation of compounds a3 and a4. LCMS m / z: 289[M+H] + HPLC retention time: 0.38 min (analysis condition C)

[0273] Compound c4: 5-[(2-aminopyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzamide (compound c1) under the same conditions as in the preparation examples of compounds a5 and a6. However, instead of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridine-4-yl]boronic acid (compound c4) used in the preparation example of compound a5, [2-[(2,4-dimethoxyphenyl)methylamino]pyridine-4-yl]boronic acid (compound c2) was used. LCMS m / z: 649[M+H] + HPLC retention time: 0.71 min (analysis condition C)

[0274] Compound C-1: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[2-(Sulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-aminopyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound c4) and the corresponding sulfamoyl chloride under the same conditions as in the preparation example of compound A-1. LCMS m / z: 578[M+H] + HPLC retention time: 1.42 minutes (analysis condition B)

[0275] Compound C-2: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[2-(2-Methoxyethylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-aminopyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound c4) and the corresponding sulfamoyl chloride under the same conditions as in the preparation example of compound A-1. However, imidazole was used instead of pyridine. LCMS m / z: 636[M+H] + HPLC retention time: 1.10 minutes (Analysis conditions A)

[0276] Compound C-3: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-aminopyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound c4) and the corresponding sulfamoyl chloride under the same conditions as the preparation example for compound A-25. LCMS m / z: 592[M+H] + HPLC retention time: 1.08 minutes (Analysis conditions A)

[0277] Compound C-4: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-[[methyl-(methylamino)-oxo-λ6-sulfanylidene]amino]pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-aminopyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound c4) and the corresponding sulfamoyl chloride under the same conditions as in the preparation example of compound A-43. LCMS m / z: 590[M+H] + HPLC retention time: 0.92 minutes (Analysis conditions A)

[0278] Compound c5: 5-Ethenyl-3,4-difluoro-2-(4-iodo-2-methylanilino)benzoic acid [ka] A 1.8 ml solution of 4-iodo-2-methylaniline (636 mg, 2.73 mmol) in anhydrous THF was cooled to -78°C, and a 5.08 mL solution of 1.3 M lithium bis(trimethylsilyl)amide THF (6.60 mmol) was added over 1 hour, followed by stirring for 1 hour. Next, a 3.9 mL solution of 2,3,4-trifluoro-5-vinylbenzoic acid (460 mg, 2.28 mmol) in anhydrous THF was added, and the mixture was stirred at 0°C for 2 hours. Water and 2 M hydrochloric acid were added to the reaction mixture, and it was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered off the drying agent, and concentrated under reduced pressure. The resulting residue was suspended and washed with DCM to obtain the title compound (631 mg, 67%) as a brown solid. LCMS m / z: 416[M+H] + HPLC retention time: 0.99 minutes (analysis condition E)

[0279] Compound c6: 3,4-Difluoro-5-formyl-2-(4-iodo-2-methylanilino)benzoic acid [ka] To a 6.3 mL solution of 5-ethenyl-3,4-difluoro-2-(4-iodo-2-methylanilino)benzoic acid (compound c5, 626 mg, 1.51 mmol) in anhydrous THF, 3.02 mL of 1 M aqueous sodium bicarbonate, 1.29 g of sodium periodate, and osmium(VIII) oxide, microencapsulated (38.3 mg, 0.015 mmol) were added, and the mixture was stirred at room temperature for 6 hours. Ethyl acetate was added to the reaction mixture, and it was washed with 1 M hydrochloric acid and 0.2 M aqueous sodium thiosulfate. The organic layer was dried over anhydrous sodium sulfate, the drying agent was filtered off, and the mixture was concentrated under reduced pressure. The resulting residue was suspended and washed with ethyl acetate / hexane (1 / 25, 42 mL), and the solid was filtered off. The obtained solid was washed with hexane to obtain the title compound (558 mg, 89%) as a colorless solid. LCMS m / z: 418[M+H] + HPLC retention time: 0.86 minutes (analysis condition C)

[0280] Compound C-5: 3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-2-(4-iodo-2-methylanilino)benzamide [ka] The title compound was synthesized from 3,4-difluoro-5-formyl-2-(4-iodo-2-methylanilino)benzoic acid (compound c6) under the same conditions as the preparation examples for compounds c1, a5, a6, and A-1. LCMS m / z: 606[M+H] + HPLC retention time: 1.20 minutes (Analysis conditions A)

[0281] Compound C-6: N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-(methylsulfamoylamino)phenyl]methyl]benzamide [ka] The title compound was synthesized from 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-formylbenzoic acid under the same conditions as in the preparation examples of compound a2, compound a10, compound a5, and compound A-1. LCMS m / z: 631[M+H] + HPLC retention time: 1.70 minutes (analysis condition B)

[0282] Compound d1: 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate [ka] The title compound was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]methyl benzoate (compound a2) under the same conditions as in the preparation example of compound a5. However, (3-amino-2-fluorophenyl)boronic acid salt was used instead of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridine-4-yl]boronic acid (compound a4). LCMS m / z: 531[M+H] + HPLC retention time: 0.96 minutes (analysis condition D)

[0283] Compound d2: 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) under the same conditions as in the preparation example of compound a7. LCMS m / z: 517[M+H] + HPLC retention time: 0.95 minutes (analysis condition C)

[0284] Compound D-1: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[2-Fluoro-3-(2-methoxyethylsulfamoylamino)phenyl]methyl]benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid (compound d2) under the same conditions as in the preparation examples of compound a8 and compound A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 653[M+H] + HPLC retention time: 1.24 minutes (Analysis conditions A)

[0285] Compound D-2: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[2-Fluoro-3-[(1-Methoxy-2-methylpropan-2-yl)sulfamoylamino]phenyl]methyl]benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid (compound d2) under the same conditions as in the preparation examples of compound a8 and compound A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 681[M+H] + HPLC retention time: 1.35 minutes (Analysis conditions A)

[0286] Compound D-3: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[2-Fluoro-3-[[(2R)-Oxolan-2-yl]methylsulfamoylamino]phenyl]methyl]benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid (compound d2) under the same conditions as in the preparation examples of compound a8 and compound A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 679[M+H] + HPLC retention time: 1.27 minutes (Analysis conditions A)

[0287] Compound D-4: 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid (compound d2) under the same conditions as in the preparation examples of compound a8 and compound A-25. However, the corresponding sulfonyl chloride was used instead of the methylsulfamoyl chloride used in the preparation example of compound A-25. In addition, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 608[M+H] + HPLC retention time: 1.26 minutes (analysis condition A)

[0288] Compound D-5: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(2-methoxyethylsulfonylamino)phenyl]methyl]benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid (compound d2) under the same conditions as in the preparation examples of compound a8 and compound A-25. However, the corresponding sulfonyl chloride was used instead of the methylsulfamoyl chloride used in the preparation example of compound A-25. In addition, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 638[M+H] + HPLC retention time: 1.67 minutes (analysis condition B)

[0289] Compound D-6: N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid (compound d2) and the corresponding amine under the same conditions as in the preparation examples of compound a8 and compound A-1. LCMS m / z: 649[M+H] + HPLC retention time: 1.71 minutes (analysis condition B)

[0290] Compound D-7: N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(sulfamoylamino)phenyl]methyl]benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid (compound d2) and the corresponding amine under the same conditions as in the preparation examples of compound a8 and compound A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 635[M+H] + HPLC retention time: 1.65 minutes (analysis condition B)

[0291] Compound D-8: N-Cyclopropyl-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid (compound d2) and the corresponding amine under the same conditions as in the preparation examples of compound a8 and compound A-25. However, the corresponding sulfonyl chloride was used instead of the methylsulfamoyl chloride used in the preparation example of compound A-25. In addition, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 648[M+H] + HPLC retention time: 1.77 minutes (analysis condition B)

[0292] Compound D-9: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[2-Fluoro-3-[(1-methylcyclobutyl)sulfamoylamino]phenyl]methyl]benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid (compound d2) under the same conditions as in the preparation examples of compound a8 and compound A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 663[M+H] + HPLC retention time: 0.95 minutes (analysis condition C)

[0293] Compound D-10: N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclobutyl)sulfamoylamino]phenyl]methyl]benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid (compound d2) and the corresponding amine under the same conditions as in the preparation examples of compound a8 and compound A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 703[M+H] + HPLC retention time: 1.01 min (analysis condition C)

[0294] Compound D-11: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]-N-methoxybenzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid (compound d2) and the corresponding amine under the same conditions as in the preparation examples of compound a8 and compound A-1. However, triethylamine was used instead of DIPEA, which was used in the preparation example of compound a8. LCMS m / z: 639[M+H] + HPLC retention time: 1.62 minutes (analysis condition B)

[0295] Compound D-12: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(sulfamoylamino)phenyl]methyl]-N-methoxybenzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid (compound d2) and the corresponding amine under the same conditions as in the preparation examples of compound a8 and compound A-1. However, triethylamine was used instead of DIPEA, which was used in the preparation example of compound a8, and the corresponding sulfamic acid 4-nitrophenyl was used instead of methylsulfamic acid 4-nitrophenyl, which was used in the preparation example of compound A-1. LCMS m / z: 625[M+H] + HPLC retention time: 0.81 min (analysis condition C)

[0296] Compound D-13: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[2-Fluoro-3-[(1-methylcyclobutyl)sulfamoylamino]phenyl]methyl]-N-methoxybenzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid (compound d2) and the corresponding amine under the same conditions as in the preparation examples of compound a8 and compound A-1. However, triethylamine was used instead of DIPEA, which was used in the preparation example of compound a8, and the corresponding sulfamic acid 4-nitrophenyl was used instead of methylsulfamic acid 4-nitrophenyl, which was used in the preparation example of compound A-1. LCMS m / z: 693[M+H] + HPLC retention time: 0.95 minutes (analysis condition C)

[0297] Compound D-14: 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) under the same conditions as in the preparation examples for compounds a9, a7, a8, and A-25. However, a 1M aqueous sodium hydroxide solution was used instead of the lithium hydroxide monohydrate used in the preparation example for compound a7. LCMS m / z: 523[M+H] + HPLC retention time: 1.58 minutes (analysis condition B)

[0298] Compound D-15: N-Cyclopropyl-2-(4-Cyclopropyl-2-Fluoroanilino)-3,4-Difluoro-5-[[2-Fluoro-3-(Methylsulfamoylamino)phenyl]methyl]benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) under the same conditions as in the preparation examples for compounds a9, a7, a8, and A-25. However, a 1M aqueous sodium hydroxide solution was used instead of the lithium hydroxide monohydrate used in the preparation example for compound a7, and the corresponding amine was used instead of the 7M ammonia MeOH solution used in the preparation example for compound a8. LCMS m / z: 563[M+H] + HPLC retention time: 1.68 minutes (analysis condition B)

[0299] Compound D-16: 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]-N-methoxybenzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) under the same conditions as in the preparation examples for compounds a9, a7, a8, and A-25. However, a 1M aqueous sodium hydroxide solution was used instead of the lithium hydroxide monohydrate used in the preparation example for compound a7, and the corresponding amine was used instead of the 7M ammonia MeOH solution used in the preparation example for compound a8. LCMS m / z: 551[MH] - HPLC retention time: 0.85 minutes (analysis condition C)

[0300] Compound E-1: 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for compounds A-25, b2, and a12. However, pyridine was used as the solvent in the sulfonamidation step. In addition, the corresponding amine was used instead of tert-butoxyamine hydrochloride, which was used in the preparation example for compound a12. LCMS m / z: 638[M+H] + HPLC retention time: 1.68 minutes (analysis condition B)

[0301] Compound E-2: 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-[(2-methylpropan-2-yl)oxy]benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of compounds A-25, b2, and a12. However, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 680[M+H] + HPLC retention time: 1.80 minutes (Analysis condition B)

[0302] Compound E-3: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[[1-(methoxymethyl)cyclopropyl]sulfonylamino]phenyl]methyl]-N-methoxybenzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for compounds A-25, b2, and a12. However, pyridine was used as the solvent in the sulfonamidation step. In addition, the corresponding amine was used instead of tert-butoxyamine hydrochloride, which was used in the preparation example for compound a12. LCMS m / z: 694[M+H] + HPLC retention time: 1.74 minutes (analysis condition B)

[0303] Compound E-4: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[[1-(methoxymethyl)cyclopropyl]sulfonylamino]phenyl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of compounds A-25, b2, and a12. However, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 736[M+H]+ HPLC retention time: 1.87 minutes (analysis condition B)

[0304] Compound E-5: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclopropyl)sulfonylamino]phenyl]methyl]-N-methoxybenzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for compounds A-25, b2, and a12. However, pyridine was used as the solvent in the sulfonamidation step. In addition, the corresponding amine was used instead of tert-butoxyamine hydrochloride, which was used in the preparation example for compound a12. LCMS m / z: 664[M+H] + HPLC retention time: 1.73 minutes (analysis condition B)

[0305] Compound E-6: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclopropyl)sulfonylamino]phenyl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of compounds A-25, b2, and a12. However, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 706[M+H] + HPLC retention time: 1.86 minutes (analysis condition B)

[0306] Compound E-7: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) under the same conditions as in the preparation examples for compounds A-25, b2, and a12. However, pyridine was used as the solvent in the sulfamidation step. In addition, the corresponding amine was used instead of tert-butoxyamine hydrochloride, which was used in the preparation example for compound a12. LCMS m / z: 609[M+H] + HPLC retention time: 1.23 minutes (analysis condition A)

[0307] Compound e11: tert-butyl N-[[3-[[5-carbamoyl-2,3-difluoro-4-(2-fluoro-4-iodoanilino)phenyl]methyl]-2-fluorophenyl]sulfamoyl]carbamate [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) and the corresponding sulfamoyl chloride under the same conditions as in the preparation examples for compounds A-25, b2, and a12. However, pyridine was used as the solvent in the sulfamidation step. In addition, the corresponding amine was used instead of tert-butoxyamine hydrochloride, which was used in the preparation example for compound a12. LCMS m / z: 695[M+H] + HPLC retention time: 0.74 minutes (analysis condition D)

[0308] Compound E-8: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(sulfamoylamino)phenyl]methyl]benzamide [ka] The title compound was synthesized from tert-butyl N-[[3-[[5-carbamoyl-2,3-difluoro-4-(2-fluoro-4-iodoanilino)phenyl]methyl]-2-fluorophenyl]sulfamoyl]carbamate (compound e11) under the same conditions as in the preparation example of compound b9. LCMS m / z: 595[M+H]+ HPLC retention time: 1.17 minutes (Analysis conditions A)

[0309] Compound E-9: 2-(2-chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-methoxybenzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate methyl (compound b14) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for compounds A-25, b2, and a12. However, pyridine was used as the solvent in the sulfonamidation step. In addition, the corresponding amine was used instead of tert-butoxyamine hydrochloride, which was used in the preparation example for compound a12. LCMS m / z: 654[M+H] + HPLC retention time: 1.75 minutes (analysis condition B)

[0310] Compound E-10: 2-(2-chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-[(2-methylpropan-2-yl)oxy]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate methyl (compound b14) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for compounds A-25, b2, and a12. However, pyridine was used as the solvent in the sulfonamidation step. In addition, the corresponding amine was used instead of tert-butoxyamine hydrochloride, which was used in the preparation example for compound a12. LCMS m / z: 696[M+H] + HPLC retention time: 1.87 minutes (analysis condition B)

[0311] Compound E-11: 2-(2-chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluorobenzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate methyl (compound b14) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for compounds A-25, b2, and a12. However, pyridine was used as the solvent in the sulfonamidation step. In addition, the corresponding amine was used instead of tert-butoxyamine hydrochloride, which was used in the preparation example for compound a12. LCMS m / z: 624[M+H] + HPLC retention time: 1.73 minutes (analysis condition B)

[0312] Compound e17: 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate methyl [ka] The title compound was synthesized from 2-(2-chloro-4-iodoanilino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]methyl benzoate (compound b12) under the same conditions as in the preparation example of compound a5. However, (3-amino-2-fluorophenyl)boronic acid salt was used instead of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridine-4-yl]boronic acid (compound a4), and DIPEA was used instead of potassium carbonate. LCMS m / z: 547[M+H] + HPLC retention time: 1.13 minutes (analysis condition C)

[0313] Compound E-12: 2-(2-chloro-4-iodoanilino)-5-[[3-(cyclopropylsulfamoylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-[(2-methylpropan-2-yl)oxy]benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate methyl (compound e17) and the corresponding sulfamic acid 4-nitrophenyl under the same conditions as in the preparation examples of compounds A-1, b2, and a12. LCMS m / z: 723[M+H] + HPLC retention time: 1.87 minutes (analysis condition B)

[0314] Compound e20: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]methyl benzoate [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl 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 retention time: 1.01 min (analysis condition C)

[0315] Compound E-13: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide [ka] A mixture of 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]methyl benzoate (compound e20, 23.0 mg, 0.038 mmol) in THF (0.7 mL) and water (0.3 mL) was mixed with lithium hydroxide monohydrate (7.9 mg, 0.19 mmol) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, 1 M hydrochloric acid (0.76 mL) was added, and the mixture was further concentrated under reduced pressure. To a solution of the resulting mixture in anhydrous DMF (0.3 mL), HOOBt (9.3 mg, 0.057 mmol) and EDC·HCl (10.9 mg, 0.057 mmol) were added and stirred at room temperature for 3 hours. Then, a solution of 7 M ammonia MeOH (22 μL, 0.15 mmol) was added at 0°C and stirred for 30 minutes. 1 mL of 10% trifluoroacetic acid aqueous solution was added to the reaction mixture, and the mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to obtain the title compound (19.7 mg, 97%) as a colorless solid. LCMS m / z: 594[M+H] + HPLC retention time: 1.61 minutes (analysis condition B)

[0316] Compound E-14: 5-[[3-(cyclopropylmethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of compounds A-25 and E-13. However, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 634[M+H] + HPLC retention time: 1.72 minutes (analysis condition B)

[0317] Compound E-15: 3,4-difluoro-5-[[2-fluoro-3-(3-fluoropropylsulfonylamino)phenyl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for compounds A-25 and E-13. However, anhydrous DCM was used instead of anhydrous DMA, which was used in the preparation example for compound A-25. LCMS m / z: 640[M+H] + HPLC retention time: 1.67 minutes (analysis condition B)

[0318] Compound E-16: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclopropyl)sulfonylamino]phenyl]methyl]benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of compounds A-25 and E-13. However, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 634[M+H] + HPLC retention time: 1.72 minutes (analysis condition B)

[0319] Compound E-17: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(2-methylpropylsulfonylamino)phenyl]methyl]benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of compounds A-25 and E-13. However, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 636[M+H] + HPLC retention time: 1.77 minutes (analysis condition B)

[0320] Compound E-18: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(propylsulfonylamino)phenyl]methyl]benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of compounds A-25 and E-13. However, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 622[M+H] + HPLC retention time: 1.72 minutes (analysis condition B)

[0321] Compound E-19: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[2-Fluoro-3-[[1-(Methoxymethyl)cyclopropyl]sulfonylamino]phenyl]methyl]benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of compounds A-25 and E-13. However, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 664[M+H] + HPLC retention time: 1.73 minutes (analysis condition B)

[0322] Compound E-20: 5-[[3-(cyclobutylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of compounds A-25 and E-13. However, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 634[M+H] + HPLC retention time: 1.73 minutes (analysis condition B)

[0323] Compound E-21: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxetane-3-ylsulfonylamino)phenyl]methyl]benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of compounds A-25 and E-13. However, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 636[M+H] + HPLC retention time: 1.61 minutes (analysis condition B)

[0324] Compound E-22: 5-[[3-(cyclopropylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of compounds A-25 and E-13. However, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 620[M+H] + HPLC retention time: 1.68 minutes (analysis condition B)

[0325] Compound E-23: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxan-4-ylsulfonylamino)phenyl]methyl]benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for compounds A-25 and E-13. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, as used in the preparation example for compound A-25. LCMS m / z: 664[M+H] + HPLC retention time: 1.65 minutes (analysis condition B)

[0326] Compound E-24: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(propan-2-ylsulfonylamino)phenyl]methyl]benzamide [ka] The title compound was synthesized from 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of compounds A-25 and E-13. However, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 622[M+H] + HPLC retention time: 1.71 minutes (analysis condition B)

[0327] Compound E-25: N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide [ka] The title compound was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]methyl benzoate (compound e20) under the same conditions as in the preparation examples of compounds b2 and a12. However, the corresponding amine was used instead of tert-butoxyamine hydrochloride, which was used in the preparation example of compound a12. LCMS m / z: 634[M+H] + HPLC retention time: 0.92 minutes (analysis condition C)

[0328] Compound E-26: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]-N-methoxybenzamide [ka] The title compound was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]methyl benzoate (compound e20) under the same conditions as in the preparation examples of compounds b2 and a12. However, the corresponding amine was used instead of tert-butoxyamine hydrochloride, which was used in the preparation example of compound a12. LCMS m / z: 624[M+H] + HPLC retention time: 0.86 minutes (analysis condition C)

[0329] Compound F-1: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-(methylsulfamoylamino)phenyl]methyl]benzamide [ka] The title compound was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzamide (compound c1) under the same conditions as in the preparation examples of compound a5 and compound A-25. However, 3-aminophenylboronic acid was used instead of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridine-4-yl]boronic acid (compound a4) used in the preparation example of compound a5. LCMS m / z: 591[M+H] + HPLC retention time: 0.84 minutes (analysis condition C)

[0330] Compound F-2: 5-[[3-(ethylsulfonylamino)phenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzamide (compound c1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of compound a5 and compound A-25. However, 3-aminophenylboronic acid was used instead of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridine-4-yl]boronic acid (compound a4) used in the preparation example of compound a5. In addition, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 590[M+H] + HPLC retention time: 1.26 minutes (analysis condition A)

[0331] Compound F-3: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-(2-Methoxyethylsulfonylamino)phenyl]methyl]benzamide [ka] The title compound was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzamide (compound c1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of compound a5 and compound A-25. However, 3-aminophenylboronic acid was used instead of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridine-4-yl]boronic acid (compound a4) used in the preparation example of compound a5. In addition, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 620[M+H] + HPLC retention time: 1.65 minutes (analysis condition B)

[0332] Compound g2: 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzoic acid [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (compound a7) under the same conditions as the preparation examples for compound a9 and compound A-1. LCMS m / z: 525[M+H] + HPLC retention time: 0.83 minutes (analysis condition C)

[0333] Compound G-1: N-Cyclopropyl-2-(4-Cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzoic acid (compound g2) under the same conditions as in the preparation example of compound a10. LCMS m / z: 564[M+H] + HPLC retention time: 1.61 minutes (analysis condition B)

[0334] Compound G-2: 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-methoxybenzamide [ka] To a 0.2 mL solution of anhydrous DMF containing 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzoic acid (compound g2, 20 mg, 0.038 mmol), O-methylhydroxyamine hydrochloride (6.4 mg, 0.076 mmol), propylphosphonic anhydride (cyclic trimer) (56 μL, 0.095 mmol), and triethylamine (27 μL, 0.19 mmol) were added, and the mixture was stirred at room temperature for 16 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 the title compound (14 mg, 66%) as a colorless solid. LCMS m / z: 554[M+H] + HPLC retention time: 1.53 minutes (analysis condition B)

[0335] Compound G-3: 2-(4-bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-methoxybenzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (compound a7) under the same conditions as the preparation examples for compounds a21, A-1, and G-2. LCMS m / z: 592[M+H] + HPLC retention time: 1.52 minutes (analysis condition B)

[0336] Compound G-4: 2-(4-chloro-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-methoxybenzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (compound a7) under the same conditions as in the preparation examples for compounds a21, A-1, and G-2. However, copper(I) chloride was used instead of copper(I) bromide as used in the preparation example for compound a21. LCMS m / z: 548[M+H] + HPLC retention time: 1.50 minutes (analysis condition B)

[0337] Compound G-5: N-Cyclopropyl-2-(4-Cyclopropyl-2-Fluoroanilino)-3,4-Difluoro-5-[[3-Fluoro-2-[(1-Methylcyclobutyl)Sulfamoylamino]Pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound a6) under the same conditions as in the preparation examples of compounds a9, a7, a12, and A-1. However, a 1M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate used in the preparation example of compound a7, and triethylamine was used instead of DIPEA used in the preparation example of compound a12. In addition, the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the preparation example of compound a12, and the corresponding sulfamic acid 4-nitrophenyl was used instead of methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 618[M+H] + HPLC retention time: 0.95 minutes (analysis condition C)

[0338] Compound G-6: 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridine-4-yl]methyl]-N-methoxybenzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound a6) under the same conditions as in the preparation examples of compounds a9, a7, a12, and A-1. However, a 1M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate used in the preparation example of compound a7, and triethylamine was used instead of DIPEA used in the preparation example of compound a12. In addition, the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the preparation example of compound a12, and the corresponding sulfamic acid 4-nitrophenyl was used instead of methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 608[M+H] + HPLC retention time: 0.90 minutes (analysis condition C)

[0339] Compound G-7: N-Cyclopropyl-2-(4-Cyclopropyl-2-Fluoroanilino)-5-[[2-(Ethylsulfonylamino)-3-Fluoropyridine-4-yl]methyl]-3,4-Difluorobenzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound a6) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for compounds A-25, a9, a7, and a12. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, in the preparation example for compound A-25, and a 1M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate, respectively, in the preparation example for compound a7. In addition, the corresponding amine was used instead of tert-butoxyamine hydrochloride, which was used in the preparation example for compound a12. LCMS m / z: 563[M+H] + HPLC retention time: 0.88 min (analysis condition C)

[0340] Compound G-8: 2-(4-cyclopropyl-2-fluoroanilino)-5-[[2-(ethylsulfonylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-N-methoxybenzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound a6) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for compounds A-25, a9, a7, and a12. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, in the preparation example for compound A-25, and a 1M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate, respectively, in the preparation example for compound a7. In addition, the corresponding amine was used instead of tert-butoxyamine hydrochloride, which was used in the preparation example for compound a12. LCMS m / z: 553[M+H] + HPLC retention time: 0.82 minutes (analysis condition C)

[0341] Compound G-9: 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methanesulfonamide)pyridine-4-yl]methyl]-N-methoxybenzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound a6) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for compounds A-25, a9, a7, and a12. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, in the preparation example for compound A-25, and a 1M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate, respectively, in the preparation example for compound a7. In addition, the corresponding amine was used instead of tert-butoxyamine hydrochloride, which was used in the preparation example for compound a12. LCMS m / z: 539[M+H] + HPLC retention time: 0.79 min (analysis condition C)

[0342] Compound h1: 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-[4-[3-(2-ethylhexaoxy)-3-oxopropyl]sulfanyl-2-fluoroanilino]-3,4-difluorobenzoate methyl [ka] A 1,4-dioxane suspension (17 mL) containing 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)methyl benzoate (compound a6, 500 mg, 0.941 mmol), 2-ethylhexyl 3-mercaptopropionate (226 mg, 1.04 mmol), Xantphos (109 mg, 0.188 mmol), tris(dibenzylideneacetone)dipalladium (0) (86 mg, 0.094 mmol), and DIPEA (0.492 mL, 2.82 mmol) was stirred at 110°C for 1 hour. Acetonitrile was added to the reaction mixture, filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained 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 retention time: 1.14 minutes (analysis condition G)

[0343] Compound h2: 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluorobenzoate methyl [ka] A methanol solution (9 mL) of 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-[4-[3-(2-ethylhexaoxy)-3-oxopropyl]sulfanyl-2-fluoroanilino]-3,4-difluorobenzoate methyl (compound h1, 584 mg, 0.939 mmol) was cooled to 0°C, and a 25% sodium methoxide methanol solution (1.29 mL, 5.64 mmol) was added. The mixture was stirred at room temperature for 3 hours. Then, at 0°C, diethyl (bromodifluoromethyl)phosphonate (1.00 g, 3.76 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0°C, and a 25% sodium methoxide methanol solution (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 cooled to 0°C, formic acid (0.213 mL, 5.64 mmol) was added, and the mixture was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% aqueous formic acid solution / 0.1% formic acid acetonitrile solution) to obtain the title compound (195 mg, 43%) as a colorless solid. LCMS m / z: 488[M+H] + HPLC retention time: 0.81 min (analysis condition G)

[0344] Compound h3: 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluorobenzamide [ka] A mixture of 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluorobenzoate methyl (compound h2, 60.0 mg, 0.123 mmol) and 7 M ammonia MeOH solution (1.80 mL, 12.6 mmol) was stirred in a sealed tube at 85°C for 6 hours using a microwave reactor. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.05% trifluoroacetic acid aqueous solution / 0.05% trifluoroacetic acid acetonitrile solution) to obtain the title compound (53.2 g, 91%) as a yellow oily substance. LCMS m / z: 473[M+H] + HPLC retention time: 0.63 minutes (analysis condition C)

[0345] Compound H-1: 2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-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 retention time: 1.49 minutes (analysis condition B)

[0346] Compound H4: 2-(1-benzothiophen-5-ylamino)-3,4-difluoro-5-formylbenzoic acid [ka] A 30 mL solution of 2,2,6,6-tetramethylpiperidine (2.53 g, 17.9 mmol) in anhydrous THF was cooled to -78°C, and under a nitrogen atmosphere, a 1.6 M n-butyllithium hexane solution (11.2 mL, 17.9 mmol) was added and the mixture was stirred for 5 minutes. The reaction mixture was added to a 9.0 mL solution of 2,3,4-trifluorobenzoic acid (1.50 g, 8.52 mmol) in THF at -78°C and stirred for 10 minutes, then anhydrous DMF (0.759 mL, 9.80 mmol) was added and the mixture was stirred at 0°C for 2 hours. In a separate flask, a THF solution (30 mL) of benzo[b]thiophenone-5-amine (1.65 g, 11.1 mmol) was cooled to -78°C, and the 1.3 M lithium bis(trimethylsilyl)amide THF solution (15.1 mL, 19.6 mmol) and the previously prepared reaction mixture were added. The mixture was stirred at room temperature for 24 hours. 2 M hydrochloric acid was added to the reaction mixture and stirred for 24 hours. After adding water and 2 M hydrochloric acid, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered off 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 obtain the title compound (609 mg, 21%) as a gray solid. LCMS m / z: 334[M+H] + HPLC retention time: 0.80 min (analysis condition C)

[0347] Compound h5: 2-(1-benzothiophen-5-ylamino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzamide [ka] 2-(1-benzothiophen-5-ylamino)-3,4-difluoro-5-formylbenzoic acid (compound h4, 608 mg, 1.82 mmol) was added to an anhydrous DMF suspension (9.1 mL) with HOOBt (595 mg, 3.65 mmol) and EDC·HCl (699 mg, 3.65 mmol), and the mixture was stirred at room temperature for 1.5 hours. Then, 7 M ammonia MeOH solution (0.912 mL, 6.38 mmol) was added at 0°C, and the mixture was stirred for 30 minutes. Finally, 4-methylbenzenesulfonyl hydrazide (340 mg, 1.82 mmol) was added at 0°C, and the mixture was stirred at room temperature for 16 hours. After filtering the reaction mixture, acetonitrile (14 mL) and 0.1 M hydrochloric acid (100 mL) were added to the filtrate. After filtering the solid, it was washed with water to obtain the title compound (412 mg, 45%) as a light brown solid. LCMS m / z: 501[M+H] + HPLC retention time: 0.83 minutes (analysis condition C)

[0348] Compound h7: 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(1-benzothiophen-5-ylamino)-3,4-difluorobenzamide [ka] The title compound was synthesized from 2-(1-benzothiophen-5-ylamino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzamide (compound h5) under the same conditions as the preparation examples for compounds a5 and a6. LCMS m / z: 429[M+H] + HPLC retention time: 0.57 min (analysis condition C)

[0349] Compound H-2: 2-(1-benzothiophen-5-ylamino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(1-benzothiophen-5-ylamino)-3,4-difluorobenzamide (compound h7) under the same conditions as in the preparation example of compound A-1. LCMS m / z: 522[M+H] + HPLC retention time: 1.06 minutes (Analysis conditions A)

[0350] Compound h8: 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]benzamide [ka] A 0.3 mL solution of anhydrous acetonitrile containing 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(1-benzothiophen-5-ylamino)-3,4-difluorobenzamide (compound h7, 22 mg, 0.051 mmol) was cooled to 0°C, and N-fluoro-N'-(chloromethyl)triethylenediaminebis(tetrafluoroborate) (9.5 mg, 0.027 mmol) was added and the mixture was stirred for 2.5 hours. Then, N-fluoro-N'-(chloromethyl)triethylenediaminebis(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 (8.0 mg, 35%) as a brown solid. LCMS m / z: 447[M+H] + HPLC retention time: 0.61 min (analysis condition C)

[0351] Compound H-3: 3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-3,4-difluoro-2-[(4-fluoro-1-benzothiophen-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 retention time: 1.10 minutes (Analysis conditions A)

[0352] Compound h9: 1,2,3-Trifluoro-4-[(4-Methoxyphenyl)methoxy]benzene [ka] Potassium carbonate (9.90 g, 71.6 mmol) and 4-methoxybenzyl chloride (5.55 mL, 40.9 mmol) were added to a 101 mL solution of 2,3,4-trifluorophenol (5.05 g, 34.1 mmol) in anhydrous acetone, and the mixture was stirred at 70°C for 8 hours. Water (150 mL) was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the drying agent was filtered off, and the mixture was concentrated under reduced pressure. DMSO (15 mL) and water (100 mL) were added to the resulting residue, and the resulting solid was washed to obtain the title compound (8.72 g, 95%) as a gray solid. LCMS m / z: 267[MH] - HPLC retention time: 0.92 minutes (analysis condition C)

[0353] Compound h10: 2,3,4-Trifluoro-5-[(4-Methoxyphenyl)methoxy]benzoic acid [ka] A 15 mL solution of 2,2,6,6-tetramethylpiperidine (4.15 mL, 24.6 mmol) in anhydrous THF was cooled to -78°C, and under a nitrogen atmosphere, a 15.4 mL solution of 1.6 M lithium bis(trimethylsilyl)amidehexane (24.6 mmol) was added and the mixture was stirred for 10 minutes. The reaction mixture was added to a 15 mL solution of 1,2,3-trifluoro-4-[(4-methoxyphenyl)methoxy]benzene (compound h9, 3.00 g, 11.2 mmol) in anhydrous THF at -78°C and stirred for 3 hours, then stirred for 30 minutes while injecting carbon dioxide gas. 1 M hydrochloric acid (60 mL) was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered off 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 obtain the title compound (1.32 g, 34%) as a gray solid. LCMS m / z: 311[MH] - HPLC retention time: 0.80 min (analysis condition C)

[0354] Compound h13: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-hydroxybenzoate methyl [ka] The title compound was synthesized from 2,3,4-trifluoro-5-[(4-methoxyphenyl)methoxy]benzoic acid (compound h10) under the same conditions as in the preparation examples for compounds c5, a1, and a6. However, 2-fluoro-4-iodoaniline was used instead of 4-iodo-2-methylaniline used in the preparation example for compound c5, and anhydrous THF was used instead of toluene used in the preparation example for compound a1. LCMS m / z: 424[M+H] + HPLC retention time: 0.91 min (analysis condition C)

[0355] Compound h14: 5-[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridine-4-yl]oxy-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate [ka] To a 15 mL DCM solution (3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-hydroxybenzoate methyl (compound h13, 375 mg, 0.886 mmol), [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridine-4-yl]boronic acid (compound a4, 814 mg, 2.66 mmol), molecular sieves 4A (375 mg), tetrakis(acetonitrile)copper(I) hexafluorophosphate (495 mg, 1.33 mmol), and pyridine (0.287 mL, 3.55 mmol) were added, and the mixture was stirred at room temperature for 2.5 hours. Then, [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridine-4-yl]boronic acid (compound a4, 231 mg, 0.753 mmol) was added, and the mixture was stirred for 4 hours. N-acetylcysteine ​​(434 mg, 2.66 mmol) was added to the reaction mixture and stirred for 3 hours. The solid was 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 foamy substance. LCMS m / z: 684[M+H] + HPLC retention time: 1.07 minutes (analysis condition C)

[0356] Compound H-4: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]oxybenzamide [ka] The title compound was synthesized from 5-[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridine-4-yl]oxy-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound h14) under the same conditions as the preparation examples of compound a6, compound E-13, and compound A-1. LCMS m / z: 612[M+H] + HPLC retention time: 1.55 minutes (analysis condition B)

[0357] Compound h17: 5-[[6-[bis[(4-methoxyphenyl)methyl]amino]pyridine-2-yl]-hydroxymethyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid [ka] A 12 mL solution of 6-bromo-N,N-bis(4-methoxybenzyl)pyridine-2-amine (1.22 g, 2.95 mmol) in anhydrous THF was cooled to -40°C, and under a nitrogen atmosphere, a 1.85 mL solution of 1.6 M lithium bis(trimethylsilyl)amide in THF (2.95 mmol) was added and the mixture was stirred for 30 minutes. The reaction mixture was added to a 2.4 mL solution of 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-formylbenzoic acid (414 mg, 0.984 mmol) in anhydrous THF (2.4 mL) at -78°C and stirred for 20 minutes. A 2 mL solution of 1 M hydrochloric acid was added to the reaction mixture and the mixture was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (10 mM aqueous ammonium acetate / methanol) to obtain the title compound (192 mg, 26%) as a yellow solid. LCMS m / z: 756[M+H] + HPLC retention time: 1.06 minutes (analysis condition E)

[0358] Compound h18: 5-[(6-aminopyridine-2-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid [ka] To a DCM solution (0.8 mL) of 5-[[6-[bis[(4-methoxyphenyl)methyl]amino]pyridine-2-yl]-hydroxymethyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid (compound h17, 130 mg, 0.162 mmol), triethylsilane (0.129 mL, 0.810 mmol), trifluoroacetic acid (0.520 mL, 6.75 mmol), and trifluoromethanesulfonic acid (14 μL, 0.162 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Then, more triethylsilane (0.129 mL, 0.810 mmol) and trifluoromethanesulfonic acid (14 μL, 0.162 mmol) were added, and the mixture was stirred at room temperature for 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 the title compound (72.7 mg, 90%) as a pink solid. LCMS m / z: 500[M+H] + HPLC retention time: 0.61 min (analysis condition C)

[0359] Compound H-5: 3,4-Difluoro-2-(2-Fluoro-4-iodoanilino)-5-[[6-(methylsulfamoylamino)pyridine-2-yl]methyl]benzamide [ka] The title compound was synthesized from 5-[(6-aminopyridine-2-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid (compound h18) under the same conditions as the preparation examples of compound a8 and compound A-1. LCMS m / z: 592[M+H] + HPLC retention time: 1.19 minutes (analysis condition A)

[0360] Compound I-1: 4-Fluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 2,4-difluoro-5-vinylbenzoic acid under the same conditions as in the preparation examples for compounds c5, c6, c1, a5, a6, and A-1. However, 2-fluoro-4-iodoaniline was used instead of 4-iodo-2-methylaniline, which was used in the preparation example for compound c5. LCMS m / z: 592[M+H] + HPLC retention time: 1.17 minutes (Analysis conditions A)

[0361] Compound I-2: 5-[[2-(ethylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-4-fluoro-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 2,4-difluoro-5-vinylbenzoic acid under the same conditions as in the preparation examples for 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 preparation example for compound c5, and the corresponding sulfamic acid 4-nitrophenyl was used instead of methylsulfamic acid 4-nitrophenyl used in the preparation example for compound A-1. LCMS m / z: 606[M+H] + HPLC retention time: 1.62 minutes (analysis condition B)

[0362] Compound I-3: 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-4-fluoro-2-(2-fluoro-4-iodoanilino)benzamide [ka] The title compound was synthesized from 2,4-difluoro-5-vinylbenzoic acid under the same conditions as in the preparation examples for 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 preparation example for compound c5, and the corresponding sulfamic acid 4-nitrophenyl was used instead of methylsulfamic acid 4-nitrophenyl used in the preparation example for compound A-1. LCMS m / z: 618[M+H] + HPLC retention time: 1.64 minutes (analysis condition B)

[0363] Compound I-4: 4-Fluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(2-methoxyethylsulfamoylamino)pyridine-4-yl]methyl]benzamide [ka] The title compound was synthesized from 2,4-difluoro-5-vinylbenzoic acid under the same conditions as in the preparation examples for 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 preparation example for compound c5, and the corresponding sulfamic acid 4-nitrophenyl was used instead of methylsulfamic acid 4-nitrophenyl used in the preparation example for compound A-1. LCMS m / z: 636[M+H] + HPLC retention time: 1.19 minutes (analysis condition A)

[0364] Compound j1: Methyl 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate [ka] To a DCM suspension (91 mL) of (2-amino-3-fluoropyridine-4-yl)methanol (10.3 g, 72.7 mmol), thionyl chloride (10.6 mL, 145 mmol) was added over 10 minutes, and the mixture was stirred at room temperature for 65 minutes. After filtering the reaction mixture, the resulting solid was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and after filtration off the drying agent, it was concentrated under reduced pressure to obtain the crude product of 2-amino-4-(chloromethyl)-3-fluoropyridine (10.3 g).

[0365] To a 1,3-dimethyl-2-imidazolidinone solution (39 mL) of methyl 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (7.90 g, 19.7 mmol) and tetrabutylammonium iodide (0.726 g, 1.97 mmol), crude product of 2-amino-4-(chloromethyl)-3-fluoropyridine (3.47 g) and tripotassium phosphate (5.00 g, 23.6 mmol) were added, and the mixture was stirred at 50°C for 4 hours. Water was added to the reaction mixture, and the resulting solid was filtered and washed with an acetonitrile / water mixture to obtain the title compound (10.3 g, 60%). LCMS m / z: 527[M+H] + HPLC retention time: 0.63 minutes (analysis condition C)

[0366] Compound j2: 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate hydrochloride [ka] The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (compound j1) under the same conditions as in the preparation example of compound a7. LCMS m / z: 513[M+H] + HPLC retention time: 0.76 minutes (analysis condition E)

[0367] Compound j3: 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate hydrochloride (compound j2) under the same conditions as in the preparation example of compound a8. LCMS m / z: 512[M+H] + HPLC retention time: 0.84 min (analysis condition E)

[0368] Compound J-1: 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide (compound j3) under the same conditions as the preparation example for compound A-25. LCMS m / z: 605[M+H] + HPLC retention time: 0.95 minutes (Analysis conditions A)

[0369] Compound J-2: 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate hydrochloride (compound j2) under the same conditions as in the preparation examples of compound a8 and compound A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 649[M+H] + HPLC retention time: 0.97 minutes (Analysis conditions A)

[0370] Compound J-5: N-Cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate hydrochloride (compound j2) and the corresponding amine under the same conditions as in the preparation examples of compound a8 and compound A-1. LCMS m / z: 645[M+H] + HPLC retention time: 1.40 minutes (Analysis condition B)

[0371] Compound J-6: N-Cyclopropyl-5-[[2-(Cyclopropylsulfamoylamino)-3-Fluoropyridine-4-yl]methyl]-2-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate hydrochloride (compound j2) and the corresponding amine under the same conditions as in the preparation examples of compound a8 and compound A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 671[M+H] + HPLC retention time: 1.47 minutes (analysis condition B)

[0372] Compound J-7: N-Cyclopropyl-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(2-methoxyethylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate hydrochloride (compound j2) and the corresponding amine under the same conditions as in the preparation examples of compound a8 and compound A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 689[M+H]+ HPLC retention time: 1.43 minutes (analysis condition B)

[0373] Compound J-8: 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate hydrochloride (compound j2) and the corresponding amine under the same conditions as in the preparation examples of compound a12 and compound A-1. LCMS m / z: 635[M+H] + HPLC retention time: 1.29 minutes (analysis condition B)

[0374] Compound J-9: 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridine-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate hydrochloride (compound j2) and the corresponding amine under the same conditions as in the preparation examples of compound a12 and compound A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 679[M+H] + HPLC retention time: 1.31 minutes (analysis condition B)

[0375] Compound J-10: 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate hydrochloride (compound j2) under the same conditions as the preparation examples of compound a12 and compound A-1. LCMS m / z: 677[M+H] + HPLC retention time: 1.46 minutes (analysis condition B)

[0376] Compound J-11: 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-N-[(2-methylpropane-2-yl)oxy]-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate hydrochloride (compound j2) under the same conditions as in the preparation examples of compound a12 and compound A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 703[M+H] + HPLC retention time: 1.52 minutes (analysis condition B)

[0377] Compound J-13: 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate hydrochloride (compound j2) under the same conditions as in the preparation examples of compound a8 and compound A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 631[M+H] + HPLC retention time: 1.37 minutes (analysis condition B)

[0378] Compound J-14: 5-[[2-(ethylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate hydrochloride (compound j2) under the same conditions as in the preparation examples of compound a8 and compound A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 619[M+H] + HPLC retention time: 1.35 minutes (analysis condition B)

[0379] Compound J-15: 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate hydrochloride (compound j2) under the same conditions as in the preparation examples of compound a8 and compound A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 659[M+H] + HPLC retention time: 0.77 min (analysis condition C)

[0380] Compound J-3: 2-(4-cyclopropyl-2-fluoroanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide (compound j3) under the same conditions as the preparation examples of compound a9 and compound A-1. LCMS m / z: 519[M+H] + HPLC retention time: 1.31 minutes (analysis condition B)

[0381] Compound J-4: 2-(4-cyclopropyl-2-fluoroanilino)-5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from 5-[(2-amino-3-fluoropyridine-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide (compound j3) under the same conditions as in the preparation examples of compound a9 and compound A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 545[M+H] + HPLC retention time: 1.37 minutes (analysis condition B)

[0382] Compound j12: 5-[[2-(ethylsulfonylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid [ka] The title compound was synthesized from 2-amino-4-(hydroxymethyl)pyridine under the same conditions as in the preparation examples for compound j1, compound A-25, and compound a7. However, the corresponding sulfonyl chloride was used instead of the methylsulfamoyl chloride used in the preparation example for compound A-25. In addition, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 587[M+H] + HPLC retention time: 0.64 min (analysis condition C)

[0383] Compound J-12: 5-[[2-(ethylsulfonylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide [ka] 5-[[2-(ethylsulfonylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid (compound j12, 10 mg, 0.017 mmol) and ammonium chloride (2.74 mg, 0.051 mmol) were dissolved in DMF (85 μL) and cooled to 0°C. HATU (13.0 mg, 0.034 mmol) and DIPEA (17.9 μL, 0.102 mmol) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to obtain the title compound (7.2 mg, 29%) as a colorless solid. LCMS m / z: 586[M+H] + HPLC retention time: 1.24 minutes (analysis condition B)

[0384] Compound k1: Methyl 2-(2-fluoro-4-iodoanilino)-5-formyl-1-methyl-6-oxopyridine-3-carboxylate [ka] To a 2.7 mL solution of methyl 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (132 mg, 0.328 mmol) in acetonitrile, (chloromethylene)dimethyliminium chloride (168 mg, 1.31 mmol) was added and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture and stirred for 30 minutes, after which the solid was filtered to obtain the title compound (108 mg, 76%). LCMS m / z: 431[M+H] + HPLC retention time: 0.80 min (analysis condition C)

[0385] Compound k4: Methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate [ka] The title compound was synthesized from methyl 2-(2-fluoro-4-iodoanilino)-5-formyl-1-methyl-6-oxopyridine-3-carboxylate (compound k1) under the same conditions as in the preparation examples of compounds a2, a5, and a6. However, 2-nitrobenzene-1-sulfonohydrazide was used instead of 4-methylbenzenesulfonylhydrazide used in the preparation example of compound a2. Also, [2-fluoro-3-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]boronic acid and DIPEA were used instead of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridine-4-yl]boronic acid (compound a4) and potassium carbonate used in the preparation example of compound a5, respectively. LCMS m / z: 526[M+H] + HPLC retention time: 0.90 minutes (analysis condition C)

[0386] Compound K-1: 2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (compound k4) under the same conditions as the preparation examples for compounds b2, a8, and A-1. LCMS m / z: 604[M+H] + HPLC retention time: 1.37 minutes (analysis condition B)

[0387] Compound K-2: 5-[[3-(ethylsulfamoylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (compound k4) under the same conditions as in the preparation examples of compounds b2, a8, and A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 618[M+H] + HPLC retention time: 1.41 minutes (analysis condition B)

[0388] Compound K-3: 5-[[3-(cyclopropylsulfamoylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (compound k4) under the same conditions as in the preparation examples of compounds b2, a8, and A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 630[M+H] + HPLC retention time: 1.43 minutes (analysis condition B)

[0389] Compound K-4: N-Cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (compound k4) under the same conditions as the preparation examples of compound b2, compound a10, and compound A-1. LCMS m / z: 644[M+H] + HPLC retention time: 1.48 minutes (analysis condition B)

[0390] Compound K-5: N-Cyclopropyl-5-[[3-(Cyclopropylsulfamoylamino)-2-Fluorophenyl]methyl]-2-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (compound k4) under the same conditions as in the preparation examples of compounds b2, a10, and A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 670[M+H] + HPLC retention time: 1.53 minutes (analysis condition B)

[0391] Compound K-13: N-Cyclopropyl-5-[[3-(ethylsulfamoylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (compound k4) under the same conditions as in the preparation examples of compounds b2, a10, and A-1. However, the corresponding sulfamic acid 4-nitrophenyl was used instead of the methylsulfamic acid 4-nitrophenyl used in the preparation example of compound A-1. LCMS m / z: 658[M+H] + HPLC retention time: 1.52 minutes (analysis condition B)

[0392] Compound K-6: 2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclopropyl)sulfonylamino]phenyl]methyl]-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (compound k4) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of compounds A-25, b2, and a8. However, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 629[M+H] + HPLC retention time: 1.48 minutes (analysis condition B)

[0393] Compound K-7: 2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclopropyl)sulfonylamino]phenyl]methyl]-N-methoxy-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (compound k4) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of compounds A-25, b2, and a12. However, pyridine was used as the solvent in the sulfonamidation step. In addition, the corresponding amine was used instead of tert-butoxyamine hydrochloride, which was used in the preparation example of compound a12. LCMS m / z: 659[M+H] + HPLC retention time: 1.47 minutes (analysis condition B)

[0394] Compound K-11: N-Cyclopropyl-2-(2-Fluoro-4-iodoanilino)-5-[[2-Fluoro-3-[(1-methylcyclopropyl)sulfonylamino]phenyl]methyl]-1-methyl-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (compound k4) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of compounds A-25, b2, and a8. However, pyridine was used as the solvent in the sulfonamidation step. In addition, the corresponding amine was used instead of the 7M ammonia MeOH solution used in the preparation example of compound a8. LCMS m / z: 669[M+H] + HPLC retention time: 1.59 minutes (analysis condition B)

[0395] Compound K-12: 2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclopropyl)sulfonylamino]phenyl]methyl]-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide [ka] The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (compound k4) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of compounds A-25, b2, and a12. However, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 701[M+H] + HPLC retention time: 1.62 minutes (analysis condition B)

[0396] Compound k11: 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid [ka] The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (compound k4) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of compounds A-25 and b2. However, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 604[M+H] + HPLC retention time: 0.77 min (analysis condition C) ...

Claims

1. A composition comprising a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, and a dispersant. 【Chemistry 1】 [In the formula, Ring A is given by the following general formulas (2), (3), (4), or (5) (where the bonds marked with *, **, and *** are -NH-, -CONH-, and -CH, respectively). ２ It is a group that is bonded to (-). 【Chemistry 2】 X １ , X ２ , X ３ , X ４ , X ５ and X ６ Each is independently -CR ２ = or -N = R ２ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, R １ ha -S (=O) ２ -NH-R ８ or -S (=O) ２ -R ８ And, R ８ These are a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, or a C3-6 heterocycloalkyl group), a monocyclic or bicyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group or a C1-6 alkoxy group), or a monocyclic or bicyclic C3-6 heterocycloalkyl group. R ３ These are a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group), or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), R ５ is a halogen atom or a C1-6 alkyl group, R ６ R is a hydrogen atom, a halogen atom, or a C1-6 alkyl group, ４ 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, or R ６ and R ４ These, together with the carbon atoms to which they are bonded, form an unsaturated hetero 5-membered ring. R ７ is a hydrogen atom or a C1-6 alkyl group, R ９ [These are hydrogen atoms, halogen atoms, or C1-6 alkyl groups.]

2. The composition according to claim 1, wherein the dispersant is at least one selected from the group consisting of methylcellulose, polyvinyl alcohol, hydroxypropylcellulose, copolyvidone, hydroxypropylmethylcellulose, methacrylate copolymer, polyvinylpyrrolidone, and hypromellose acetate succinate.

3. The composition according to claim 1 or 2, wherein the dispersant is methylcellulose.

4. The composition according to any one of claims 1 to 3, wherein the content of the dispersant is 0.1 to 20 parts by weight per 1 part by weight of the compound of general formula (1), the salt, or the solvate.

5. The composition according to any one of claims 1 to 4, further comprising a basic compound.

6. A composition comprising a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, and a basic compound. 【Transformation 3】 [In the formula, Ring A is given by the following general formulas (2), (3), (4), or (5) (where the bonds marked with *, **, and *** are -NH-, -CONH-, and -CH, respectively). ２ It is a group that is bonded to (-). 【Chemistry 4】 X １ , X ２ , X ３ , X ４ , X ５ and X ６ Each is independently -CR ２ = or -N = R ２ is a hydrogen atom, a halogen atom, or a C1-6 alkyl group. R １ ha -S (=O) ２ -NH-R ８ or -S (=O) ２ -R ８ And, R ８ These are a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, or a C3-6 heterocycloalkyl group), a monocyclic or bicyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group or a C1-6 alkoxy group), or a monocyclic or bicyclic C3-6 heterocycloalkyl group. R ３ These are a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group), or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), R ５ is a halogen atom or a C1-6 alkyl group, R ６ R is a hydrogen atom, a halogen atom, or a C1-6 alkyl group, ４ 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, or R ６ and R ４ These, together with the carbon atoms to which they are bonded, form an unsaturated hetero 5-membered ring. R ７ is a hydrogen atom or a C1-6 alkyl group, R ９ [These are hydrogen atoms, halogen atoms, or C1-6 alkyl groups.]

7. The composition according to claim 5 or 6, wherein the basic compound is at least one selected from the group consisting of meglumine, arginine, histidine, magnesium oxide, calcium silicate, and magnesium stearate.

8. The composition according to any one of claims 5 to 7, wherein the basic compound is meglumine.

9. The composition according to any one of claims 5 to 8, wherein the content of the basic compound is 0.2 to 40 parts by weight per 1 part by weight of the compound of general formula (1), the salt, or the solvate.

10. Ring A is a group represented by general formula (2) or (4), R ８ These are a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), R ３ These are a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxyl group), R ６ R is a hydrogen atom, a halogen atom, or a C1-6 alkyl group, ４ is a halogen atom or a cyclopropyl group, R ７ is a hydrogen atom or a methyl group. The composition according to any one of claims 1 to 9.

11. The composition according to any one of claims 1 to 10, wherein the compound of general formula (1) is 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide.

12. A composition according to any one of claims 1 to 11, comprising a pharmaceutically acceptable excipient.

13. A composition according to any one of claims 1 to 12, in the form of a capsule or a tablet.

14. A method for producing the composition described in any one of claims 1 to 13, A method comprising the step of providing a mixture comprising the compound of general formula (1), the salt or solvate, and the dispersant and / or the basic compound.

15. A composition comprising 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, together with a compound represented by the following formula (X), A composition in which the content of the compound of formula (X) is 3.0% by weight or less relative to the content of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, the salt, or the solvate. 【Transformation 5】

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