Arylamide derivative having antitumor activity

Abstract

The present disclosure provides, for example, compounds represented by general formula (6) [in the formula, X1, X2, X3, and X4 are each independently -CR2= or -N=; R2 is, for example, a halogen atom; R1 is, for example, -S(=O)2-NH-R8; R8 is, for example, a C1-6 alkyl group; R3 is, for example, a hydrogen atom; R5 is, for example, a halogen atom; R6 is, for example, a hydrogen atom; and R4 is, for example, a cyclopropyl group] or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt. The compounds, salts, and solvates provided by the disclosure have high RAF / MEK complex stabilization activities and can be used for the treatment or prevention of cell proliferation diseases and particularly cancers.

Description

Arylamide derivatives with antitumor activity

[0001] The present disclosure relates to arylamide derivatives that have RAF / MEK complex stabilizing activity and / or MEK inhibitory activity and are useful for treating or preventing cell proliferative diseases, particularly cancer, and to RAF / MEK complex stabilizers or MEK inhibitors that contain such arylamide derivatives as active ingredients.

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

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

[0004] CH5126766, known not only as a MEK inhibitor but also as a stabilizer of the RAF / MEK complex (see Patent Document 2 and Non-Patent Documents 7 and 8), has been reported to show clinical efficacy against non-small cell lung cancer with RAS mutations (see Non-Patent Document 9). It has also been reported that CH5126766 stabilizes the RAF / MEK complex and inhibits increased MEK phosphorylation (feedback activation of the MAPK 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 MEK inhibitors are not always effective clinically against cancers with RAS mutations (see Non-Patent Document 10).

[0005] International Publication No. WO 2006 / 011466 International Publication No. WO 2007 / 091736

[0006] Nature. 2018, vol. 15, p. 709-720 Molecules. 2017, vol. 22, e1551N. Engl. J. Med. 2012, vol. 367, p. 107-114N. Engl. J. Med. 2012, vol. 367, p. 1694-1703 JAMA. 2017, vol. 317, no. 18, p. 1844-1853 Ann. Oncol. 2015, vol. 26, no. 5, p. 894-901 Cancer Res. 2013, vol. 73, no. 13, p. 4050-4060 Cancer Cell. 2014, vol. 25, no. 5, p. 697-710J. Clin. Oncol. 2017, vol. 35, no. 15, suppl. , 2506 Nat. Rev. Clin. Oncol. 2014, vol. 11, p. 385-400

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

[0008] Therefore, an object of the present disclosure is to provide a novel compound that has RAF / MEK complex stabilizing activity and / or MEK inhibitory activity and is useful for the treatment or prevention of cell proliferative diseases, particularly cancer, or a novel RAF / MEK complex stabilizer or MEK inhibitor that is useful for the treatment or prevention of cell proliferative diseases, particularly cancer.

[0009] In order to create the above-mentioned novel compounds, the present inventors focused on the following CH4987655, a known MEK inhibitor, and the following CH5126766, a known RAF / MEK complex stabilizer.

[0010] Compared with another MEK inhibitor, PD0325901, CH4987655 has comparable MEK inhibitory activity in a non-cellular system, but exhibits slower dissociation from MEK. Furthermore, it exhibits stronger MEK inhibitory activity than PD0325901 in peripheral blood of cynomolgus monkeys (IC ５０ These results suggest that CH4987655 exhibits lower activity and longer-lasting MEK inhibition. These results are believed to be due to the unique substituent, including a 3-oxo-[1,2]oxazinane ring structure, at the 5'-position of the benzamide skeleton of CH4987655 (see Bioorg. Med. Chem. Lett. 2011, vol. 21, no. 6, pp. 1795-1801).

[0011] CH5126766 forms a complex with MEK with a unique structure. Specifically, upon binding to MEK, the MEK activation segment shifts, resulting in a spatially distinct arrangement of Asn221 and Ser222 of MEK compared to when PD0325089 (the enantiomer of PD0325901) binds. In the complex, the sulfamide group of CH5126766 forms a direct hydrogen bond with Asn221 of MEK and a hydrogen bond with Ser222 via water. Since Ser222 is one of the two amino acids phosphorylated by RAF, the RAF / MEK complex stabilizing effect of CH5126766 and the inhibitory effect of CH5126766 on the enhancement of MEK phosphorylation (feedback activation of the MAPK signaling pathway) are thought to be due to such a complex structure (see Cancer Cell. 2014, vol. 25, no. 5, pp. 697-710 (Non-Patent Document 8)).

[0012] When CH4987655 binds to MEK, it brings about a spatial arrangement of Asn221 and Ser222 similar to that of CH5126766. It also resembles CH5126766 in its interaction with Asn221. Although CH4987655 has a weak inhibitory effect on MEK phosphorylation, this is thought to be due to the complex structure (see Cancer Cell. 2014, vol. 25, no. 5, pp. 697-710 (Non-Patent Document 8)).

[0013] CH4987655 differs from CH5126766 in that it does not interact with Ser222 due to distance and that its interaction with Asn221 is weak via the 3-oxo-[1,2]oxazinane ring structure. On the other hand, CH5126766 does not interact with Lys97, unlike MEK inhibitors such as CH4987655 and PD0325901.

[0014] Based on the above analysis, the present inventors have proposed the following two hypotheses. (Hypothesis 1) If a chemical structure capable of forming a hydrogen bond with Lys97 is introduced into CH5126766, MEK inhibitory activity equivalent to that of CH4987655 can be achieved while maintaining the RAF / MEK complex stabilizing activity and MEK phosphorylation enhancement (feedback activation of the MAPK signaling pathway) inhibitory activity of CH5126766. (Hypothesis 2) If a chemical structure capable of forming strong hydrogen bonds with Asn221 and Ser222 is introduced into CH4987655, RAF / MEK complex stabilizing activity and MEK phosphorylation enhancement (feedback activation of the MAPK signaling pathway) inhibitory activity equivalent to that of CH5126766 can be achieved while maintaining the MEK inhibitory activity of CH4987655.

[0015] In the complex of CH4987655 and MEK, the hydroxamate structure of CH4987655 interacts with Lys97 of MEK. Based on hypothesis 1, the following compound AA-2 was produced by introducing a substituent having a hydroxamate structure into the structure of CH5126766.

[0016] In the complex of CH5126766 and MEK, the sulfamide structure of CH5126766 interacts with Asn221 and Ser222 of MEK. Based on hypothesis 2, the following compound AA-1 was produced, in which a sulfamide structure was introduced into the terminal site of the structure corresponding to the 5'-side chain of CH4987655.

[0017] The MEK1 inhibitory activity (IC ５０ ), BRAF inhibitory activity (IC ５０ ), HCT-116 proliferation inhibitory activity (IC ５０ ) and / or Colo-205 proliferation inhibitory activity (IC５０ ) was measured in the same manner as in Test Examples 3, 4, or 5 described below (HCT-116 and Colo-205 were obtained from ATCC). The results are shown in Table 1 below. HCT-116 and Colo-205 are human cancer cells with RAS mutation and BRAF mutation, respectively.

[0018] As is clear from Table 1, compound AA-2 did not achieve the expected profile, whereas compound AA-1 exhibited significant MEK1 inhibitory activity, BRAF inhibitory activity, HCT-116 growth inhibitory activity, and Colo-205 growth inhibitory activity.

[0019] The present inventors have conducted extensive research using compound AA-1 as a lead compound, and as a result have found that specific arylamide derivatives have RAF / MEK complex stabilizing activity and / or MEK inhibitory activity and are useful for the treatment or prevention of cell proliferative diseases, particularly cancer.

[0020] The present disclosure provides compounds, salts, or solvates described in the following (A1) to (A6): (A1) A compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt: [wherein ring A is a group represented by the following general formula (2), (3), (4) or (5) (wherein bonds marked with *, ** and *** are -NH-, -CONH- and -CH ２ - is bonded to. X １ , X ２ , X ３ , X ４ , X ５ and X ６ are each independently -CR ２ = or -N=, and R ２ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R １ is -S(=O) ２ -NH-R ８ Or -S(=O) ２ -R ８ and R ８is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy 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, and R ３ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group, or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group), or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a halogen atom, a hydroxy group, or a C1-6 alkoxy group), and R ５ is a halogen atom or a C1-6 alkyl group, and R ６ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R 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 form an unsaturated 5-membered heterocyclic ring together with the carbon atoms to which they are attached, and R ７ is a hydrogen atom or a C1-6 alkyl group, and R ９ is a hydrogen atom, a halogen atom, or a C1-6 alkyl group.

[0021] (A2) Ring A is a group represented by general formula (2) or (4), and R ８ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), and R ３is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxy group), and R ６ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R ４ is a halogen atom or a cyclopropyl group, R ７ is a hydrogen atom or a methyl group.

[0022] (A3) The compound, salt, or solvate according to (A1), wherein the compound represented by general formula (1) is a compound represented by the following general formula (6): [In the formula, X １ , X ２ , X ３ and X ４ are each independently -CR ２ = or -N=, and R ２ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R １ is -S(=O) ２ -NH-R ８ Or -S(=O) ２ -R ８ and R ８ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), and R ３ 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 hydroxy group), and R ５ is a halogen atom or a C1-6 alkyl group, and R ６ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R ４ is a halogen atom or a cyclopropyl group.

[0023] (A4) R ２ is a hydrogen atom or a halogen atom, R ８is 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), and R ３ 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 hydroxy group), and R ５ is a halogen atom, R ６ is a hydrogen atom, and R ４ The compound, salt or solvate according to any one of (A1) to (A3), wherein is a halogen atom or a cyclopropyl group.

[0024] (A5) R ２ is a hydrogen atom or a fluorine atom, R ８ 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), and R ３ 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 hydroxy group), and R ５ is a fluorine atom, and R ６ is a hydrogen atom, and R ４ The compound, salt or solvate according to any one of (A1) to (A3), wherein: is an iodine atom or a cyclopropyl group.

[0025] (A6) R ２ is a fluorine atom, and R １ is -S(=O) ２ -NH-R ８ and R ８ is a C1-4 alkyl group, and R ３ is a hydrogen atom or a cyclopropyl group, R ５ is a fluorine atom, and R ６ is a hydrogen atom, and R ４The compound, salt or solvate according to any one of (A1) to (A3), wherein: is an iodine atom or a cyclopropyl group.

[0026] The present disclosure also provides agents described in the following (A7) to (A10). The compounds, salts, or solvates described in the following (A7) include the compounds, salts, or solvates described in (A1) to (A6). (A7) A stabilizer for a RAF / MEK complex, comprising, as an active ingredient, a compound represented by the following general formula (11) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt: [wherein ring A is a group represented by the following general formula (2), (3), (4) or (5) (wherein bonds marked with *, ** and *** are -NH-, -CONH- and -X, respectively). ７ - is bonded to. X １ , X ２ , X ３ , X ４ , X ５ and X ６ are each independently -CR ２ = or -N=, and R ２ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, ７ Ha-(CH ２ ) ｍ - or -O-, m is 1, 2 or 3, R １ is -S(=O) ２ -NH-R ８ Or -S(=O) ２ -R ８ and R ８ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy 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, and R ３is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group, or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group), or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a halogen atom, a hydroxy group, or a C1-6 alkoxy group), and R ５ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R ６ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R 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 form an unsaturated 5-membered heterocyclic ring together with the carbon atoms to which they are attached, and R ７ is a hydrogen atom or a C1-6 alkyl group, and R ９ is a hydrogen atom, a halogen atom, or a C1-6 alkyl group.

[0027] (A8) Ring A is a group represented by general formula (2) or (4), and X ７ Ha-CH ２ - and R ８ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), and R ３ 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 hydroxy group), and R ５ is a halogen atom or a C1-6 alkyl group, and R ６ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R ４ is a halogen atom or a cyclopropyl group, R ７is a hydrogen atom or a methyl group.

[0028] (A9) The stabilizer for a RAF / MEK complex according to (A7), wherein the compound represented by general formula (11) is a compound represented by the following general formula (6): [In the formula, X １ , X ２ , X ３ and X ４ are each independently -CR ２ = or -N=, and R ２ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R １ is -S(=O) ２ -NH-R ８ Or -S(=O) ２ -R ８ and R ８ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), and R ３ 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 hydroxy group), and R ５ is a halogen atom or a C1-6 alkyl group, and R ６ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R ４ is a halogen atom or a cyclopropyl group.

[0029] (A10) R ２ is a hydrogen atom or a halogen atom, R ８ 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), and R ３is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxy group), and R ５ is a halogen atom, R ６ is a hydrogen atom, and R ４ The stabilizer for a RAF / MEK complex according to any one of (A7) to (A9), wherein is a halogen atom or a cyclopropyl group.

[0030] The present disclosure also provides compounds, salts, or solvates described in the following (A11) to (A15). Note that the compound, salt, or solvate described in (A7) includes the compounds, salts, or solvates described in the following (A11) to (A15). (A11) N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]benzamide (Compound A-1), N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-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)pyridin-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)pyridin-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)pyridin-4-yl]methyl]-N-methoxybenzamide (Compound A-13), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-25), 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-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)pyridin-4-yl]methyl]benzamide (Compound A-31), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-33), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-34), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide (Compound A-35), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-41), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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-(methanesulfonamido)phenyl]methyl]benzamide (Compound E-13), 4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound I-1), N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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]pyridin-4-yl]methyl]-N-methoxybenzamide (Compound A-15), 3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]benzamide (Compound A-20), 2-(4-bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]benzamide (Compound H-1), 3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound H-3), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]oxybenzamide (Compound H-4), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine-3-carboxamide (Compound J-8), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide (Compound J-10), 5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-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)pyridin-4-yl]methyl]pyridine-4-carboxamide (Compound L-1), 5-(2-fluoro-4-iodoanilino)-8-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (compound N-1), 5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (compound N-2), 4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (compound P-1), and 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide (Compound P-2) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt.

[0031] (A12) N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]benzamide (Compound A-1), N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-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)pyridin-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)pyridin-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)pyridin-4-yl]methyl]-N-methoxybenzamide (Compound A-13), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-25), 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-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)pyridin-4-yl]methyl]benzamide (Compound A-31), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-33), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-34), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide (Compound A-35), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-41), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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,A compound selected from 4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzamide (Compound E-13), 4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound I-1), and N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (Compound J-5), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

[0032] (A13) A compound selected from N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]benzamide (Compound A-1), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt.

[0033] (A14) 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (compound A-1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt.

[0034] (A15) 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (compound A-1) or its sodium salt or potassium salt, or a pharmaceutically acceptable solvate of the compound or salt.

[0035] The compounds, salts, or solvates described in (A1) to (A15) have high RAF / MEK complex stabilizing activity and can be used as active ingredients in therapeutic or preventive agents for cell proliferative diseases, particularly cancer (more specifically, cancers with RAS mutations, for example). That is, the present disclosure also provides a pharmaceutical composition comprising, as an active ingredient, the compound, salt, or solvate described in any of (A1) to (A15). Also provided is a therapeutic or preventive agent for cell proliferative diseases, particularly cancer, comprising, as an active ingredient, the compound, salt, or solvate described in any of (A1) to (A15).

[0036] The present disclosure also provides compounds, salts, or solvates described in the following (B1) to (B3) and an agent described in the following (B4): (B1) A compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt: [wherein ring A is a group represented by the following general formula (2), (3) or (4) (wherein bonds marked with *, ** and *** are -NH-, -CONH- and -CH ２ - is bonded to. X １ , X ２ , X ３ , X ４ and X ５ are each independently -CR ２ = or -N=, and R ２ is a hydrogen atom, a halogen atom or a C1-4 alkyl group, and R １ is -S(=O) ２ -NH-R ８ Or -S(=O) ２ -R ８ and R ８is a C1-4 alkyl group (the C1-4 alkyl group may be substituted with a halogen atom, a hydroxy 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), and R ３ is a hydrogen atom, a C3-6 cycloalkyl group or a C1-6 alkoxy group, R ５ is a halogen atom, R ６ is a hydrogen atom, and R ４ is a halogen atom or a C3-6 cycloalkyl group, R ７ is a C1-4 alkyl group, and R ９ is a hydrogen atom.]

[0037] (B2) 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-1), (+ / -)-3,4-difluoro-5-[[3-fluoro-2-(2-hydroxypropylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]benzamide (Compound A-21), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-25), 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-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)pyridin-4-yl]methyl]benzamide (Compound A-33), 5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-40), 3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-42), 5-[[2-(ethylsulfonylamino)-3-fluoropyridin-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)pyridin-4-yl]methyl]benzamide (Compound C-3), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]pyridine-4-carboxamide (Compound L-1), 5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (Compound N-1), 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide (Compound P-2), 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-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)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (Compound P-6) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt.

[0038] (B3) (+ / -)-3,4-difluoro-5-[[3-fluoro-2-(2-hydroxypropylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]benzamide (Compound A-21), 5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-40), 3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-42), 5-[[2-(ethylsulfonylamino)-3-fluoropyridin-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)pyridin-4-yl]methyl]benzamide (Compound C-3), A compound selected from 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-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)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (Compound P-6), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

[0039] (B4) A MEK inhibitor containing the compound, salt or solvate according to any one of (B1) to (B3) as an active ingredient.

[0040] 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 preventive agents for cell proliferative diseases, particularly cancer (more specifically, for example, cancer with a RAF mutation). That is, the present disclosure also provides a pharmaceutical composition containing, as an active ingredient, the compound, salt, or solvate described in any of (B1) to (B3). Also provided is a therapeutic or preventive agent for cell proliferative diseases, particularly cancer, containing, as an active ingredient, the compound, salt, or solvate described in any of (B1) to (B3).

[0041] The present disclosure provides novel compounds that have RAF / MEK complex stabilizing activity and / or MEK inhibitory activity and are useful for the treatment or prevention of cell proliferative diseases, particularly cancer, or novel RAF / MEK complex stabilizers or MEK inhibitors that are useful for the treatment or prevention of cell proliferative diseases, particularly cancer.

[0042] FIG. 1 shows the powder X-ray diffraction pattern of sample A-1a (Form I). FIG. 2 shows the powder X-ray diffraction pattern of sample A-1b. FIG. 3 shows the powder X-ray diffraction pattern of sample A-1c. FIG. 4 is a sensorgram showing the time course of the amount of MEK1 bound to the surface of a sensor chip on which RAF1 has been immobilized, when the amount of MEK1 bound to the surface of a sensor chip on which RAF1 has been immobilized has been added together with a test compound (ref-2, ref-3, ref-4, A-1, ref-1, ref-5, or B-1). FIG. 5 is a sensorgram showing the time course of the amount of MEK1 bound to the surface of a sensor chip on which RAF1 has been immobilized, when ... has been added together with a test compound (A-2, A-25, J-1, E-1, M-1, N-1, or H-3). Figure 6 is a sensorgram showing the time course of the amount of MEK1 binding to the surface of a sensor chip on which RAF1 has been immobilized, which has been added together with a test compound (I-1, H-4, L-1, P-1, E-7, or A-27). Figure 7 is a sensorgram showing the time course of the amount of MEK1 binding to the surface of a sensor chip on which RAF1 has been immobilized, which has been added together with a test compound (A-33, A-18, N-2, A-20, A-8, E-13, or H-1). Figure 8 is a sensorgram showing the time course of the amount of MEK1 binding to the surface of a sensor chip on which RAF1 has been immobilized, which has been added together with a test compound (P-2, A-41, E-9, A-6, J-14, A-31, or A-34). FIG. 9 is a sensorgram showing the time course of the amount of MEK1 binding to the surface of a sensor chip on which RAF1 has been immobilized, which has been added together with a test compound (A-35, A-30, D-4, A-15, J-8, J-5, or A-4). FIG. 10 is a sensorgram showing the time course of the amount of MEK1 binding to the surface of a sensor chip on which RAF1 has been immobilized, which has been added together with a test compound (A-13, E-23, or J-10). FIG. 11 is a sensorgram showing the time course of the amount of MEK1 binding to the surface of a sensor chip on which RAF1 has been immobilized, which has been added together with a test compound (ref-4, A-1, P-2, or A-6). FIG. 12 is an electrophoretic image showing the results of Western blotting of proteins (p-MEK, MEK, p-ERK, and ERK) extracted from A549 cells cultured in the presence of a test compound (ref-5 or compound A-1).FIG. 13 is a graph showing the time course of tumor volume (mean±standard deviation) in nude mice subcutaneously implanted with the human lung cancer cell line Calu-6.

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

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

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

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

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

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

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

[0050] In the present disclosure, a C3-6 cycloalkyl group refers to a cyclic alkyl group having 3 to 6 atoms constituting the ring. It may be monocyclic or bicyclic, but unless otherwise specified, it refers to a monocyclic group. Examples of monocyclic groups include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Examples of bicyclic groups include a bicyclo[1.1.1]pentanyl group and a bicyclo[2.1.1]hexyl group.

[0051] In the present disclosure, a C3-6 heterocycloalkyl group refers to a C3-6 cycloalkyl group in which at least one of the carbon atoms constituting the ring is replaced with a nitrogen atom, oxygen atom, or sulfur atom. It may be monocyclic or bicyclic, but unless otherwise specified, it refers to a monocyclic group. Examples of monocyclic groups include tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl groups. Examples of bicyclic groups include oxabicyclo[3.1.0]hexan-6-yl and azabicyclo[2.1.1]hexanyl groups.

[0052] In the present disclosure, the term "unsaturated five-membered heterocyclic ring" refers to an unsaturated five-membered ring containing at least one heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and examples thereof include furan, thiophene, pyrrole, imidazole, and thiazole.

[0053] In the present disclosure, examples of pharmaceutically acceptable salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate; sulfonates such as methanesulfonate, benzenesulfonate, and toluenesulfonate; carboxylates such as formate, acetate, oxalate, maleate, fumarate, citrate, malate, succinate, malonate, gluconate, mandelate, benzoate, salicylate, fluoroacetate, trifluoroacetate, tartrate, propionate, and glutarate; alkali metal salts such as lithium salt, sodium salt, potassium salt, cesium salt, and rubidium salt; alkaline earth metal salts such as magnesium salt and calcium salt; and ammonium salts such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, and tetraalkylammonium salt. Among these, alkali metal salts such as lithium salt, sodium salt, potassium salt, cesium salt, and rubidium salt are preferred, and sodium salt and potassium salt are more preferred.

[0054] In the present disclosure, a pharmaceutically acceptable solvate is, for example, a solvate with water, alcohol (e.g., methanol, ethanol, 1-propanol, or 2-propanol), acetone, dimethylformamide, or dimethylacetamide. The solvate may be with a single solvent or with multiple solvents. Preferred examples of the solvate include hydrates.

[0055] A first aspect of the present disclosure provides a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt: [wherein ring A is a group represented by the following general formula (2), (3), (4) or (5) (wherein bonds marked with *, ** and *** are -NH-, -CONH- and -CH ２ - is bonded to. X １ , X ２ , X ３ , X ４ , X ５ and X ６are each independently -CR ２ = or -N=, and R ２ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R １ is -S(=O) ２ -NH-R ８ Or -S(=O) ２ -R ８ and R ８ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy 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, and R ３ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group, or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group), or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a halogen atom, a hydroxy group, or a C1-6 alkoxy group), and R ５ is a halogen atom or a C1-6 alkyl group, and R ６ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R 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 form an unsaturated 5-membered heterocyclic ring together with the carbon atoms to which they are attached, and R ７ is a hydrogen atom or a C1-6 alkyl group, and R ９ is a hydrogen atom, a halogen atom, or a C1-6 alkyl group.

[0056] The compound, salt, or solvate according to the first aspect has high RAF / MEK complex stabilizing activity and can be used for the treatment or prevention of cell proliferative diseases, particularly cancer (more specifically, for example, cancer with a RAS mutation). Many of them also have, for example, high MEK inhibitory activity, and such compounds, salts, or solvates are also suitable for, for example, cancer with a RAF mutation.

[0057] Ring A is preferably a group represented by general formula (2) or (4), more preferably a group represented by general formula (2). ２ 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. １ is preferably —S(═O) ２ -NH-R ８ It is. ８ is preferably a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), or a 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) or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl 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. R ３ is preferably a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxy group), more preferably a hydrogen atom, a C1-4 alkyl group, a cyclopropyl group, or a C1-4 alkoxy group (the C1-4 alkoxy group may be substituted with a hydroxy group), and even more preferably a hydrogen atom or a cyclopropyl group. ５is preferably a halogen atom, more preferably a fluorine atom. ６ is preferably a hydrogen atom, a halogen atom or a C1-6 alkyl group, more preferably a hydrogen atom. ４ is preferably a halogen atom or a cyclopropyl group, more preferably an iodine atom or a cyclopropyl group. ７ is preferably a hydrogen atom or a methyl group.

[0058] The compound represented by the general formula (1) is preferably a compound represented by the following general formula (6): [In the formula, X １ , X ２ , X ３ and X ４ are each independently -CR ２ = or -N=, and R ２ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R １ is -S(=O) ２ -NH-R ８ Or -S(=O) ２ -R ８ and R ８ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), and R ３ 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 hydroxy group), and R ５ is a halogen atom or a C1-6 alkyl group, and R ６ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R ４ is a halogen atom or a cyclopropyl group.

[0059] Examples of the compound represented by general formula (1) include N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]benzamide (compound A-1), N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-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)pyridin-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)pyridin-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)pyridin-4-yl]methyl]-N-methoxybenzamide (Compound A-13), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-25), 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-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)pyridin-4-yl]methyl]benzamide (Compound A-31), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-33), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-34), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide (Compound A-35), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-41), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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-(methanesulfonamido)phenyl]methyl]benzamide (Compound E-13), 4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound I-1), N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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]pyridin-4-yl]methyl]-N-methoxybenzamide (Compound A-15), 3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]benzamide (Compound A-20), 2-(4-bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]benzamide (Compound H-1), 3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound H-3), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine-3-carboxamide (Compound J-8), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide (Compound J-10), 5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-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)pyridin-4-yl]methyl]pyridine-4-carboxamide (Compound L-1), 5-(2-fluoro-4-iodoanilino)-8-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (compound N-1), 5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (compound N-2), 4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (compound P-1), and 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide (compound P-2).

[0060] Among these compounds, in terms of, for example, MEK inhibitory activity, RAF inhibitory activity, cell proliferation inhibitory activity and / or metabolic stability, there are, for example, N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]benzamide (Compound A-1), N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-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)pyridin-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)pyridin-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)pyridin-4-yl]methyl]-N-methoxybenzamide (Compound A-13), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-25), 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-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)pyridin-4-yl]methyl]benzamide (Compound A-31), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-33), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-34), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide (Compound A-35), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-41), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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-(methanesulfonamido)phenyl]methyl]benzamide (Compound E-13), 4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound I-1), and N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (Compound J-5) are preferred; N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]benzamide (compound A-1) are more preferred, 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-1) is particularly preferred. Preferred pharmaceutically acceptable salts of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-1) include, for example, sodium salt and potassium salt.

[0061] A second aspect of the present disclosure provides a stabilizer for a RAF / MEK complex, comprising, as an active ingredient, a compound represented by the following general formula (11) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt: [wherein ring A is a group represented by the following general formula (2), (3), (4) or (5) (wherein bonds marked with *, ** and *** are -NH-, -CONH- and -X, respectively). ７ - is bonded to. X １ , X ２ , X ３ , X ４ , X ５ and X ６ are each independently -CR ２ = or -N=, and R ２ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, ７ Ha-(CH ２ ) ｍ - or -O-, m is 1, 2 or 3, R １ is -S(=O) ２ -NH-R ８ Or -S(=O) ２ -R ８ and R ８ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy 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, and R ３ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group, or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group), or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a halogen atom, a hydroxy group, or a C1-6 alkoxy group), and R ５ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R ６ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R ４is 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 form an unsaturated 5-membered heterocyclic ring together with the carbon atoms to which they are attached, and R ７ is a hydrogen atom or a C1-6 alkyl group, and R ９ is a hydrogen atom, a halogen atom, or a C1-6 alkyl group.

[0062] The compound, salt, or solvate according to the second aspect has high RAF / MEK complex stabilizing activity and can be used for the treatment or prevention of cell proliferative diseases, particularly cancer (more specifically, for example, cancer with a RAS mutation). Many of them also have, for example, high MEK inhibitory activity, and such compounds, salts, or solvates are also suitable for, for example, cancer with a RAF mutation.

[0063] Ring A is preferably a group represented by general formula (2) or (4), more preferably a group represented by general formula (2). ２ 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. ７ is preferably —CH ２ - is. R １ is preferably —S(═O) ２ -NH-R ８ It is. ８is preferably a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), or a 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) or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl 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. R ３ is preferably a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxy group), more preferably a hydrogen atom, a C1-4 alkyl group, a cyclopropyl group, or a C1-4 alkoxy group (the C1-4 alkoxy group may be substituted with a hydroxy group), and even more preferably a hydrogen atom or a cyclopropyl group. ５ is preferably a halogen atom or a C1-6 alkyl group, more preferably a halogen atom, and even more preferably a fluorine atom. ６ is preferably a hydrogen atom, a halogen atom or a C1-6 alkyl group, more preferably a hydrogen atom. ４ is preferably a halogen atom or a cyclopropyl group, more preferably an iodine atom or a cyclopropyl group. ７ is preferably a hydrogen atom or a methyl group.

[0064] The compound represented by the general formula (11) is preferably a compound represented by the following general formula (6): [In the formula, X １ , X ２ , X ３ and X ４ are each independently -CR２ = or -N=, and R ２ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R １ is -S(=O) ２ -NH-R ８ Or -S(=O) ２ -R ８ and R ８ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), and R ３ 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 hydroxy group), and R ５ is a halogen atom or a C1-6 alkyl group, and R ６ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R ４ is a halogen atom or a cyclopropyl group.

[0065] Examples of the compound represented by general formula (11) include N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]benzamide (compound A-1), N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-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)pyridin-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)pyridin-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)pyridin-4-yl]methyl]-N-methoxybenzamide (Compound A-13), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-25), 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-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)pyridin-4-yl]methyl]benzamide (Compound A-31), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-33), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-34), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide (Compound A-35), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-41), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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-(methanesulfonamido)phenyl]methyl]benzamide (Compound E-13), 4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound I-1), N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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]pyridin-4-yl]methyl]-N-methoxybenzamide (Compound A-15), 3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]benzamide (Compound A-20), 2-(4-bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]benzamide (Compound H-1), 3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound H-3), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]oxybenzamide (Compound H-4), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine-3-carboxamide (Compound J-8), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide (Compound J-10), 5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-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)pyridin-4-yl]methyl]pyridine-4-carboxamide (Compound L-1), 5-(2-fluoro-4-iodoanilino)-8-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (compound N-1), 5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (compound N-2), 4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (compound P-1), and 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide (compound P-2).

[0066] Among these compounds, in terms of, for example, MEK inhibitory activity, RAF inhibitory activity, cell proliferation inhibitory activity and / or metabolic stability, there are, for example, N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]benzamide (Compound A-1), N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-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)pyridin-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)pyridin-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)pyridin-4-yl]methyl]-N-methoxybenzamide (Compound A-13), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-25), 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-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)pyridin-4-yl]methyl]benzamide (Compound A-31), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-33), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-34), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide (Compound A-35), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-41), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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-(methanesulfonamido)phenyl]methyl]benzamide (Compound E-13), 4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound I-1), and N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (Compound J-5) are preferred; N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]benzamide (compound A-1) are more preferred, 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-1) is particularly preferred. Preferred pharmaceutically acceptable salts of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-1) include, for example, sodium salt and potassium salt.

[0067] A third aspect of the present disclosure provides a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt. A fourth aspect of the present disclosure provides a MEK inhibitor containing such a compound, salt, or solvate as an active ingredient: [wherein ring A is a group represented by the following general formula (2), (3) or (4) (wherein bonds marked with *, ** and *** are -NH-, -CONH- and -CH ２ - is bonded to. X １ , X ２ , X ３ , X ４ and X ５ are each independently -CR ２ = or -N=, and R ２ is a hydrogen atom, a halogen atom or a C1-4 alkyl group, and R １ is -S(=O) ２ -NH-R ８ Or -S(=O) ２ -R ８ and R ８ is a C1-4 alkyl group (the C1-4 alkyl group may be substituted with a halogen atom, a hydroxy 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), and R ３ is a hydrogen atom, a C3-6 cycloalkyl group or a C1-6 alkoxy group, R ５ is a halogen atom, R ６ is a hydrogen atom, and R ４ is a halogen atom or a C3-6 cycloalkyl group, R ７ is a C1-4 alkyl group, and R ９ is a hydrogen atom.]

[0068] The compound, salt, or solvate according to the third or fourth aspect has high MEK inhibitory activity and can be used for the treatment or prevention of cell proliferative diseases, particularly cancer (more specifically, for example, cancer with RAF mutation).

[0069] Examples of the compound of the third or fourth aspect include, for example, 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (compound A-1), (+ / -)-3,4-difluoro-5-[[3-fluoro-2-(2-hydroxypropylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]benzamide (compound A-21), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-25), 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-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)pyridin-4-yl]methyl]benzamide (Compound A-33), 5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-40), 3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-42), 5-[[2-(ethylsulfonylamino)-3-fluoropyridin-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)pyridin-4-yl]methyl]benzamide (Compound C-3), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]pyridine-4-carboxamide (Compound L-1), 5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (Compound N-1), 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide (Compound P-2), 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-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)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (compound P-6) is preferred.

[0070] Examples of abbreviations used herein are listed below along with their meanings: 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: dimethylsulfoxide 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(diphenylphosphino)-9,9-dimethylxanthene

[0071] Next, an example of a preferred method for producing the compound of the present disclosure will be described. １ , R １ , R ２ , R ３ , R ４ , R ５ and R ７ The definition of R is as stated above unless otherwise interpreted in the context. ａ represents, for example, a 4-methylphenyl group or a 2-nitrophenyl group, and R ｂ represents, for example, a Boc group or a 2,4-dimethoxybenzyl group.

[0072] (General Production Method-1) General Production Method-1 is a method for producing a compound represented by general formula (6) in which X ２ , X ３ and X ４ (X ２ , X ３ and X ４ may be the same or different. ２ = and R ６ is a hydrogen atom.

[0073]

[0074] Step 1-1: S-reaction of aniline derivative 1b with fluorobenzene derivative 1a Ｎ Ar Reaction: Aniline derivative 1b is reacted with fluorobenzene derivative 1a in the presence of a base. Examples of the base include organolithium reagents, and lithium bis(trimethylsilyl)amide and lithium diisopropylamide are preferred. Examples of the solvent include polar aprotic solvents such as THF, 1,4-dioxane, and NMP, and THF is preferred.

[0075] Step 1-2: Methylation of Benzoic Acid Derivative 1c Benzoic acid derivative 1c is reacted with a methylating reagent. Examples of the methylating reagent include diazomethane derivatives, and diazomethyltrimethylsilane is preferred. Examples of the solvent include alcohols, nonpolar solvents, and mixed solvents thereof, and mixed solvents of toluene and methanol and THF and methanol are preferred.

[0076] Step 1-3: Hydrazonization of Aldehyde Derivative 1d The aldehyde derivative 1d is reacted with an arylsulfonyl hydrazide. Examples of the arylsulfonyl hydrazide include methylbenzenesulfonyl hydrazide and nitrobenzenesulfonyl hydrazide, with 4-methylbenzenesulfonyl hydrazide and 2-nitrobenzenesulfonyl hydrazide being preferred. Examples of the solvent include polar solvents such as alcohol, with methanol and ethanol being preferred.

[0077] Step 1-4: Coupling of Hydrazone Derivative 1e with Arylboronic Acid Derivative 1f Hydrazone derivative 1e is reacted with arylboronic acid derivative 1f in the presence of a base. Examples of the base include carbonates and amines, with potassium carbonate and DIPEA being preferred. Examples of the solvent 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.

[0078] Step 1-5: Deprotection of methyl benzoate derivative 1g The methyl benzoate derivative 1g is subjected to acidic conditions to remove the protecting group R ｂ The acid may be, for example, sulfuric acid, hydrochloric acid, methanesulfonic acid, or trifluoroacetic acid, with trifluoroacetic acid being preferred. The solvent may be, for example, an alcohol or a non-polar solvent such as DCM, with DCM being preferred.

[0079] Step 1-6: Hydrolysis of Ester Derivative 1h The ester derivative 1h is reacted with a hydroxide. Examples of the hydroxide include lithium hydroxide, potassium hydroxide, and sodium hydroxide, with lithium hydroxide being preferred. Examples of the solvent include alcohols, polar solvents such as THF, water, and mixed solvents thereof, with aqueous THF being preferred.

[0080] Step 1-7: Amidation of Benzoic Acid Derivative 1i Benzoic acid derivative 1i is reacted with a corresponding amine or amine hydrochloride in the presence of a condensing agent. 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, if appropriate, HOOBt or HOAt may also be added. Preferably, for example, a combination of EDC or EDC·HCl with HOOBt, or HATU is used. In addition to the condensing agent, a base such as DIPEA or triethylamine may be used, with DIPEA being preferred as the base. Examples of solvents include polar solvents such as DMF, DMA, NMP, methanol, and ethanol, as well as mixed solvents thereof, with DMF being preferred.

[0081] Step 1-8: Sulfamidation or Sulfonamidation of Amine Derivative 1j, 1ja, or 1jb Sulfamidation: In the presence of a base, amine derivative 1j, 1ja, or 1jb is reacted with the corresponding sulfamoyl chloride or 4-nitrophenyl sulfamate. The corresponding sulfamoyl chloride or 4-nitrophenyl sulfamate may have a Boc group. Examples of the base include amines, and pyridine, triethylamine, DIPEA, and imidazole are preferred. Examples of the solvent 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.

[0082] Sulfonamidation: Amine derivative 1j, 1ja, or 1jb is reacted with the corresponding sulfonyl chloride in the presence of a base. Examples of the base include amines, and pyridine, triethylamine, DIPEA, and imidazole are preferred. Examples of the solvent include polar solvents such as DMF, DMA, NMP, THF, 1,4-dioxane, acetonitrile, and pyridine, nonpolar solvents such as dichloromethane and dichloroethane, and mixtures thereof, with dichloromethane and pyridine being preferred.

[0083] Step 1-9-1: Boc-removal of sulfamide or sulfonamide derivative 1k1 R of sulfamide or sulfonamide derivative 1k1 １ or R ３ When compound 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, the Boc group may be removed by generating an acid in an alcohol, for example, with chlorotrimethylsilane (TMSCl). Examples of solvents include alcohols and nonpolar solvents such as DCM. Preferred combinations of acids and solvents include, for example, a combination of TMSCl and 2,2,2-trifluoroethanol or a combination of trifluoroacetic acid and DCM.

[0084] Step 1-9-2: Alkylation, alkenylation, alkynylation or thioetherification of sulfamide or sulfonamide derivative 1k1 R of sulfamide or sulfonamide derivative 1k1 ４ or R ５ When is a halogen, alkylation, alkenylation, alkynylation or thioetherification can be carried out, for example, by the following method.

[0085] Method 1 (Alkylation or Alkenylation by Suzuki-Miyaura Cross-Coupling): In the presence of Pd, compound 1k1 is reacted with the corresponding boronic acid, boronic ester, or borate. This reaction can be carried out, for example, 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. Preferred are sodium carbonate, potassium carbonate, and triethylamine. Examples of solvents include polar solvents such as THF, 1,4-dioxane, DMF, DMA, NMP, methanol, ethanol, 2-propanol, and water, as well as mixed solvents thereof. Preferred are mixed solvents of THF and 2-propanol and mixed solvents of THF and water. Pd and ligands can be selected from the group consisting of 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, and PdCl ２ (PPh ３ ) ２ , Pd(PPh ３ ) ４ and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride are preferred. The reaction temperature is preferably 80°C or higher.

[0086] Method 2 (Alkylation or Alkenylation by Negishi Cross-Coupling): In the presence of Pd or Ni, compound 1k1 is reacted with the corresponding organozinc reagent. For example, this can be performed by the method described in Tetrahedron. 1992, vol. 48, no. 44, p. 9577 or Aldrichimica Acta. 2005, vol. 38, p. 71. Examples of the solvent include polar solvents such as THF, 1,4-dioxane, DMF, DMA, and NMP, and mixed solvents thereof, with THF being preferred. Pd and Ni can be used in the presence of Pd or Ni, for example, as described in Tetrahedron. 1992, vol. 48, no. 44, p. 9577 and Aldrichimica Acta. 2005, vol. 38, p. 71. 71, as well as PdCl ２ (PPh ３ ) ２ , Pd(PPh ３ ) ４ and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, PdCl ２ (PPh ３ ) ２ , Pd(PPh ３ ) ４ and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride are preferred.

[0087] Method 3 (alkynylation by Sonogashira cross-coupling): In the presence of Pd and Cu, compound 1k1 is reacted with the corresponding alkyne. For example, this can be performed by the method described in Chem. Soc. Rev. 2011, vol. 40, p. 5048. The corresponding alkyne may have a silyl group, 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 PdCl ２ (PPh ３ ) ２ , Pd(PPh ３ ) ４, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, Pd(OAc) ２ , and Pd ２ (dba) ３ and PdCl ２ (PPh ３ ) ２ , Pd(PPh ３ ) ４ and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride are preferred. Examples of Cu 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.

[0088] Method 4 (thioetherification): Compound 1k1 is reacted with the corresponding mercaptan or mercaptan salt in the presence of Pd. Examples of the base include amines such as triethylamine, DIPEA, DBU, and piperidine, with triethylamine and DIPEA being preferred. Examples of the Pd catalyst include Pd(PPh ３ ) ４ Examples of the solvent include zero-valent Pd complexes such as [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate. Examples of the solvent 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.

[0089] Step 1-10: Bromination or chlorination of amine derivative 1j R of amine derivative 1j ４ or R ５ When is a halogen, compound 1j can be brominated or chlorinated by reacting it with copper bromide or copper chloride. Examples of the solvent include polar solvents such as THF, 1,4-dioxane, DMF, DMA, and NMP, with DMF being preferred.

[0090] Step 1-11: TBS reaction of amine derivative 1j R of amine derivative 1j ３ When 1j has a hydroxy group, TBS conversion can be carried out by reacting compound 1j with tert-butyldimethylchlorosilane (TBSCl) in the presence of a base. Examples of the base include triethylamine, DIPEA, and imidazole, with triethylamine being preferred. Examples of the solvent include polar solvents such as THF, 1,4-dioxane, DMF, DMA, and NMP, with DMF being preferred.

[0091] Step 1-12-1: Detangling of TBS from sulfamide or sulfonamide derivative 1k2 R of sulfamide or sulfonamide derivative 1k2 ３ When compound 1k2 has a TBS group, the TBS group is removed by reacting compound 1k2 with tetrabutylammonium fluoride. Examples of the solvent include polar solvents such as THF, 1,4-dioxane, and DMF, and THF is preferred.

[0092] Step 1-12-2: Desilylation of sulfamide or sulfonamide derivative 1k2 R of sulfamide or sulfonamide derivative 1k2 ４ or R ５ When compound 1k2 has a silyl group, the silyl group is removed by reacting compound 1k2 with a base. Examples of the base include carbonates, and potassium carbonate is preferred. Examples of the solvent include alcohols such as methanol and ethanol, and methanol is preferred.

[0093] (General Production Method-2) General Production Method-2 is another preferred method for producing compound 1k1.

[0094] Step 2-1: Sulfamidation or sulfonamidation of amine derivative 1h is carried out in the same manner as in Step 1-8. Step 2-2: Hydrolysis of ester derivative 2a is carried out in the same manner as in Step 1-6. Step 2-3: Amidation of benzoic acid derivative 2b is carried out in the same manner as in Step 1-7. Before the amidation, Boc deprotection, alkylation, alkenylation, alkynylation, thioetherification, bromination, or chlorination of benzoic acid derivative 2b may be carried out as necessary in the same manner as in Step 1-9-1, 1-9-2, or 1-10.

[0095] (General Production Method-3) General Production Method-3 is another preferred method for producing compound 1k1.

[0096] Step 3-1: Hydrazone formation of aldehyde derivative 1c is carried out in the same manner as in Step 1-3. Step 3-2: Amidation of benzoic acid derivative 3a is carried out in the same manner as in Step 1-7. Step 3-3: Coupling of hydrazone derivative 3b with arylboronic acid derivative 1f, and addition of a protecting group R ｂ and 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.

[0097] (General Production Method-4) General Production Method-4 is a compound represented by general formula (1) in which ring A is a group represented by general formula (4), and X １ is -N=, and X ２ is -CF= and R ６ and R ９ is a hydrogen atom.

[0098] Step 4-1: Alkylation of Compound 4a Compound 4a is reacted with compound 4b in the presence of a base. Examples of the base include phosphates and metal alkoxides such as sodium tert-butoxide, with tripotassium phosphate being preferred. Potassium iodide or tetrabutylammonium iodide may be added to accelerate the reaction, with tetrabutylammonium iodide being preferred. Examples of the solvent 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.

[0099] In producing the compounds of the present disclosure, the starting compounds or reagents may form salts or solvates as long as the desired reaction is not inhibited.

[0100] When the compound of the present disclosure is obtained in the form of a free form, it can be converted into a pharmaceutically acceptable salt or solvate by a conventional method. When the compound of the present disclosure is obtained in the form of a pharmaceutically acceptable salt or solvate, it can be converted into a free form by a conventional method.

[0101] The compounds of the present disclosure can be isolated or purified, for example, by distillation, recrystallization, or chromatography. Also, when isomers (e.g., enantiomers, diastereomers, or conformers) exist, they can be isolated or purified, for example, by recrystallization, diastereomeric salt methods, enzymatic resolution, or chromatography (e.g., thin layer chromatography, column chromatography, high performance liquid chromatography, or gas chromatography).

[0102] In one aspect, the present disclosure provides a pharmaceutical composition comprising, as an active ingredient, a compound, salt, or solvate of any one of the first to fourth aspects.

[0103] In another aspect, the present disclosure provides an agent for treating or preventing cell proliferative diseases, particularly cancer, which comprises the compound, salt, or solvate of any one of the first to fourth aspects as an active ingredient.

[0104] The subject to which the compounds, salts, or solvates of the present disclosure are administered is an animal, preferably a mammal (e.g., a mouse, rat, rabbit, dog, monkey (e.g., a cynomolgus monkey), or human), and particularly preferably a human. The human may be an adult (18 years of age or older) or a child (under 18 years of age). The child is preferably, for example, 6 months of age or older.

[0105] When the compound, salt, or solvate of the present disclosure is used for the treatment or prevention of a cell proliferative disorder, the dosage and administration interval can be determined appropriately depending on the severity of symptoms, the age and body weight of the subject, the presence or absence of concomitant medications, the administration method, etc. For example, when the subject is a human, the dosage is typically 0.00001 to 5000 mg per kg of body weight, preferably 0.01 to 100 mg, administered once a day to once every three weeks. When administered daily, the above amount may be divided into 2 to 4 doses.

[0106] Methods of administration to a subject include, for example, systemic administration such as oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneous administration, intracisternal administration, intravaginal administration, intraperitoneal administration, intravesical administration, and inhalation administration, and local administration using an ointment, gel, or cream, with oral administration being preferred.

[0107] The compounds, salts or solvates of the present disclosure are usually formulated into certain preparations (dosage forms) for use. Such preparations include, for example, tablets, capsules, granules, powders, fine granules, pills, and aqueous or non-aqueous solutions and suspensions. The solutions and suspensions can be filled and stored in suitable containers for dividing into individual doses.

[0108] The various formulations described above can be prepared by well-known methods by mixing the compound, salt, or solvate of the present disclosure with pharmaceutically acceptable additives, such as excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavoring agents, bases, dispersants, diluents, surfactants, and emulsifiers.

[0109] Examples of excipients include starch (starch, potato starch, corn starch, etc.), lactose, crystalline cellulose, and calcium hydrogen phosphate.

[0110] Lubricants (coating agents) include, for example, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, and paraffin.

[0111] Examples of binders include polyvinylpyrrolidone and macrogol, as well as compounds similar to the above-mentioned excipients.

[0112] Examples of disintegrants include chemically modified starches and celluloses such as croscarmellose sodium, carboxymethyl starch sodium, and cross-linked polyvinylpyrrolidone, as well as compounds similar to the above-mentioned excipients.

[0113] Examples of stabilizers include paraoxybenzoic acid esters such as methylparaben and propylparaben; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.

[0114] Flavoring agents include, for example, commonly used sweeteners, acidulants and fragrances.

[0115] Examples of bases include fats such as lard; vegetable oils such as olive oil and sesame oil; higher alcohols such as stearyl alcohol and cetanol; animal oils; lanolin; petrolatum; paraffin; bentonite; glycerin; and glycolic oil.

[0116] Dispersing agents include, for example, cellulose derivatives (e.g., gum arabic, tragacanth, and methylcellulose), stearic acid polyesters, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbates, and sorbitan fatty acid esters.

[0117] Examples of solvents or diluents in the liquid formulation include phenol, chlorocresol, purified water, and distilled water.

[0118] Surfactants or emulsifiers include, for example, polysorbate 80, polyoxyl 40 stearate, and lauromacrogol.

[0119] The preferred content of the compound, salt or solvate of the present disclosure in the formulation varies depending on the dosage form, but is usually 0.01 to 100% by weight based on the total weight of the formulation.

[0120] Cell proliferative diseases to be treated or prevented using the compounds, salts, or solvates of the present disclosure include cancer, rheumatism, and inflammation, preferably cancer.

[0121] Examples of cancer include blood and lymphatic cancers such as leukemia (acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, etc.), malignant lymphoma (Hodgkin's disease, non-Hodgkin's lymphoma, etc.), multiple myeloma, and 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, stomach cancer, and colorectal cancer (appendicitis cancer, colon cancer, rectal cancer, etc.). solid cancers such as 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 / ureter cancer, malignant melanoma, 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, trichoepithelioma, etc.).

[0122] Cancer may have a genetic mutation, may not have a genetic mutation, or it may be unclear whether it has a genetic mutation or not. Examples of genes that may be mutated include EGFR, FGFR, ALK, ROS1, PI3K, BRAF, HRAS, KRAS, and NRAS.

[0123] When the compound, salt, or solvate of the first or second aspect is used, the cancer is preferably, for example, a cancer with a RAS mutation, and particularly preferably, for example, a solid cancer with a KRAS mutation (particularly, non-small cell lung cancer). In one embodiment, it is also used for a cancer with a RAF mutation, particularly, a cancer with both a RAF mutation and a RAS mutation. When the compound, salt, or solvate of the third or fourth aspect is used, the cancer is preferably, for example, a cancer with a RAF mutation, and particularly preferably, for example, a solid cancer with a BRAF mutation (particularly, malignant melanoma).

[0124] The present disclosure will be explained in more detail below based on examples (production examples and test examples), but the present disclosure is not limited to the following examples.

[0125] [Preparation Example] NMR analysis was carried out using an AVANCE III HD400 (400 MHz) manufactured by BRUKER Corp. NMR data are given in ppm (parts per million) (δ) and were referenced to the deuterium lock signal from the sample solvent.

[0126] Mass spectral data were obtained using a Shimadzu single quadrupole mass spectrometer (LCMS-2020) equipped with an ultra-high performance liquid chromatograph (Nexera UC) or a Waters single quadrupole mass spectrometer (SQD or SQD2) equipped with an Acquity ultra-high performance liquid chromatograph (UPLC or UPLC I-Class).

[0127] High performance liquid chromatography was performed under any of analytical conditions A to G shown in Table 2 below. In Table 2 below, "TFA" means trifluoroacetic acid, "FA" means formic acid, and "AA" means ammonium acetate.

[0128] The microwave reaction was carried out using an Initiator manufactured by Biotage Inc. A snap-cap reaction vial was used for the microwave reaction.

[0129] Commercially available reagents were used without further purification. All non-aqueous reactions were carried out in anhydrous solvents. Concentration under reduced pressure or solvent evaporation was performed using a rotary evaporator.

[0130] As used herein, "room temperature" means a temperature of about 20°C to about 25°C.

[0131] In the following Preparation Examples, "Preparation Example for Compound A-1" means Preparation Example A-1-1, and "Preparation Example for Compound a9" means Preparation Example a9-1.

[0132] Compound a1: methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-formylbenzoate A suspension of 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-formylbenzoic acid (5.50 g, 13.1 mmol) in toluene (44 mL) and MeOH (11 mL) was cooled to 0°C, and 10% diazomethyltrimethylsilane hexane solution (21.8 mL, 13.1 mmol) was added, followed by stirring at room temperature for 64 hours. To the reaction mixture was added acetic acid (0.748 mL), and the mixture was concentrated under reduced pressure. The resulting residue was purified by trituration (hexane / ethyl acetate) to give the title compound (5.01 g, 88%) as a colorless solid. LCMS m / z: 436 [M+H] ＋ HPLC retention time: 1.00 minutes (Analysis conditions D)

[0133] Compound a2: methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzoate 4-Methylbenzenesulfonyl hydrazide (2.14 g, 11.5 mmol) was added to a suspension of methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-formylbenzoate (compound a1, 5.00 g, 11.5 mmol) in EtOH (100 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then hexane (150 mL) was added. The mixture was cooled to 0°C, filtered, and washed with hexane (30 mL) to obtain the title compound (7.05 g, quant.) as a solid. LCMS m / z: 604 [M+H] ＋ HPLC retention time: 1.06 minutes (Analysis conditions D)

[0134] Compound a3: N-(2,4-dimethoxybenzyl)-3-fluoro-4-iodopyridin-2-amine Triethylamine (3.63 mL, 26.0 mmol) and 1-(2,4-dimethoxyphenyl)methanamine (3.26 mL, 21.7 mmol) were added to a solution of 2,3-difluoro-4-iodopyridine (2.09 g, 8.67 mmol) in NMP (32 mL), and the mixture was stirred at 100° C. for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 13% brine, dried over anhydrous sodium sulfate, and the drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (3.20 g, 95%) as an oily substance. LCMS m / z: 389 [M+H] ＋ HPLC retention time: 0.94 minutes (Analysis conditions C)

[0135] Compound a4: [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid A 1,4-dioxane solution (27 mL) of N-(2,4-dimethoxybenzyl)-3-fluoro-4-iodopyridin-2-amine (compound a3, 2.70 g, 6.96 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (568 mg, 0.696 mmol), potassium acetate (2.05 g, 20.9 mmol), and bis(pinacolato)diboron (2.65 g, 10.4 mmol) was stirred at 90° C. for 5 hours and then at 110° C. for 19 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give the title compound (2.07 g, 97%) as an oil. LCMS m / z: 307 [M+H] ＋ HPLC retention time: 0.44 minutes (Analysis conditions C)

[0136] Compound a5: 5-[[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate methyl A suspension of methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzoate (Compound a2, 1.30 g, 2.16 mmol), [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (Compound a4, 1.98 g, 6.46 mmol), and potassium carbonate (357 mg, 2.59 mmol) in 1,4-dioxane (59 mL) was stirred under a nitrogen atmosphere at 100°C for 2.5 hours and then at 110°C for 3 hours. Ethyl acetate was added to the reaction mixture, which was washed with water and 13% brine. The organic layer was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (524 mg, 36%) as a foam. LCMS m / z: 682 [M+H] ＋ HPLC retention time: 1.03 minutes (Analysis conditions D)

[0137] Compound a6: methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate A DCM solution (16 mL) of methyl 5-[[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound a5, 523 mg, 0.768 mmol) was cooled to 0°C, trifluoroacetic acid (15.7 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.05% aqueous trifluoroacetic acid / 0.05% acetonitrile trifluoroacetic acid solution) to give the title compound (321 mg, 79%) as an oil. LCMS m / z: 532 [M+H] ＋ HPLC retention time: 0.55 minutes (Analysis conditions D)

[0138] Compound a7: 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride A solution of methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound a6, 4.00 g, 7.53 mmol) in THF (64 mL) and water (32 mL) was cooled to 0°C, lithium hydroxide monohydrate (948 mg, 22.6 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. After cooling to 0°C, 5M hydrochloric acid (15.1 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was washed with water and TBME to give the title compound (4.20 g, quant.) as a purple solid. LCMS m / z: 518 [M+H] ＋ HPLC retention time: 0.68 minutes (Analysis conditions C)

[0139] Compound a8: 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide A solution of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride (compound a7, 200 mg, 0.361 mmol) in anhydrous DMF (3.6 mL) was cooled to 0 ° C., and HOOBt (67.8 mg, 0.415 mmol) and EDC·HCl (80.0 mg, 0.415 mmol) were added, followed by stirring at room temperature for 1.5 hours. Further, HOOBt (8.8 mg, 0.054 mmol) and EDC·HCl (10.4 mg, 0.054 mmol) were added, followed by stirring at room temperature for 1 hour. After stirring at room temperature, 7M ammonia in MeOH (0.103 mL, 0.722 mmol) and DIPEA (0.189 mL, 1.08 mmol) were added at 0 ° C., followed by stirring at room temperature for 30 minutes. Water and saturated aqueous sodium bicarbonate solution were added to the reaction mixture in a 1:1 ratio, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (1 mL), and hexane (10 mL) was added. The resulting solid was collected by filtration and washed with hexane to give the title compound (162 mg, 87%) as a colorless solid. LCMS m / z: 517 [M+H] ＋ HPLC retention time: 0.64 minutes (Analysis conditions C)

[0140] Compound a9: 5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluorobenzamide Preparation Example a9-1: Tetrakis(triphenylphosphine)palladium(0) (11.2 mg, 9.68 μmol) and 0.5 M cyclopropylzinc bromide (1.94 mL, 0.969 mmol) were added to an anhydrous THF solution (1.9 mL) of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (Compound a8, 100 mg, 0.194 mmol), and the mixture was stirred at room temperature under a nitrogen atmosphere for 2.5 hours. Ethyl acetate (5 mL) was added to the reaction mixture, which was then filtered through Celite and washed with ethyl acetate (3 mL). The filtrate was washed with water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the mixture was concentrated under reduced pressure. Dichloromethane / hexane (1 / 10, 11 mL) was added to the obtained residue, and the solid was collected by filtration and washed with hexane (3 mL) to obtain compound a9 (63.4 mg, 76%) as a colorless solid. LCMS m / z: 431 [M+H] ＋ HPLC retention time: 0.61 minutes (Analysis conditions C)

[0141] Compound r1: 4-nitrophenyl methylsulfamate A dichloromethane solution (60 mL) of 4-nitrophenol (5.00 g, 35.9 mmol) and triethylamine (11.3 mL, 81.0 mmol) was cooled to -78°C, and a dichloromethane solution (15 mL) of methylsulfamoyl chloride (5.82 g, 44.9 mmol) was added, followed by stirring 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 reverse-phase column chromatography (0.1% aqueous formic acid / 0.1% formic acid in acetonitrile) to give the title compound (5.51 g, 66%) as a colorless solid. HPLC retention time: 0.63 minutes (analysis condition C). １ H-NMR (400MHz, CDCl ３) δ: 8.31 (2H, m), 7.46 (2H, m), 4.68 (1H, m), 3.00 (3H, d, J=5.4Hz).

[0142] Compound A-1: ​​2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide Preparation Example A-1-1: 5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluorobenzamide (Compound a9, 2.47 g, 5.74 mmol) was dissolved in anhydrous DMF (28.7 mL), pyridine (2.78 mL, 34.4 mmol) and 4-nitrophenyl methylsulfamate (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, and the solid was collected by filtration. 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 conditions A)

[0143] Compound a10: 5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-cyclopropyl-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride (compound a7, 100 mg, 0.193 mmol) was dissolved in anhydrous DMF (1 mL), and HOOBt (63.1 mg, 0.387 mmol) and EDC.HCl (74.1 mg, 0.387 mmol) were added at room temperature. After stirring at room temperature for 3 hours, aminocyclopropane (33.1 mg, 0.580 mmol) and DIPEA (0.101 mL, 0.580 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid in water / 0.1% formic acid in acetonitrile) to give the title compound (103 mg, 96%) as a brown solid. LCMS m / z: 557 [M+H] ＋ HPLC retention time: 0.73 minutes (Analysis conditions C)

[0144] Compound A-2: N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-cyclopropyl-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (Compound a10) under the same conditions as in the production example for Compound A-1. LCMS m / z: 650 [M+H] ＋ HPLC retention time: 1.65 minutes (Analysis conditions B)

[0145] Compound r2: 1-chlorosulfonyloxy-4-nitrobenzene A solution of 4-nitrophenol (12.0 g, 86 mmol) and pyridine (6.98 mL, 86 mmol) in Et ２ The suspension (96 mL) was cooled to -78°C and dissolved in sulfuryl chloride (6.98 mL, 86 mmol) in Et ２ A solution of 100 ml of HCl (96 mL) was added over 10 minutes, and the mixture was stirred at room temperature for 6.5 hours. The reaction mixture was filtered and ２After washing with 0 (15 mL), the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / DCM) to give the title compound (19.8 g, 97%) as a yellow oil. HPLC retention time: 0.77 min (analysis condition C). １ H-NMR (400MHz, CDCl ３ ) δ: 8.41 (2H, m), 7.61 (2H, m).

[0146] Compound r3: N-[(2,4-dimethoxyphenyl)methyl]sulfamic acid 4-nitrophenyl A DCM solution (36 mL) of 1-chlorosulfonyloxy-4-nitrobenzene (compound r2, 1.78 g, 7.48 mmol) was cooled to -78°C, and a DCM solution (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) was added over 10 minutes, followed by stirring 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% aqueous formic acid / 0.1% formic acid acetonitrile solution) and silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.28 g, 58%) as a colorless solid. LCMS m / z: 367 [M-H] － HPLC retention time: 0.81 minutes (Analysis conditions C)

[0147] Compound r4: 4-nitrophenyl sulfamate The title compound was synthesized from 4-nitrophenyl N-[(2,4-dimethoxyphenyl)methyl]sulfamate (Compound r3) under the same conditions as in the production example for Compound a6. LCMS m / z: 217 [M−H] － HPLC retention time: 0.53 minutes (Analysis conditions C)

[0148] Compound r5: 4-nitrophenyl N-ethylsulfamate 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 [M−H]－ HPLC retention time: 0.68 minutes (Analysis conditions C)

[0149] Compound r6: N-cyclopropylsulfamic acid 4-nitrophenyl 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 [M−H] － HPLC retention time: 0.70 minutes (Analysis conditions C)

[0150] Compound r7: N-(2-fluoroethyl)sulfamic acid 4-nitrophenyl 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 [M−H] － HPLC retention time: 0.65 minutes (Analysis conditions C)

[0151] Compound r11: N-[2-[tert-butyl(dimethyl)silyl]oxypropyl]sulfamic acid 4-nitrophenyl 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 [M−H] － HPLC retention time: 1.03 minutes (Analysis conditions C)

[0152] Compound r8: N-(2-methoxyethyl)sulfamic acid 4-nitrophenyl 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 minutes (Analysis conditions C)

[0153] Compound r9: N-(1-methylcyclobutyl)sulfamic acid 4-nitrophenyl 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 minutes (Analysis conditions C)

[0154] Compound r10: N-[1-(methoxymethyl)cyclopropyl]sulfamic acid 4-nitrophenyl 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 minutes (Analysis conditions C)

[0155] Compound r12: 4-nitrophenyl N-propylsulfamate 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 conditions C)

[0156] Compound r13: N-(oxetan-3-ylmethyl)sulfamic acid 4-nitrophenyl 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 conditions C)

[0157] Compound r14: N-(3-oxabicyclo[3.1.0]hexan-6-yl)sulfamic acid 4-nitrophenyl 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 conditions C)

[0158] Compound r15: N-(1-methylcyclopropyl)sulfamic acid 4-nitrophenyl 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 conditions C)

[0159] Compound r16: N-[[(2R)-oxolan-2-yl]methyl]sulfamic acid 4-nitrophenyl 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 minutes (Analysis conditions C)

[0160] Compound r17: N-(1-methoxy-2-methylpropan-2-yl)sulfamic acid 4-nitrophenyl 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 for compound r3. HPLC retention time: 0.76 minutes (analysis condition C). １ H-NMR (400MHz, DMSO-d ６ ) 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).

[0161] Compound A-3: N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(sulfamoylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-cyclopropyl-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (Compound a10) and the corresponding 4-nitrophenyl sulfamate under the same conditions as in the preparation example for Compound A-1. LCMS m / z: 636 [M+H]＋ HPLC retention time: 1.58 minutes (Analysis conditions B)

[0162] Compound A-4: N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide The title compound was synthesized from 5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-cyclopropyl-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (Compound a10) and the corresponding 4-nitrophenyl sulfamate under the same conditions as in the preparation example for Compound A-1. LCMS m / z: 664 [M+H] ＋ HPLC retention time: 1.70 minutes (Analysis conditions B)

[0163] Compound A-5: N-cyclopropyl-5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide The title compound was synthesized from 5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-cyclopropyl-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (Compound a10) and the corresponding 4-nitrophenyl sulfamate under the same conditions as in the preparation example for Compound A-1. LCMS m / z: 676 [M+H] ＋ HPLC retention time: 1.70 minutes (Analysis conditions B)

[0164] Compound A-6: N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide The title compound was synthesized from 5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-cyclopropyl-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (Compound a10) and the corresponding 4-nitrophenyl sulfamate under the same conditions as in the preparation example for Compound A-1. LCMS m / z: 682 [M+H] ＋ HPLC retention time: 1.66 minutes (Analysis conditions B)

[0165] Compound A-7: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methylbenzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid hydrochloride (Compound a7) under the same conditions as in the preparation examples for Compound a10 and Compound A-1. However, a 2M methylamine THF solution was used in place of the aminocyclopropane used in the preparation example for Compound a10. LCMS m / z: 624 [M+H] ＋ HPLC retention time: 1.62 minutes (Analysis conditions B)

[0166] Compound a12: 5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-(tert-butoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid hydrochloride (compound a7, 100 mg, 0.181 mmol) was dissolved in anhydrous DMF (0.9 mL), HOOBt (58.9 mg, 0.361 mmol) and EDC.HCl (69.2 mg, 0.361 mmol) were added, and the mixture was stirred at room temperature for 3.5 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 minutes (Analysis conditions C)

[0167] Compound A-8: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide The title compound was synthesized from 5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-(tert-butoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (Compound a12) under the same conditions as in the production example for Compound A-1. LCMS m / z: 682 [M+H] ＋ HPLC retention time: 1.69 minutes (Analysis conditions B)

[0168] Compound A-9: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide The title compound was synthesized from 5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-(tert-butoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (Compound a12) and the corresponding 4-nitrophenyl sulfamate under the same conditions as in the preparation example for Compound A-1. LCMS m / z: 726 [M+H] ＋ HPLC retention time: 1.71 minutes (Analysis conditions B)

[0169] Compound A-10: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-propan-2-yloxybenzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid hydrochloride (Compound a7) and the corresponding amine under the same conditions as in the production example for Compound a12 and Compound A-1. LCMS m / z: 668 [M+H] ＋ HPLC retention time: 1.24 minutes (Analysis conditions A)

[0170] Compound A-11: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]-N-propan-2-yloxybenzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid hydrochloride (Compound a7) and the corresponding amine under the same conditions as in the preparation example for Compound a12 and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 712 [M+H] ＋ HPLC retention time: 1.26 minutes (Analysis conditions A)

[0171] Compound A-12: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]-N-propan-2-yloxybenzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid hydrochloride (Compound a7) and the corresponding amine under the same conditions as in the preparation example for Compound a12 and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 722 [M+H] ＋ HPLC retention time: 1.81 minutes (Analysis conditions B)

[0172] Compound A-13: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid hydrochloride (Compound a7) and the corresponding amine under the same conditions as in the production example for Compound a12 and Compound A-1. LCMS m / z: 640 [M+H] ＋ HPLC retention time: 1.16 minutes (Analysis conditions A)

[0173] Compound A-14: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid hydrochloride (Compound a7) and the corresponding amine under the same conditions as in the preparation example for Compound a12 and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 684 [M+H] ＋ HPLC retention time: 1.18 minutes (Analysis conditions A)

[0174] Compound A-15: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]-N-methoxybenzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid hydrochloride (Compound a7) and the corresponding amine under the same conditions as in the preparation example for Compound a12 and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 694 [M+H] ＋ HPLC retention time: 1.72 minutes (Analysis conditions B)

[0175] Compound A-16: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[[1-(methoxymethyl)cyclopropyl]sulfamoylamino]pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid hydrochloride (Compound a7) and the corresponding amine under the same conditions as in the preparation example for Compound a12 and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 680 [M+H]＋ HPLC retention time: 1.20 minutes (Analysis conditions A)

[0176] Compound a15: 5-[[2-[2-[tert-butyl(dimethyl)silyl]oxypropylsulfamoylamino]-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid hydrochloride (Compound a7) and the corresponding amine under the same conditions as in the preparation example for Compound a12 and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 768 [M+H] ＋ HPLC retention time: 1.12 minutes (Analysis conditions C)

[0177] Compound A-17: (+ / -)-3,4-difluoro-5-[[3-fluoro-2-(2-hydroxypropylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (racemic) 5-[[2-[2-[tert-Butyl(dimethyl)silyl]oxypropylsulfamoylamino]-3-fluoropyridin-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), and (-)-10-camphorsulfonic acid (27.2 mg, 0.117 mmol) was added and 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 give 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)

[0178] Compound a16: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-methylsulfanylanilino)benzamide 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8, 30.0 mg, 0.058 mmol) was dissolved in anhydrous 1,4-dioxane (0.3 mL), and methyl mercaptan sodium (12.2 mg, 0.174 mmol), DIPEA (30.4 μL, 0.174 mmol), and [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (11.2 mg, 0.012 mmol) were added, followed by stirring at room temperature for 30 minutes under a nitrogen atmosphere. The reaction mixture was purified by reverse phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give the title compound (15 mg, 59%) as a colorless solid. LCMS m / z: 437 [M+H] ＋ HPLC retention time: 0.60 minutes (Analysis conditions C)

[0179] Compound A-18: 3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-methylsulfanylanilino)benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-methylsulfanylanilino)benzamide (Compound a16) under the same conditions as in the production example for Compound A-1. LCMS m / z: 530 [M+H] ＋ HPLC retention time: 1.09 minutes (Analysis conditions A)

[0180] Compound a17: 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzamide 5-[(2-amino-3-fluoropyridin-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), and potassium vinyltrifluoroborate (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, followed by stirring at 80°C for 2 hours under a nitrogen atmosphere. The reaction mixture was filtered through Celite, and the solid was 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 give the title compound (343 mg, 85%) as a colorless solid. LCMS m / z: 417 [M+H] ＋ HPLC retention time: 0.60 minutes (Analysis conditions C)

[0181] Compound A-19: 2-(4-ethenyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzamide (Compound a17) under the same conditions as in the production example for Compound A-1. LCMS m / z: 510 [M+H] ＋ HPLC retention time: 1.11 minutes (Analysis conditions A)

[0182] Compound a18: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-[2-fluoro-4-(2-trimethylsilylethynyl)anilino]benzamide To a solution of 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8, 2.67 g, 5.17 mmol) in anhydrous THF (26 mL), 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 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)

[0183] Compound a19: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-ethynyl-2-fluoroanilino)-3,4-difluorobenzamide Potassium carbonate (17.0 mg, 0.123 mmol) was added to a solution (0.411 mL) of 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-[2-fluoro-4-(2-trimethylsilylethynyl)anilino]benzamide (Compound a18, 20.0 mg, 0.041 mmol) in MeOH, 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 give the title compound (14 mg, 82%) as a colorless solid. LCMS m / z: 415 [M+H] ＋ HPLC retention time: 0.60 minutes (analysis condition G)

[0184] Compound A-20: 2-(4-ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-ethynyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound a19) and the corresponding 4-nitrophenyl sulfamate under the same conditions as in the preparation example for Compound A-1. LCMS m / z: 536 [M+H] ＋ HPLC retention time: 1.18 minutes (Analysis conditions A)

[0185] Compound A-21: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(oxetan-3-ylmethylsulfamoylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding 4-nitrophenyl sulfamate under the same conditions as in the preparation example for Compound A-1, except that imidazole was used instead of pyridine. LCMS m / z: 666 [M+H] ＋ HPLC retention time: 1.11 minutes (Analysis conditions A)

[0186] Compound A-22: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(3-oxabicyclo[3.1.0]hexan-6-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding 4-nitrophenyl sulfamate under the same conditions as in the preparation example for Compound A-1, except that imidazole was used instead of pyridine. LCMS m / z: 678 [M+H] ＋ HPLC retention time: 1.16 minutes (Analysis conditions A)

[0187] Compound A-23: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclopropyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding 4-nitrophenyl sulfamate under the same conditions as in the preparation example for Compound A-1, except that 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)

[0188] Compound A-24: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methoxy-2-methylpropan-2-yl)sulfamoylamino]pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding 4-nitrophenyl sulfamate under the same conditions as in the preparation example for Compound A-1, except that 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)

[0189] Compound A-25: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8, 10.0 mg, 0.019 mmol) was dissolved in anhydrous DMA (0.1 mL), and pyridine (2.3 μL, 0.029 mmol) and methylsulfamoyl chloride (2.5 μL, 0.029 mmol) were added at 0° C., followed by stirring at room temperature for 1 hour. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give the title compound (10.2 mg, 86%) as a colorless solid. LCMS m / z: 610 [M+H] ＋ HPLC retention time: 1.15 minutes (Analysis conditions A)

[0190] Compound s2: N-(1-bicyclo[1.1.1]pentanyl)sulfamoyl chloride Sulfuryl chloride (0.102 mL, 1.25 mmol) was dissolved in anhydrous acetonitrile (1.5 mL), and bicyclo[1.1.1]pentan-1-amine hydrochloride (50.0 mg, 0.418 mmol) was added at 0° C., followed by stirring at 80° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to obtain the title compound as a crude product.

[0191] Compound s3: N-(oxan-4-yl)sulfamoyl chloride The title compound was synthesized from the corresponding amine under the same conditions as in the preparation example for compound s2, except that triethylamine was also added.

[0192] Compound A-28: 5-[[2-(1-bicyclo[1.1.1]pentanylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding sulfamoyl chloride under the same conditions as in the production example for Compound A-25. LCMS m / z: 662 [M+H] ＋ HPLC retention time: 1.27 minutes (Analysis conditions A)

[0193] Compound A-29: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(oxan-4-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding sulfamoyl chloride under the same conditions as in the production example for Compound A-25. LCMS m / z: 680 [M+H] ＋ HPLC retention time: 1.16 minutes (Analysis conditions A)

[0194] Compound A-30: 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding sulfamoyl chloride under the same conditions as in the production example for Compound A-25. LCMS m / z: 636 [M+H] ＋ HPLC retention time: 1.21 minutes (Analysis conditions A)

[0195] Compound A-31: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding sulfamoyl chloride under the same conditions as in the production example for Compound A-25. LCMS m / z: 638 [M+H] ＋ HPLC retention time: 1.24 minutes (Analysis conditions A)

[0196] Compound A-32: 5-[[2-(cyclobutylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding sulfamoyl chloride under the same conditions as in the production example for Compound A-25. LCMS m / z: 650 [M+H] ＋ HPLC retention time: 1.26 minutes (Analysis conditions A)

[0197] Compound A-33: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding sulfamoyl chloride under the same conditions as in the production example for Compound A-25. LCMS m / z: 654 [M+H] ＋ HPLC retention time: 1.17 minutes (Analysis conditions A)

[0198] Compound A-34: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding sulfamoyl chloride under the same conditions as in the production example for Compound A-25. LCMS m / z: 652 [M+H] ＋ HPLC retention time: 1.31 minutes (Analysis conditions A)

[0199] Compound A-35: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding sulfamoyl chloride under the same conditions as in the preparation example for Compound A-25, except that the reaction was performed at 0°C. LCMS m / z: 664 [M+H] ＋ HPLC retention time: 1.30 minutes (Analysis conditions A)

[0200] Compound A-36: 5-[[2-(cyclopropylmethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding sulfamoyl chloride under the same conditions as in the preparation example for Compound A-25, except that the reaction was performed at 0°C. LCMS m / z: 650 [M+H] ＋ HPLC retention time: 1.26 minutes (Analysis conditions A)

[0201] Compound A-37: 5-[[2-(tert-butylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding sulfamoyl chloride under the same conditions as in the preparation example for Compound A-25, except that the reaction was performed at 0°C. LCMS m / z: 652 [M+H] ＋ HPLC retention time: 1.28 minutes (Analysis conditions A)

[0202] Compound A-38: 5-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding sulfonyl chloride under the same conditions as in the preparation example for Compound A-25, except that pyridine was used as the solvent. LCMS m / z: 609 [M+H] ＋ HPLC retention time: 1.20 minutes (Analysis conditions A)

[0203] Compound A-39: N-cyclopropyl-5-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-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 for Compound A-25, except that pyridine was used as the solvent. LCMS m / z: 649 [M+H] ＋ HPLC retention time: 1.68 minutes (Analysis conditions B)

[0204] Compound A-40: 5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding sulfamoyl chloride under the same conditions as in the production example for Compound A-25. LCMS m / z: 624 [M+H] ＋ HPLC retention time: 1.20 minutes (Analysis conditions A)

[0205] Compound A-41: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding sulfamoyl chloride under the same conditions as in the production example for Compound A-25. LCMS m / z: 638 [M+H] ＋ HPLC retention time: 1.25 minutes (Analysis conditions A)

[0206] Compound A-42: 3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding sulfamoyl chloride under the same conditions as in the production example for Compound A-25. LCMS m / z: 642 [M+H] ＋ HPLC retention time: 1.17 minutes (Analysis conditions A)

[0207] Compound a20: 3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-2-[2-fluoro-4-(2-trimethylsilylethynyl)anilino]benzamide 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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, followed by stirring 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 give the title compound (12.4 mg) as an oil. LCMS m / z: 580 [M+H] ＋ HPLC retention time: 0.95 minutes (Analysis conditions C)

[0208] Compound A-26: 2-(4-ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide 3,4-Difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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 give 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)

[0209] Compound a21: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-bromo-2-fluoroanilino)-3,4-difluorobenzamide 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8, 60.0 mg, 0.116 mmol) was dissolved in anhydrous DMF (1.2 mL), copper(I) bromide (83.0 mg, 0.581 mmol) was added, and the mixture was stirred at 100° C. for 24 hours. The reaction mixture was purified by preparative HPLC (TSK-gel ODS 80TS 5 μm, 20×250 mm column (TOSOH), 0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give the title compound (35.6 mg) as a solid. LCMS m / z: 469 [M+H] ＋ HPLC retention time: 0.61 minutes (Analysis conditions C)

[0210] Compound A-27: 2-(4-bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-bromo-2-fluoroanilino)-3,4-difluorobenzamide (Compound a21) under the same conditions as in the production example for Compound A-25. LCMS m / z: 562 [M+H] ＋ HPLC retention time: 1.13 minutes (Analysis conditions A)

[0211] Compound A-43: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[[methyl-(methylamino)-oxo-λ6-sulfanylidene]amino]pyridin-4-yl]methyl]benzamide 5-[(2-amino-3-fluoropyridin-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 methanesulfinic acid 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 the mixture was stirred for 1 minute, followed by the addition of tert-butyl hypochlorite (44.6 μL, 0.395 mmol). After adding 2M methylamine THF solution (1.98 mL, 3.95 mmol) 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 give 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)

[0212] Compound a22: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid trifluoroacetate Methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)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, followed by stirring at room temperature for 2 hours. Trifluoroacetic acid (305 mL) was added to the reaction mixture, which was then concentrated under reduced pressure. The resulting residue was washed with water to give the title compound (1.06 g, 85%) as a colorless solid. LCMS m / z: 518 [M+H] ＋ HPLC retention time: 0.68 minutes (Analysis conditions C)

[0213] Compound a23: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-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 for Compound a12. LCMS m / z: 577 [M+H] ＋ HPLC retention time: 0.58 minutes (Analysis conditions C)

[0214] Compound a24: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-N-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide 5-[(2-amino-3-fluoropyridin-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, followed by stirring 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, followed by stirring for 7 hours. The reaction mixture was purified by reverse-phase column chromatography (10 mM aqueous ammonium acetate / methanol) to obtain the title compound (302 mg, 79%) as a yellow solid. LCMS m / z: 691 [M+H] ＋ HPLC retention time: 0.98 minutes (Analysis conditions C)

[0215] Compound a25: N-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide 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 under the same conditions as in the production example for Compound A-25. LCMS m / z: 798 [M+H] ＋ HPLC retention time: 1.11 minutes (Analysis conditions C)

[0216] Compound A-44: 5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)benzamide N-[2-[tert-Butyl(dimethyl)silyl]oxyethoxy]-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a25, 18 mg, 0.023 mmol) was dissolved in anhydrous THF (0.2 mL), and 1 M tetrabutylammonium fluoride THF solution (27 μL, 0.27 mmol) was added at 0° C. and stirred for 2 hours. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give the title compound (14 mg, 91%) as a yellow solid. LCMS m / z: 684 [M+H] ＋ HPLC retention time: 0.79 minutes (Analysis conditions C)

[0217] Compound A-45: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide 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 under the same conditions as in the production example for Compound A-25. LCMS m / z: 698 [M+H] ＋ HPLC retention time: 0.83 minutes (Analysis conditions C)

[0218] Compound A-46: 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound a9) and the corresponding 4-nitrophenyl sulfamate under the same conditions as in the preparation example for Compound A-1. LCMS m / z: 578 [M+H] ＋ HPLC retention time: 0.89 minutes (Analysis conditions C)

[0219] Compound A-47: N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a10) and the corresponding 4-nitrophenyl sulfamate under the same conditions as in the preparation example for Compound A-1. LCMS m / z: 704 [M+H] ＋ HPLC retention time: 0.97 minutes (Analysis conditions C)

[0220] Compound a26: 5-bromo-2,3,4-trifluorobenzoic acid A reaction vessel containing water (81 mL) was cooled to an external temperature of 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 external temperature was heated to 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. The reaction mixture was cooled to 0°C, and an aqueous solution prepared from sodium sulfite (24.3 g, 161 mmol) and water (324 mL) was added. The crystals were collected by filtration, washed with water (162 mL), and blow-dried to obtain the title compound (27.9 g, 71%) as a colorless solid. LCMS m / z: 253 [M-H] － HPLC retention time: 0.66 minutes (Analysis conditions C)

[0221] Compound a27: 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzoic acid A reaction vessel containing a 1M lithium bis(trimethylsilyl)amide THF solution (206 mL, 206 mmol) was cooled to an external temperature of -15°C, and a THF (30 mL) solution of 4-cyclopropyl-2-fluoroaniline (11.6 g, 76.5 mmol) was added dropwise. Furthermore, a THF (120 mL) solution of 5-bromo-2,3,4-trifluorobenzoic acid (Compound a26, 15.0 g, 58.8 mmol) was added dropwise over 30 minutes, followed by stirring for 30 minutes. 5M hydrochloric acid (118 mL) was added to the reaction mixture, which was then warmed to room temperature and extracted with isopropyl acetate (75 mL). The organic layer was washed twice with water (75 mL) and once with 15% aqueous sodium chloride solution (75 mL), and then concentrated under reduced pressure. Acetone (120 mL) was added to the resulting concentrated residue, and the mixture was heated to dissolve. Water (45 mL) and seed crystals (150 mg) were then added to precipitate crystals. Water (45 mL) was added to the resulting slurry, and the crystals were collected by filtration. The mixture was washed with a mixture of acetone / water (1 / 2) and dried under reduced pressure at an external 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 conditions C)

[0222] Compound a28: 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide Acetonitrile (104 mL), THF (26 mL), and 1,1'-carbonyldiimidazole (8.2 g, 50.5 mmol) were added to a reaction vessel containing 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzoic acid (compound a27, 13.0 g, 33.7 mmol), and the mixture was stirred at room temperature for 2 hours. 28% aqueous ammonia (13 mL) was added to the reaction mixture, which was then stirred at room temperature for 30 minutes, and water (117 mL) was added over 1 hour. The crystals were collected by filtration, washed with water, and dried under reduced pressure at an external temperature of 40°C to obtain the title compound (12.0 g, 93%). LCMS m / z: 385 [M+H] ＋ HPLC retention time: 0.52 minutes (Analysis conditions C)

[0223] Compound a30: N-[3-fluoro-4-(hydroxymethyl)pyridin-2-yl]acetamide methanesulfonate (1) Synthesis of N-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-fluoropyridin-2-yl]acetamide tert-Butyl-[(2-chloro-3-fluoropyridin-4-yl)methoxy]-dimethylsilane (180 g, 653 mmol), Xantphos (22.7 g, 39.2 mmol), potassium carbonate (135 g, 979 mmol), acetamide (77.1 g, 1.31 mol), and 2-methyl-2-butanol (540 mL) were added to a reaction vessel, degassed under reduced pressure, and purged with nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (14.9 g, 16.3 mmol) and toluene (540 mL) were added, and the mixture was further degassed under reduced pressure and purged with nitrogen. Under a nitrogen atmosphere, the mixture was heated to an external temperature of 120°C and stirred for 7 hours. The external temperature was cooled to room temperature, and the reaction mixture was filtered and washed with toluene (450 mL). Activated carbon (9.00 g, 749 mmol) was added to the filtrate, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and washed twice with toluene (270 mL for the first time and 180 mL for the second time) to obtain a crude product of N-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-fluoropyridin-2-yl]acetamide as a toluene solution. LCMS m / z: 299 [M+H] ＋ HPLC retention time: 0.81 minutes (Analysis conditions C)

[0224] (2) Synthesis of Compound a30 The obtained toluene solution of N-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-fluoropyridin-2-yl]acetamide, toluene (175 mL), and methanol (195 mL) were added to a reaction vessel, and the mixture was degassed under reduced pressure and purged with nitrogen. Methanesulfonic acid (188 g, 1.96 mol) was added dropwise at an external temperature of 10°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to an external temperature of 0°C and stirred for 3 hours. The precipitate was collected by filtration and washed with a cooled mixture of toluene (312 mL) and methanol (78 mL). The collected solid and a mixture of toluene (1.1 L) and ethanol (492 mL) were added to a reaction vessel, and the mixture was stirred at an external temperature of 0°C for 1 hour. The solid was collected by filtration, washed with a mixture of toluene (281 mL) and ethanol (117 mL), and dried under reduced pressure at an external 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)

[0225] Compound a31: (2-acetamido-3-fluoropyridin-4-yl)methyl methyl carbonate 4-Dimethylaminopyridine (52.3 g, 428 mmol) was added to a reaction vessel containing N-[3-fluoro-4-(hydroxymethyl)pyridin-2-yl]acetamide methanesulfonate (compound a30, 50.0 g, 178 mmol) and 2-methyltetrahydrofuran (750 mL) at room temperature. The external temperature was cooled to 0 °C, and methyl chloroformate (21.9 g, 232 mmol) was added. The mixture was then warmed to room temperature and stirred. The precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure at an external temperature of 40 °C. Ethyl acetate (300 mL) was added to the concentrated residue, and the mixture was dissolved at room temperature. DIPEA (31.2 mL, 178 mmol), heptane (150 mL), and seed crystals were then added. After confirming the precipitation of crystals, heptane (1 L) was added. The slurry was cooled to an external temperature of 0 °C, and the crystals were collected by filtration and washed with a mixture of ethyl acetate / heptane (2 / 7). The mixture was dried under reduced pressure at an external temperature of 40° C. to give the title compound (31.3 g, 72%) as a colorless solid. LCMS m / z: 243 [M+H] ＋ HPLC retention time: 0.37 minutes (Analysis conditions C)

[0226] Compound a32: 5-[(2-acetamido-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide A reaction vessel was charged with 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound a28, 10.0 g, 26.0 mmol), bis(pinacolato)diboron (7.3 g, 28.6 mmol), potassium acetate (7.6 g, 77.9 mmol), and 2-methyltetrahydrofuran (150 mL), and the mixture was degassed under reduced pressure and replaced with nitrogen. (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (440 mg, 0.52 mmol) was added, and the mixture was further degassed under reduced pressure and replaced with nitrogen. Under a nitrogen atmosphere, the mixture was heated to an external temperature of 80°C and stirred for 6 hours. The external temperature was cooled to room temperature, potassium carbonate (10.8 g, 77.9 mmol) was added, the mixture was degassed under reduced pressure, and the atmosphere was replaced with nitrogen. (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (1.1 g, 1.3 mmol) was added, the mixture was further degassed under reduced pressure, and the atmosphere was replaced with nitrogen. Then, a solution of (2-acetamido-3-fluoropyridin-4-yl)methyl methyl carbonate (Compound a31, 12.6 g, 51.9 mmol) in 2-methyltetrahydrofuran (150 mL) was added. Under a nitrogen atmosphere, the mixture was heated to an external temperature of 70°C, and water (935 μL, 51.9 mmol) was added three times every 20 minutes, followed by stirring for 20 minutes. Further, water (7.0 mL) was added dropwise and stirred for 2 hours. A solution prepared from N-acetylcysteine ​​(847 mg, 5.2 mmol) and water (150 mL) was added, and stirred for 1 hour. After cooling to an external temperature of 40°C, the aqueous layer was discarded. The organic layer was washed with a 15% aqueous sodium chloride solution (150 mL), and insoluble matter was filtered off and concentrated under reduced pressure. Acetonitrile (500 mL) was added to the resulting concentrated residue, and the mixture was heated to an external temperature of 100°C to dissolve the solids, and then cooled to room temperature. The crystals were collected by filtration, washed with acetonitrile (200 mL), and dried under reduced pressure at an external temperature of 40°C to obtain the title compound (8.34 g, 68%). LCMS m / z: 471 [M-H] － HPLC retention time: 0.74 minutes (Analysis conditions C)

[0227] Compound a9: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide Preparation Example a9-2: Methanol (3 mL) and 5 M hydrochloric acid (0.42 mL, 2.1 mmol) were added to a reaction vessel containing 5-[(2-acetamido-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound a32, 100 mg, 0.21 mmol), and the mixture was stirred at an external temperature of 50°C for 6 hours. The reaction mixture was cooled to room temperature, and a 2 M aqueous sodium hydroxide solution (1.1 mL, 2.1 mmol) was added. Water (0.5 mL) was added to the resulting slurry, and the crystals were collected by filtration. The mixture was washed with a mixture of methanol / water (3 / 2) and dried under reduced pressure at an external 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 minutes (Analysis conditions C)

[0228] Compound A-1: ​​2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide Preparation Example A-1-2: 5-[(2-amino-3-fluoropyridin-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 stirred for 1 hour. To the reaction mixture were added acetonitrile (0.6 mL), water (0.3 mL), and seed crystals (1 mg), and the mixture was warmed 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 collected by filtration and washed with a mixed solution 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 conditions A)

[0229] Sodium salt of compound A-1: ​​2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide sodium salt (1) Preparation of Sample A-1a (Form I) 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-1, 3.03 g) was added to acetone (10.6 mL) and DMSO (1.51 mL) and dissolved at room temperature. To this solution was added 20% sodium ethoxide ethanol solution (3.03 mL) and seed crystals of the sodium salt of Compound A-1 (Sample A-1b described below), and the mixture was stirred at room temperature for 1 hour. Ethanol (15.1 mL) was then added and the mixture was stirred at room temperature for 4 hours. Thereafter, further 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 powdery crystal (Sample A-1a (Form I)).

[0230] (2) Preparation of Sample A-1b To Compound A-1 (53.6 mg), 20% sodium ethoxide ethanol solution (0.054 mL) and methyl isobutyl ketone (0.161 mL) were added, followed by stirring at room temperature for 30 minutes. Methyl isobutyl ketone (0.161 mL) was then added, and the mixture was stirred at 60° C. for 4 days. DMSO (0.054 mL) was then 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 powdery crystals (Sample A-1b).

[0231] (3) Preparation of Sample A-1c DMSO (4.26 mL) and 2 M aqueous sodium hydroxide solution (1.07 mL) were added to Compound A-1 (1.02 g). 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. After stirring at room temperature for 6 hours, the sodium salt of Compound A-1 (0.966 g) was obtained as a powdery crystal (Sample A-1c).

[0232] (4) Powder X-ray Diffraction Measurement Sample A-1a (Form I), Sample A-1b, and Sample A-1c were subjected to powder X-ray diffraction measurement under the following conditions: Measurement device: SmartLab, D / Tex Ultra detector (manufactured by Rigaku Corporation) Anticathode: Cu Tube voltage: 45 kV Tube current: 200 mA Sampling width: 0.02°

[0233] The results of the powder X-ray diffraction measurements are shown in Figures 1 to 3. Figure 1 shows the powder X-ray diffraction pattern of Sample 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.

[0234] (5) Ion Chromatography The proportion of sodium ions in the crystals of Sample A-1a (Form I) was measured by ion chromatography, and the molar ratio of sodium ions to Compound A-1 was found to be 0.99. This confirmed that Sample A-1a was a monosodium salt. Ion chromatography was performed under the following conditions. Measurement equipment: Dionex ICS-1600, AS-AP (manufactured by Thermo Fisher Scientific) Column: 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 4 mm, 88 mA (manufactured by Thermo Fisher Scientific) Column temperature: 40°C Eluent flow rate: 1.00 mL / min Sample injection volume: 10 μL Detector: Electrical conductivity detector Sample treatment: Sample A-1a was dissolved in 20 mmol / L The sample was suspended in a methanesulfonic acid solution at a concentration of 0.5 mg / mL, and the suspension was shaken and stirred for 17 hours to extract sodium ions, and the supernatant was measured.

[0235] Compound b1: methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoate The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound a6) under the same conditions as in the production example for Compound A-25, except that anhydrous NMP was used instead of anhydrous DMA. LCMS m / z: 436 [M+H] ＋ HPLC retention time: 1.00 minutes (Analysis conditions D)

[0236] Compound b2: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoic acid A solution of methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoate (Compound b1, 158 mg, 0.253 mmol) in THF (4.8 mL) and water (2.4 mL) was cooled to 0°C, lithium hydroxide monohydrate (60.6 mg, 2.53 mmol) was added, and the mixture was stirred at room temperature for 2 hours. 2M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the mixture was concentrated under reduced pressure to obtain the title compound (161 mg) as a foam. LCMS m / z: 611 [M+H] ＋ HPLC retention time: 0.67 minutes (Analysis conditions D)

[0237] Compound B-1: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide The title compound was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoic acid (Compound b2) and the corresponding amine under the same conditions as in the preparation example for Compound a8. LCMS m / z: 670 [M+H] ＋ HPLC retention time: 1.07 minutes (Analysis conditions A)

[0238] Compound B-2: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-methoxyethoxy)benzamide The title compound was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoic acid (Compound b2) and the corresponding amine under the same conditions as in the preparation example for Compound a8. LCMS m / z: 684 [M+H] ＋ HPLC retention time: 1.56 minutes (Analysis conditions B)

[0239] Compound B-3: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-methylcyclopropyl)benzamide (mixture of 4 isomers) The title compound was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoic acid (Compound b2) and the corresponding amine under the same conditions as in the preparation example for Compound a8. LCMS m / z: 664 [M+H] ＋ HPLC retention time: 1.70 minutes and 1.72 minutes (analysis condition B)

[0240] Compound B-6: (+ / -)-N-(2,2-difluorocyclopropyl)-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (racemic form) The title compound was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoic acid (Compound b2) and the corresponding amine under the same conditions as in the preparation example for Compound a12. LCMS m / z: 686 [M+H] ＋ HPLC retention time: 1.69 minutes (Analysis conditions B)

[0241] Compound B-4: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(1S,2R)-(+ / -)-2-methylcyclopropyl]benzamide (racemic form) Compound B-5: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(1R,2R)-(+ / -)-2-methylcyclopropyl]benzamide (racemic form) 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-methylcyclopropyl)benzamide (mixture of 4 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), each as a solid. Compound B-4 LCMS m / z: 664 [M + H] ＋ HPLC retention time: 1.70 minutes (Analysis conditions B) Compound B-5 LCMS m / z: 664 [M+H] ＋ HPLC retention time: 1.72 minutes (Analysis conditions B)

[0242] Compound B-8: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfonylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound a6) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for Compound A-25, Compound b2, and Compound a8. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, used in the preparation example for Compound A-25. LCMS m / z: 623 [M+H] ＋ HPLC retention time: 1.63 minutes (Analysis conditions B)

[0243] Compound B-9: 3,4-difluoro-5-[[3-fluoro-2-(2-hydroxyethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound a6) and the corresponding sulfamoyl chloride under the same conditions as in the preparation examples for Compound A-25, Compound b2, and Compound a8. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, used in the preparation example for Compound A-25. LCMS m / z: 640 [M+H] ＋ HPLC retention time: 1.06 minutes (Analysis conditions A)

[0244] Compound b8: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(2-methylpropan-2-yl)oxycarbonylsulfamoylamino]pyridin-4-yl]methyl]benzoic acid The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound a6) and the corresponding sulfamoyl chloride under the same conditions as in the preparation examples for Compound A-25 and Compound b2. However, anhydrous NMP was used instead of anhydrous DMA used in the preparation example for Compound A-25. LCMS m / z: 697 [M+H] ＋HPLC retention time: 0.71 minutes (Analysis conditions D)

[0245] Compound b9: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(sulfamoylamino)pyridin-4-yl]methyl]benzoic acid 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]pyridin-4-yl]methyl]benzoic acid (Compound b8, 131 mg, 0.188 mmol), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give the title compound (75.0 mg, 67%) as a foam. LCMS m / z: 597 [M+H] ＋ HPLC retention time: 0.60 minutes (Analysis conditions D)

[0246] Compound B-10: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(sulfamoylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(sulfamoylamino)pyridin-4-yl]methyl]benzoic acid (Compound b9) and the corresponding amine under the same conditions as in the preparation example for Compound a12. LCMS m / z: 596 [M+H] ＋ HPLC retention time: 1.11 minutes (Analysis conditions A)

[0247] Compound b10: 2-(2-chloro-4-iodoanilino)-3,4-difluoro-5-formylbenzoic acid A 2M LDA THF solution (6.53 mL, 13.1 mmol) was cooled to -78°C, and a THF solution (6 mL) of 2,3,4-trifluorobenzoic acid (1.00 g, 5.68 mmol) was slowly added under a nitrogen atmosphere. 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 (15 mL) of 2-chloro-4-iodoaniline (1.44 g, 5.68 mmol) 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 previous 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 the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the drying agent was removed by filtration, and the mixture was concentrated under reduced pressure to give the title compound as a crude product (1.2 g). LCMS m / z: 438 [M+H] ＋ HPLC retention time: 0.91 minutes (analysis condition G)

[0248] Compound b12: methyl 2-(2-chloro-4-iodoanilino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzoate 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 production examples for compounds a1 and a2. LCMS m / z: 620 [M+H] ＋ HPLC retention time: 1.09 minutes (analysis condition G)

[0249] Compound b14: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate methyl The title compound was synthesized from methyl 2-(2-chloro-4-iodoanilino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzoate (Compound b12) under the same conditions as in the preparation examples for Compound a5 and Compound a6. However, DIPEA was used instead of potassium carbonate used in the preparation example for Compound a5. LCMS m / z: 548 [M+H]＋ HPLC retention time: 0.89 minutes (Analysis conditions C)

[0250] Compound B-11: 2-(2-chloro-4-iodoanilino)-5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluorobenzamide The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate (Compound b14) and the corresponding 4-nitrophenyl sulfamate under the same conditions as in the production examples for Compound A-1, Compound b2, and Compound a8. LCMS m / z: 652 [M+H] ＋ HPLC retention time: 1.67 minutes (Analysis conditions B)

[0251] Compound B-12: 2-(2-chloro-4-iodoanilino)-N-cyclopropyl-5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluorobenzamide The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate (Compound b14) and the corresponding 4-nitrophenyl sulfamate under the same conditions as in the preparation examples of Compound A-1, Compound b2, and Compound 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 conditions B)

[0252] Compound B-13: 2-(2-chloro-4-iodoanilino)-5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-N-[(2-methylpropan-2-yl)oxy]benzamide The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate (Compound b14) and the corresponding 4-nitrophenyl sulfamate under the same conditions as in the preparation examples of Compound A-1, Compound b2, and Compound 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 conditions B)

[0253] Compound B-14: N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methanesulfonamido)pyridin-4-yl]methyl]benzamide The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound a6) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for Compound A-25, Compound b2, and Compound a12. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA used in the preparation example for Compound A-25, respectively; 1 M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate used in the preparation example for Compound b2; and the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the preparation example for Compound a12. LCMS m / z: 635 [M+H] ＋ HPLC retention time: 0.87 minutes (Analysis conditions C)

[0254] Compound B-15: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methanesulfonamido)pyridin-4-yl]methyl]-N-methoxybenzamide The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound a6) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for Compound A-25, Compound b2, and Compound a12. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, used in the preparation example for Compound A-25, 1 M aqueous sodium hydroxide was used instead of lithium hydroxide monohydrate used in the preparation example for Compound b2, and the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the preparation example for Compound a12. LCMS m / z: 625 [M+H] ＋ HPLC retention time: 0.80 minutes (Analysis conditions C)

[0255] Compound B-16: 5-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound a6) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for Compound A-25, Compound b2, and Compound a12. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, used in the preparation example for Compound A-25, 1 M aqueous sodium hydroxide was used instead of lithium hydroxide monohydrate used in the preparation example for Compound b2, and the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the preparation example for Compound a12. LCMS m / z: 639 [M+H] ＋ HPLC retention time: 0.83 minutes (Analysis conditions C)

[0256] Compound c1: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzamide 4-Methylbenzenesulfonyl hydrazide (2.21 g, 11.9 mmol) was added to a solution of 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-formylbenzoic acid (5.00 g, 11.9 mmol) in anhydrous DMF (59 mL), and the mixture was stirred at room temperature for 30 minutes. Next, HOOBt (1.94 g, 11.9 mmol) and EDC.HCl (2.28 g, 11.9 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. 7M ammonia in MeOH (3.39 mL, 23.8 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The solid was then filtered off and washed with DMF (30 mL). Acetonitrile (90 mL) and 0.1M hydrochloric acid (90 mL) were added to the filtrate, and the resulting solid was washed with a mixture of acetonitrile and water to give the title compound (6.27 g, 90%) as a colorless solid. LCMS m / z: 589 [M+H] ＋ HPLC retention time: 0.90 minutes (Analysis conditions C)

[0257] Compound c2: [2-[(2,4-dimethoxyphenyl)methylamino]pyridin-4-yl]boronic acid The title compound was synthesized from 4-bromo-2-fluoropyridine under the same conditions as in the production examples for Compound a3 and Compound a4. LCMS m / z: 289 [M+H] ＋ HPLC retention time: 0.38 minutes (Analysis conditions C)

[0258] Compound c4: 5-[(2-aminopyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide 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 for Compound a5 and Compound a6. However, [2-[(2,4-dimethoxyphenyl)methylamino]pyridin-4-yl]boronic acid (Compound c2) was used in place of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (Compound a4) used in the preparation example for Compound a5. LCMS m / z: 649 [M+H] ＋HPLC retention time: 0.71 minutes (Analysis conditions C)

[0259] Compound C-1: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(sulfamoylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-[(2-aminopyridin-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 for Compound A-1. LCMS m / z: 578 [M+H] ＋ HPLC retention time: 1.42 minutes (Analysis conditions B)

[0260] Compound C-2: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-[(2-aminopyridin-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 for Compound A-1, except that imidazole was used instead of pyridine. LCMS m / z: 636 [M+H] ＋ HPLC retention time: 1.10 minutes (Analysis conditions A)

[0261] Compound C-3: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-[(2-aminopyridin-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 production example for Compound A-25. LCMS m / z: 592 [M+H] ＋ HPLC retention time: 1.08 minutes (Analysis conditions A)

[0262] Compound C-4: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-[[methyl-(methylamino)-oxo-λ6-sulfanylidene]amino]pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-[(2-aminopyridin-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 production example for Compound A-43. LCMS m / z: 590 [M+H] ＋ HPLC retention time: 0.92 minutes (Analysis conditions A)

[0263] Compound c5: 5-ethenyl-3,4-difluoro-2-(4-iodo-2-methylanilino)benzoic acid A solution of 4-iodo-2-methylaniline (636 mg, 2.73 mmol) in anhydrous THF (1.8 ml) was cooled to -78°C, and a 1.3 M solution of lithium bis(trimethylsilyl)amide in THF (5.08 mL, 6.60 mmol) was added over 1 hour, followed by stirring for 1 hour. Next, a solution of 2,3,4-trifluoro-5-vinylbenzoic acid (460 mg, 2.28 mmol) in anhydrous THF (3.9 mL) was added, followed by stirring at 0°C for 2 hours. Water and 2 M hydrochloric acid were added to the reaction mixture, which was then extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was removed by filtration. The mixture was then concentrated under reduced pressure. The resulting residue was suspended and washed with DCM to give the title compound (631 mg, 67%) as a brown solid. LCMS m / z: 416 [M+H] ＋ HPLC retention time: 0.99 minutes (analysis condition E)

[0264] Compound c6: 3,4-difluoro-5-formyl-2-(4-iodo-2-methylanilino)benzoic acid To a solution (6.3 mL) of 5-ethenyl-3,4-difluoro-2-(4-iodo-2-methylanilino)benzoic acid (Compound c5, 626 mg, 1.51 mmol) in anhydrous THF, 1 M aqueous sodium bicarbonate solution (3.02 mL, 3.02 mmol), sodium periodate (1.29 g, 6.03 mmol), and osmium(VIII) oxide, microencapsulated (38.3 mg, 0.015 mmol) were added and stirred at room temperature for 6 hours. Ethyl acetate was added to the reaction mixture, which was then washed with 1 M hydrochloric acid and 0.2 M aqueous sodium thiosulfate. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the mixture was concentrated under reduced pressure. The resulting residue was suspended and washed in ethyl acetate / hexane (1 / 25, 42 mL), and the solid was collected by filtration. The resulting solid was washed with hexane to give the title compound (558 mg, 89%) as a colorless solid. LCMS m / z: 418 [M+H] ＋ HPLC retention time: 0.86 minutes (Analysis conditions C)

[0265] Compound C-5: 3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-2-(4-iodo-2-methylanilino)benzamide 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 in the production examples for Compound c1, Compound a5, Compound a6, and Compound A-1. LCMS m / z: 606 [M+H] ＋ HPLC retention time: 1.20 minutes (Analysis conditions A)

[0266] Compound C-6: N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-(methylsulfamoylamino)phenyl]methyl]benzamide 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 production examples for Compound a2, Compound a10, Compound a5, and Compound A-1. LCMS m / z: 631 [M+H] ＋ HPLC retention time: 1.70 minutes (Analysis conditions B)

[0267] Compound d1: methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate The title compound was synthesized from methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzoate (Compound a2) under the same conditions as in the preparation example for Compound a5. However, (3-amino-2-fluorophenyl)boronic acid hydrochloride was used in place of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (Compound a4). LCMS m / z: 531 [M+H] ＋ HPLC retention time: 0.96 minutes (Analysis conditions D)

[0268] Compound d2: 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) under the same conditions as in the production example for Compound a7. LCMS m / z: 517 [M+H] ＋ HPLC retention time: 0.95 minutes (Analysis conditions C)

[0269] Compound D-1: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(2-methoxyethylsulfamoylamino)phenyl]methyl]benzamide 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 example for Compound a8 and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 653 [M+H] ＋ HPLC retention time: 1.24 minutes (Analysis conditions A)

[0270] 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 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 example for Compound a8 and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 681 [M+H] ＋ HPLC retention time: 1.35 minutes (Analysis conditions A)

[0271] Compound D-3: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[[(2R)-oxolan-2-yl]methylsulfamoylamino]phenyl]methyl]benzamide 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 example for Compound a8 and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 679 [M+H] ＋ HPLC retention time: 1.27 minutes (Analysis conditions A)

[0272] Compound D-4: 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide 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 example of Compound a8 and Compound A-25. However, the corresponding sulfonyl chloride was used in place 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 conditions A)

[0273] Compound D-5: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(2-methoxyethylsulfonylamino)phenyl]methyl]benzamide 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 example of Compound a8 and Compound A-25. However, the corresponding sulfonyl chloride was used in place 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 conditions B)

[0274] Compound D-6: N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide 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 production example for Compound a8 and Compound A-1. LCMS m / z: 649 [M+H] ＋ HPLC retention time: 1.71 minutes (Analysis conditions B)

[0275] Compound D-7: N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(sulfamoylamino)phenyl]methyl]benzamide 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 example for Compound a8 and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 635 [M+H] ＋ HPLC retention time: 1.65 minutes (Analysis conditions B)

[0276] Compound D-8: N-cyclopropyl-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide 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 example of Compound a8 and Compound A-25. However, the corresponding sulfonyl chloride was used in place 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 conditions B)

[0277] Compound D-9: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclobutyl)sulfamoylamino]phenyl]methyl]benzamide 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 example for Compound a8 and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 663 [M+H] ＋ HPLC retention time: 0.95 minutes (Analysis conditions C)

[0278] Compound D-10: N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclobutyl)sulfamoylamino]phenyl]methyl]benzamide 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 example for Compound a8 and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 703 [M+H] ＋ HPLC retention time: 1.01 minutes (Analysis conditions C)

[0279] Compound D-11: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]-N-methoxybenzamide 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 example of Compound a8 and Compound A-1. However, triethylamine was used instead of DIPEA used in the preparation example of Compound a8. LCMS m / z: 639 [M+H] ＋ HPLC retention time: 1.62 minutes (Analysis conditions B)

[0280] Compound D-12: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(sulfamoylamino)phenyl]methyl]-N-methoxybenzamide 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 production example for Compound a8 and Compound A-1. However, triethylamine was used instead of DIPEA used in the production example for Compound a8, and the corresponding 4-nitrophenyl sulfamate was used instead of 4-nitrophenyl methylsulfamate used in the production example for Compound A-1. LCMS m / z: 625 [M+H] ＋ HPLC retention time: 0.81 minutes (Analysis conditions C)

[0281] Compound D-13: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclobutyl)sulfamoylamino]phenyl]methyl]-N-methoxybenzamide 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 production example for Compound a8 and Compound A-1. However, triethylamine was used instead of DIPEA used in the production example for Compound a8, and the corresponding 4-nitrophenyl sulfamate was used instead of 4-nitrophenyl methylsulfamate used in the production example for Compound A-1. LCMS m / z: 693 [M+H] ＋ HPLC retention time: 0.95 minutes (Analysis conditions C)

[0282] Compound D-14: 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) under the same conditions as in the preparation examples for Compound a9, Compound a7, Compound a8, and Compound A-25. However, 1 M aqueous sodium hydroxide solution was used in place of lithium hydroxide monohydrate used in the preparation example for Compound a7. LCMS m / z: 523 [M+H] ＋ HPLC retention time: 1.58 minutes (Analysis conditions B)

[0283] Compound D-15: N-cyclopropyl-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) under the same conditions as in the preparation examples for Compound a9, Compound a7, Compound a8, and Compound A-25. However, 1 M aqueous sodium hydroxide solution was used in place of lithium hydroxide monohydrate used in the preparation example for Compound a7, and the corresponding amine was used in place of 7 M ammonia MeOH solution used in the preparation example for Compound a8. LCMS m / z: 563 [M+H] ＋ HPLC retention time: 1.68 minutes (Analysis conditions B)

[0284] Compound D-16: 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]-N-methoxybenzamide The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) under the same conditions as in the preparation examples for Compound a9, Compound a7, Compound a8, and Compound A-25. However, 1 M aqueous sodium hydroxide solution was used in place of lithium hydroxide monohydrate used in the preparation example for Compound a7, and the corresponding amine was used in place of 7 M ammonia MeOH solution used in the preparation example for Compound a8. LCMS m / z: 551 [M-H] － HPLC retention time: 0.85 minutes (Analysis conditions C)

[0285] Compound E-1: 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for Compound A-25, Compound b2, and Compound a12. However, pyridine was used as the solvent in the sulfonamidation step. Furthermore, the corresponding amine was used in place of tert-butoxyamine hydrochloride used in the preparation example for Compound a12. LCMS m / z: 638 [M+H] ＋ HPLC retention time: 1.68 minutes (Analysis conditions B)

[0286] Compound E-2: 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-[(2-methylpropan-2-yl)oxy]benzamide The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfonyl chloride under the same conditions as in the production examples for Compound A-25, Compound b2, and Compound 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 conditions B)

[0287] Compound E-3: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[[1-(methoxymethyl)cyclopropyl]sulfonylamino]phenyl]methyl]-N-methoxybenzamide The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for Compound A-25, Compound b2, and Compound a12. However, pyridine was used as the solvent in the sulfonamidation step. Furthermore, the corresponding amine was used in place of tert-butoxyamine hydrochloride used in the preparation example for Compound a12. LCMS m / z: 694 [M+H] ＋ HPLC retention time: 1.74 minutes (Analysis conditions B)

[0288] 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 The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfonyl chloride under the same conditions as in the production examples for Compound A-25, Compound b2, and Compound 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 conditions B)

[0289] Compound E-5: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclopropyl)sulfonylamino]phenyl]methyl]-N-methoxybenzamide The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for Compound A-25, Compound b2, and Compound a12. However, pyridine was used as the solvent in the sulfonamidation step. Furthermore, the corresponding amine was used in place of tert-butoxyamine hydrochloride used in the preparation example for Compound a12. LCMS m / z: 664 [M+H] ＋ HPLC retention time: 1.73 minutes (Analysis conditions B)

[0290] 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 The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfonyl chloride under the same conditions as in the production examples for Compound A-25, Compound b2, and Compound 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 conditions B)

[0291] Compound E-7: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) under the same conditions as in the preparation examples for Compound A-25, Compound b2, and Compound a12. However, pyridine was used as a solvent in the sulfamidation step. Furthermore, the corresponding amine was used in place of tert-butoxyamine hydrochloride used in the preparation example for Compound a12. LCMS m / z: 609 [M+H] ＋HPLC retention time: 1.23 minutes (Analysis conditions A)

[0292] Compound e11: tert-butyl N-[[3-[[5-carbamoyl-2,3-difluoro-4-(2-fluoro-4-iodoanilino)phenyl]methyl]-2-fluorophenyl]sulfamoyl]carbamate The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfamoyl chloride under the same conditions as in the preparation examples for Compound A-25, Compound b2, and Compound a12. However, pyridine was used as the solvent in the sulfamidation step. Furthermore, the corresponding amine was used in place of tert-butoxyamine hydrochloride used in the preparation example for Compound a12. LCMS m / z: 695 [M+H] ＋ HPLC retention time: 0.74 minutes (Analysis conditions D)

[0293] Compound E-8: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(sulfamoylamino)phenyl]methyl]benzamide 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 production example for Compound b9. LCMS m / z: 595 [M+H] ＋ HPLC retention time: 1.17 minutes (Analysis conditions A)

[0294] Compound E-9: 2-(2-chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-methoxybenzamide The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate (Compound b14) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for Compound A-25, Compound b2, and Compound a12. However, pyridine was used as a solvent in the sulfonamidation step. Furthermore, the corresponding amine was used in place of tert-butoxyamine hydrochloride used in the preparation example for Compound a12. LCMS m / z: 654 [M+H] ＋ HPLC retention time: 1.75 minutes (Analysis conditions B)

[0295] Compound E-10: 2-(2-chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-[(2-methylpropan-2-yl)oxy]benzamide The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate (Compound b14) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for Compound A-25, Compound b2, and Compound a12. However, pyridine was used as a solvent in the sulfonamidation step. Furthermore, the corresponding amine was used in place of tert-butoxyamine hydrochloride used in the preparation example for Compound a12. LCMS m / z: 696 [M+H] ＋ HPLC retention time: 1.87 minutes (Analysis conditions B)

[0296] Compound E-11: 2-(2-chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluorobenzamide The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate (Compound b14) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for Compound A-25, Compound b2, and Compound a12. However, pyridine was used as a solvent in the sulfonamidation step. Furthermore, the corresponding amine was used in place of tert-butoxyamine hydrochloride used in the preparation example for Compound a12. LCMS m / z: 624 [M+H] ＋ HPLC retention time: 1.73 minutes (Analysis conditions B)

[0297] Compound e17: 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate methyl The title compound was synthesized from methyl 2-(2-chloro-4-iodoanilino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzoate (Compound b12) under the same conditions as in the preparation example for Compound a5. However, (3-amino-2-fluorophenyl)boronic acid hydrochloride was used in place of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (Compound a4), and DIPEA was used in place of potassium carbonate. LCMS m / z: 547 [M+H] ＋ HPLC retention time: 1.13 minutes (Analysis conditions C)

[0298] Compound E-12: 2-(2-chloro-4-iodoanilino)-5-[[3-(cyclopropylsulfamoylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-[(2-methylpropan-2-yl)oxy]benzamide The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate (Compound e17) and the corresponding 4-nitrophenyl sulfamate under the same conditions as in the preparation examples for Compound A-1, Compound b2, and Compound a12. LCMS m / z: 723 [M+H] ＋HPLC retention time: 1.87 minutes (Analysis conditions B)

[0299] Compound e20: methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzoate The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation example for Compound A-25, except that pyridine was used as the solvent. LCMS m / z: 609 [M+H] ＋ HPLC retention time: 1.01 minutes (Analysis conditions C)

[0300] Compound E-13: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzamide To a solution of methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzoate (Compound e20, 23.0 mg, 0.038 mmol) in THF (0.7 mL) and water (0.3 mL), lithium hydroxide monohydrate (7.9 mg, 0.19 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and 1 M hydrochloric acid (0.76 mL) was added, followed by further concentration 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. Next, 7 M ammonia in MeOH (22 μL, 0.15 mmol) was added at 0°C, and the mixture was stirred for 30 minutes. To the reaction mixture was added 10% aqueous trifluoroacetic acid (1 mL), and the mixture was purified by reverse phase column chromatography (0.1% aqueous formic acid / 0.1% formic acid acetonitrile solution) to give the title compound (19.7 mg, 97%) as a colorless solid. LCMS m / z: 594 [M+H] ＋ HPLC retention time: 1.61 minutes (Analysis conditions B)

[0301] Compound E-14: 5-[[3-(cyclopropylmethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfonyl chloride under the same conditions as in the production examples for Compound A-25 and Compound 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 conditions B)

[0302] Compound E-15: 3,4-difluoro-5-[[2-fluoro-3-(3-fluoropropylsulfonylamino)phenyl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of Compound A-25 and Compound E-13. However, anhydrous DCM was used instead of anhydrous DMA used in the preparation example of Compound A-25. LCMS m / z: 640 [M+H] ＋ HPLC retention time: 1.67 minutes (Analysis conditions B)

[0303] Compound E-16: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclopropyl)sulfonylamino]phenyl]methyl]benzamide The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfonyl chloride under the same conditions as in the production examples for Compound A-25 and Compound 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 conditions B)

[0304] Compound E-17: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(2-methylpropylsulfonylamino)phenyl]methyl]benzamide The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfonyl chloride under the same conditions as in the production examples for Compound A-25 and Compound 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 conditions B)

[0305] Compound E-18: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(propylsulfonylamino)phenyl]methyl]benzamide The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfonyl chloride under the same conditions as in the production examples for Compound A-25 and Compound 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 conditions B)

[0306] Compound E-19: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[[1-(methoxymethyl)cyclopropyl]sulfonylamino]phenyl]methyl]benzamide The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfonyl chloride under the same conditions as in the production examples for Compound A-25 and Compound 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 conditions B)

[0307] Compound E-20: 5-[[3-(cyclobutylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfonyl chloride under the same conditions as in the production examples for Compound A-25 and Compound 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 conditions B)

[0308] Compound E-21: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxetan-3-ylsulfonylamino)phenyl]methyl]benzamide The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfonyl chloride under the same conditions as in the production examples for Compound A-25 and Compound 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 conditions B)

[0309] Compound E-22: 5-[[3-(cyclopropylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfonyl chloride under the same conditions as in the production examples for Compound A-25 and Compound 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 conditions B)

[0310] Compound E-23: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxan-4-ylsulfonylamino)phenyl]methyl]benzamide The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples of Compound A-25 and Compound E-13. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, used in the preparation example of Compound A-25. LCMS m / z: 664 [M+H] ＋ HPLC retention time: 1.65 minutes (Analysis conditions B)

[0311] Compound E-24: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(propan-2-ylsulfonylamino)phenyl]methyl]benzamide The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfonyl chloride under the same conditions as in the production examples for Compound A-25 and Compound 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 conditions B)

[0312] Compound E-25: N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzamide The title compound was synthesized from methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzoate (Compound e20) under the same conditions as in the preparation examples for Compound b2 and Compound a12. However, the corresponding amine was used in place of tert-butoxyamine hydrochloride used in the preparation example for Compound a12. LCMS m / z: 634 [M+H] ＋ HPLC retention time: 0.92 minutes (Analysis conditions C)

[0313] Compound E-26: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]-N-methoxybenzamide The title compound was synthesized from methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzoate (Compound e20) under the same conditions as in the preparation examples for Compound b2 and Compound a12. However, the corresponding amine was used in place of tert-butoxyamine hydrochloride used in the preparation example for Compound a12. LCMS m / z: 624 [M+H] ＋ HPLC retention time: 0.86 minutes (Analysis conditions C)

[0314] Compound F-1: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-(methylsulfamoylamino)phenyl]methyl]benzamide 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 for Compound a5 and Compound A-25. However, 3-aminophenylboronic acid was used in place of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (Compound a4) used in the preparation example for Compound a5. LCMS m / z: 591 [M+H] ＋ HPLC retention time: 0.84 minutes (Analysis conditions C)

[0315] Compound F-2: 5-[[3-(ethylsulfonylamino)phenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide 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 example for Compound a5 and Compound A-25. However, 3-aminophenylboronic acid was used in place of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (Compound a4) used in the preparation example for 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 conditions A)

[0316] Compound F-3: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-(2-methoxyethylsulfonylamino)phenyl]methyl]benzamide 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 example for Compound a5 and Compound A-25. However, 3-aminophenylboronic acid was used in place of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (Compound a4) used in the preparation example for 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 conditions B)

[0317] Compound g2: 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoic acid The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid hydrochloride (Compound a7) under the same conditions as in the production example for Compound a9 and Compound A-1. LCMS m / z: 525 [M+H] ＋ HPLC retention time: 0.83 minutes (Analysis conditions C)

[0318] Compound G-1: N-cyclopropyl-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoic acid (Compound g2) under the same conditions as in the production example for Compound a10. LCMS m / z: 564 [M+H] ＋ HPLC retention time: 1.61 minutes (Analysis conditions B)

[0319] Compound G-2: 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoic acid (compound g2, 20 mg, 0.038 mmol) in anhydrous DMF (0.2 mL) was added 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), 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 give the title compound (14 mg, 66%) as a colorless solid. LCMS m / z: 554 [M+H] ＋ HPLC retention time: 1.53 minutes (Analysis conditions B)

[0320] Compound G-3: 2-(4-bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid hydrochloride (Compound a7) under the same conditions as in the production examples for Compound a21, Compound A-1, and Compound G-2. LCMS m / z: 592 [M+H] ＋ HPLC retention time: 1.52 minutes (Analysis conditions B)

[0321] Compound G-4: 2-(4-chloro-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid hydrochloride (Compound a7) under the same conditions as in the preparation examples of Compound a21, Compound A-1, and Compound G-2. However, copper(I) chloride was used instead of copper(I) bromide used in the preparation example of Compound a21. LCMS m / z: 548 [M+H] ＋ HPLC retention time: 1.50 minutes (Analysis conditions B)

[0322] Compound G-5: N-cyclopropyl-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound a6) under the same conditions as in the preparation examples for Compound a9, Compound a7, Compound a12, and Compound A-1. However, 1 M aqueous sodium hydroxide was used instead of lithium hydroxide monohydrate used in the preparation example for Compound a7, and triethylamine was used instead of DIPEA used in the preparation example for Compound a12. Furthermore, the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the preparation example for Compound a12, and the corresponding 4-nitrophenyl sulfamate was used instead of 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 618 [M+H] ＋ HPLC retention time: 0.95 minutes (Analysis conditions C)

[0323] Compound G-6: 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]-N-methoxybenzamide The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound a6) under the same conditions as in the preparation examples for Compound a9, Compound a7, Compound a12, and Compound A-1. However, 1 M aqueous sodium hydroxide was used instead of lithium hydroxide monohydrate used in the preparation example for Compound a7, and triethylamine was used instead of DIPEA used in the preparation example for Compound a12. Furthermore, the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the preparation example for Compound a12, and the corresponding 4-nitrophenyl sulfamate was used instead of 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 608 [M+H] ＋ HPLC retention time: 0.90 minutes (Analysis conditions C)

[0324] Compound G-7: N-cyclopropyl-2-(4-cyclopropyl-2-fluoroanilino)-5-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluorobenzamide The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound a6) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for Compound A-25, Compound a9, Compound a7, and Compound a12. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, used in the preparation example for Compound A-25, and 1 M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate used in the preparation example for Compound a7. Furthermore, the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the preparation example for Compound a12. LCMS m / z: 563 [M+H] ＋ HPLC retention time: 0.88 minutes (Analysis conditions C)

[0325] Compound G-8: 2-(4-cyclopropyl-2-fluoroanilino)-5-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-N-methoxybenzamide The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound a6) and the corresponding sulfonyl chloride under the same conditions as in the production examples for Compound A-25, Compound a9, Compound a7, and Compound a12. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, used in the production example for Compound A-25, and 1 M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate used in the production example for Compound a7. Furthermore, the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the production example for Compound a12. LCMS m / z: 553 [M+H] ＋ HPLC retention time: 0.82 minutes (Analysis conditions C)

[0326] Compound G-9: 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methanesulfonamido)pyridin-4-yl]methyl]-N-methoxybenzamide The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound a6) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for Compound A-25, Compound a9, Compound a7, and Compound a12. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, used in the preparation example for Compound A-25, and 1 M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate used in the preparation example for Compound a7. Furthermore, the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the preparation example for Compound a12. LCMS m / z: 539 [M+H] ＋ HPLC retention time: 0.79 minutes (Analysis conditions C)

[0327] Compound h1: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-[3-(2-ethylhexoxy)-3-oxopropyl]sulfanyl-2-fluoroanilino]-3,4-difluorobenzoate methyl A suspension of methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate (Compound a6, 500 mg, 0.941 mmol), 2-ethylhexyl 3-mercaptopropionate (226 mg, 1.04 mmol), Xantphos (109 mg, 0.188 mmol), tris(dibenzylideneacetone)dipalladium(0) (86 mg, 0.094 mmol), and DIPEA (0.492 mL, 2.82 mmol) in 1,4-dioxane (17 mL) was stirred at 110° C. for 1 hour. Acetonitrile was added to the reaction mixture, which was then filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give the title compound (584 mg, quant.) as a yellow viscous oil. LCMS m / z: 622 [M+H] ＋ HPLC retention time: 1.14 minutes (analysis condition G)

[0328] Compound h2: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluorobenzoate methyl A methanol solution (9 mL) of methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-[3-(2-ethylhexoxy)-3-oxopropyl]sulfanyl-2-fluoroanilino]-3,4-difluorobenzoate (Compound h1, 584 mg, 0.939 mmol) was cooled to 0°C, and 25% sodium methoxide methanol solution (1.29 mL, 5.64 mmol) was added, followed by stirring at room temperature for 3 hours. Subsequently, diethyl (bromodifluoromethyl)phosphonate (1.00 g, 3.76 mmol) was added at 0°C, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0°C, and 25% sodium methoxide methanol solution (1.29 mL, 5.64 mmol) and diethyl (bromodifluoromethyl)phosphonate (1.51 g, 5.64 mmol) were added, followed by stirring at room temperature for 20 minutes. The reaction mixture was cooled to 0° C., and formic acid (0.213 mL, 5.64 mmol) was added, followed by concentration under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give the title compound (195 mg, 43%) as a colorless solid. LCMS m / z: 488 [M+H] ＋ HPLC retention time: 0.81 minutes (analysis condition G)

[0329] Compound h3: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluorobenzamide A mixture of methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluorobenzoate (Compound h2, 60.0 mg, 0.123 mmol) and 7M ammonia in MeOH (1.80 mL, 12.6 mmol) was stirred in a sealed tube at 85°C for 6 hours using a microwave reactor. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.05% aqueous trifluoroacetic acid / 0.05% acetonitrile trifluoroacetic acid solution) to give the title compound (53.2 g, 91%) as a yellow oil. LCMS m / z: 473 [M+H] ＋HPLC retention time: 0.63 minutes (Analysis conditions C)

[0330] Compound H-1: 2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluorobenzamide (Compound h3) under the same conditions as in the production example for Compound A-1. LCMS m / z: 566 [M+H] ＋ HPLC retention time: 1.49 minutes (Analysis conditions B)

[0331] Compound h4: 2-(1-benzothiophen-5-ylamino)-3,4-difluoro-5-formylbenzoic acid A solution of 2,2,6,6-tetramethylpiperidine (2.53 g, 17.9 mmol) in anhydrous THF (30 mL) was cooled to -78°C, and a 1.6 M n-butyllithium hexane solution (11.2 mL, 17.9 mmol) was added under a nitrogen atmosphere and stirred for 5 minutes. The reaction mixture was added to a solution of 2,3,4-trifluorobenzoic acid (1.50 g, 8.52 mmol) in THF (9.0 mL) at -78°C and stirred for 10 minutes. Anhydrous DMF (0.759 mL, 9.80 mmol) was then added and stirred at 0°C for 2 hours. In a separate flask, a THF solution (30 mL) of benzo[b]thiophenone-5-amine (1.65 g, 11.1 mmol) was cooled to -78°C, and 1.3 M lithium bis(trimethylsilyl)amide THF solution (15.1 mL, 19.6 mmol) and the above reaction mixture were added, followed by stirring at room temperature for 24 hours. 2 M hydrochloric acid was added to the reaction mixture, and after stirring for 24 hours, water and 2 M hydrochloric acid were added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. The resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give the title compound (609 mg, 21%) as a gray solid. LCMS m / z: 334 [M+H] ＋HPLC retention time: 0.80 minutes (Analysis conditions C)

[0332] Compound h5: 2-(1-benzothiophen-5-ylamino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzamide HOOBt (595 mg, 3.65 mmol) and EDC·HCl (699 mg, 3.65 mmol) were added to a suspension of 2-(1-benzothiophen-5-ylamino)-3,4-difluoro-5-formylbenzoic acid (Compound h4, 608 mg, 1.82 mmol) in anhydrous DMF (9.1 mL), and the mixture was stirred at room temperature for 1.5 hours. Next, 7M ammonia in MeOH (0.912 mL, 6.38 mmol) was added at 0°C, and the mixture was stirred for 30 minutes. 4-Methylbenzenesulfonyl hydrazide (340 mg, 1.82 mmol) was added at 0°C, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and then acetonitrile (14 mL) and 0.1M hydrochloric acid (100 mL) were added to the filtrate. The solid was filtered and washed with water to obtain the title compound (412 mg, 45%) as a light brown solid. LCMS m / z: 501 [M+H] ＋ HPLC retention time: 0.83 minutes (Analysis conditions C)

[0333] Compound h7: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(1-benzothiophen-5-ylamino)-3,4-difluorobenzamide The title compound was synthesized from 2-(1-benzothiophen-5-ylamino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzamide (Compound h5) under the same conditions as in the production examples for Compound a5 and Compound a6. LCMS m / z: 429 [M+H] ＋ HPLC retention time: 0.57 minutes (Analysis conditions C)

[0334] Compound H-2: 2-(1-benzothiophen-5-ylamino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(1-benzothiophen-5-ylamino)-3,4-difluorobenzamide (Compound h7) under the same conditions as in the production example for Compound A-1. LCMS m / z: 522 [M+H] ＋ HPLC retention time: 1.06 minutes (Analysis conditions A)

[0335] Compound h8: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]benzamide A solution of 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(1-benzothiophen-5-ylamino)-3,4-difluorobenzamide (Compound h7, 22 mg, 0.051 mmol) in anhydrous acetonitrile (0.3 mL) was cooled to 0°C, and N-fluoro-N'-(chloromethyl)triethylenediaminebis(tetrafluoroborate) (9.5 mg, 0.027 mmol) was added and stirred for 2.5 hours. Next, N-fluoro-N'-(chloromethyl)triethylenediaminebis(tetrafluoroborate) (8.0 mg, 0.023 mmol) was added and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.05% aqueous trifluoroacetic acid / 0.05% trifluoroacetic acid in acetonitrile) to give the title compound (8.0 mg, 35%) as a brown solid. LCMS m / z: 447 [M+H] ＋ HPLC retention time: 0.61 minutes (Analysis conditions C)

[0336] Compound H-3: 3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]benzamide (Compound h8) under the same conditions as in the preparation example for Compound A-1. LCMS m / z: 540 [M+H] ＋ HPLC retention time: 1.10 minutes (Analysis conditions A)

[0337] Compound h9: 1,2,3-trifluoro-4-[(4-methoxyphenyl)methoxy]benzene Potassium carbonate (9.90 g, 71.6 mmol) and 4-methoxybenzyl chloride (5.55 mL, 40.9 mmol) were added to a solution of 2,3,4-trifluorophenol (5.05 g, 34.1 mmol) in anhydrous acetone (101 mL), and the mixture was stirred at 70°C for 8 hours. Water (150 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the mixture was concentrated under reduced pressure. DMSO (15 mL) and water (100 mL) were added to the resulting residue, and the resulting solid was washed to give the title compound (8.72 g, 95%) as a gray solid. LCMS m / z: 267 [M-H] － HPLC retention time: 0.92 minutes (Analysis conditions C)

[0338] Compound h10: 2,3,4-trifluoro-5-[(4-methoxyphenyl)methoxy]benzoic acid A solution (15 mL) 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, 1.6 M lithium bis(trimethylsilyl)amide hexane solution (15.4 mL, 24.6 mmol) was added and stirred for 10 minutes. The reaction mixture was added to a solution (15 mL) 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 the mixture was stirred for 3 hours, followed by stirring for 30 minutes while injecting carbon dioxide gas. 1 M hydrochloric acid (60 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the mixture was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give the title compound (1.32 g, 34%) as a gray solid. LCMS m / z: 311 [M−H] － HPLC retention time: 0.80 minutes (Analysis conditions C)

[0339] Compound h13: methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-hydroxybenzoate The title compound was synthesized from 2,3,4-trifluoro-5-[(4-methoxyphenyl)methoxy]benzoic acid (Compound h10) under the same conditions as in the preparation examples of Compound c5, Compound a1, and Compound a6. However, 2-fluoro-4-iodoaniline was used instead of 4-iodo-2-methylaniline used in the preparation example of Compound c5, and anhydrous THF was used instead of toluene used in the preparation example of Compound a1. LCMS m / z: 424 [M+H] ＋ HPLC retention time: 0.91 minutes (Analysis conditions C)

[0340] Compound h14: 5-[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]oxy-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate methyl To a DCM solution (15 mL) of methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-hydroxybenzoate (Compound h13, 375 mg, 0.886 mmol), [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (Compound a4, 814 mg, 2.66 mmol), molecular 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 stirred at room temperature for 2.5 hours. Then, [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (Compound a4, 231 mg, 0.753 mmol) was added and stirred for 4 hours. N-acetylcysteine ​​(434 mg, 2.66 mmol) was added to the reaction mixture, and the mixture was stirred for 3 hours. The solid matter was filtered and washed with DCM (10 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give the title compound (168 mg, 28%) as a foam. LCMS m / z: 684 [M+H] ＋ HPLC retention time: 1.07 minutes (Analysis conditions C)

[0341] Compound H-4: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]oxybenzamide The title compound was synthesized from methyl 5-[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]oxy-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound h14) under the same conditions as in the production examples for Compound a6, Compound E-13, and Compound A-1. LCMS m / z: 612 [M+H] ＋ HPLC retention time: 1.55 minutes (Analysis conditions B)

[0342] Compound h17: 5-[[6-[bis[(4-methoxyphenyl)methyl]amino]pyridin-2-yl]-hydroxymethyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid A solution of 6-bromo-N,N-bis(4-methoxybenzyl)pyridin-2-amine (1.22 g, 2.95 mmol) in anhydrous THF (12 mL) was cooled to -40°C, and under a nitrogen atmosphere, 1.6 M lithium bis(trimethylsilyl)amide THF solution (1.85 mL, 2.95 mmol) was added and stirred for 30 minutes. The reaction mixture was added to a 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 the mixture was stirred for 20 minutes. 1 M hydrochloric acid (2 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (10 mM aqueous ammonium acetate solution / methanol) to give 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)

[0343] Compound h18: 5-[(6-aminopyridin-2-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid To a DCM solution (0.8 mL) of 5-[[6-[bis[(4-methoxyphenyl)methyl]amino]pyridin-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 stirred at room temperature for 1 hour. Next, further 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 give the title compound (72.7 mg, 90%) as a pink solid. LCMS m / z: 500 [M+H] ＋ HPLC retention time: 0.61 minutes (Analysis conditions C)

[0344] Compound H-5: 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[6-(methylsulfamoylamino)pyridin-2-yl]methyl]benzamide The title compound was synthesized from 5-[(6-aminopyridin-2-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid (Compound h18) under the same conditions as in the production example for Compound a8 and Compound A-1. LCMS m / z: 592 [M+H] ＋ HPLC retention time: 1.19 minutes (Analysis conditions A)

[0345] Compound I-1: 4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from 2,4-difluoro-5-vinylbenzoic acid under the same conditions as in the preparation examples for Compound c5, Compound c6, Compound c1, Compound a5, Compound a6, and Compound A-1. However, 2-fluoro-4-iodoaniline was used instead of 4-iodo-2-methylaniline used in the preparation example for Compound c5. LCMS m / z: 592 [M+H] ＋ HPLC retention time: 1.17 minutes (Analysis conditions A)

[0346] Compound I-2: 5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-4-fluoro-2-(2-fluoro-4-iodoanilino)benzamide The title compound was synthesized from 2,4-difluoro-5-vinylbenzoic acid under the same conditions as in the preparation examples of Compound c5, Compound c6, Compound c1, Compound a5, Compound a6, and Compound A-1. However, 2-fluoro-4-iodoaniline was used in place of 4-iodo-2-methylaniline used in the preparation example of Compound c5, and the corresponding 4-nitrophenyl sulfamate was used in place of 4-nitrophenyl methylsulfamate used in the preparation example of Compound A-1. LCMS m / z: 606 [M+H] ＋ HPLC retention time: 1.62 minutes (Analysis conditions B)

[0347] Compound I-3: 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-4-fluoro-2-(2-fluoro-4-iodoanilino)benzamide The title compound was synthesized from 2,4-difluoro-5-vinylbenzoic acid under the same conditions as in the preparation examples of Compound c5, Compound c6, Compound c1, Compound a5, Compound a6, and Compound A-1. However, 2-fluoro-4-iodoaniline was used in place of 4-iodo-2-methylaniline used in the preparation example of Compound c5, and the corresponding 4-nitrophenyl sulfamate was used in place of 4-nitrophenyl methylsulfamate used in the preparation example of Compound A-1. LCMS m / z: 618 [M+H] ＋ HPLC retention time: 1.64 minutes (Analysis conditions B)

[0348] Compound I-4: 4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide The title compound was synthesized from 2,4-difluoro-5-vinylbenzoic acid under the same conditions as in the preparation examples of Compound c5, Compound c6, Compound c1, Compound a5, Compound a6, and Compound A-1. However, 2-fluoro-4-iodoaniline was used in place of 4-iodo-2-methylaniline used in the preparation example of Compound c5, and the corresponding 4-nitrophenyl sulfamate was used in place of 4-nitrophenyl methylsulfamate used in the preparation example of Compound A-1. LCMS m / z: 636 [M+H] ＋ HPLC retention time: 1.19 minutes (Analysis conditions A)

[0349] Compound j1: methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate Thionyl chloride (10.6 mL, 145 mmol) was added over 10 minutes to a suspension of (2-amino-3-fluoropyridin-4-yl)methanol (10.3 g, 72.7 mmol) in DCM (91 mL), and the mixture was stirred at room temperature for 65 minutes. The reaction mixture was filtered, and the resulting solid was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, the drying agent was removed by filtration, and the mixture was concentrated under reduced pressure to give crude 2-amino-4-(chloromethyl)-3-fluoropyridine (10.3 g).

[0350] To a 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) in 1,3-dimethyl-2-imidazolidinone, the 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 collected by filtration and washed with a mixture of acetonitrile and water to give the title compound (10.3 g, 60%). LCMS m / z: 527 [M+H] ＋ HPLC retention time: 0.63 minutes (Analysis conditions C)

[0351] Compound j2: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid hydrochloride The title compound was synthesized from methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (Compound j1) under the same conditions as in the preparation example for Compound a7. LCMS m / z: 513 [M+H] ＋ HPLC retention time: 0.76 minutes (analysis condition E)

[0352] Compound j3: 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid hydrochloride (Compound j2) under the same conditions as in the preparation example for Compound a8. LCMS m / z: 512 [M+H] ＋ HPLC retention time: 0.84 minutes (analysis condition E)

[0353] Compound J-1: 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide (Compound j3) under the same conditions as in the production example for Compound A-25. LCMS m / z: 605 [M+H] ＋ HPLC retention time: 0.95 minutes (Analysis conditions A)

[0354] Compound J-2: 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid hydrochloride (Compound j2) under the same conditions as in the preparation example for Compound a8 and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 649 [M+H] ＋ HPLC retention time: 0.97 minutes (Analysis conditions A)

[0355] Compound J-5: N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid hydrochloride (Compound j2) and the corresponding amine under the same conditions as in the preparation example for Compound a8 and Compound A-1. LCMS m / z: 645 [M+H] ＋HPLC retention time: 1.40 minutes (Analysis conditions B)

[0356] Compound J-6: N-cyclopropyl-5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid hydrochloride (Compound j2) and the corresponding amine under the same conditions as in the preparation example for Compound a8 and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 671 [M+H] ＋ HPLC retention time: 1.47 minutes (Analysis conditions B)

[0357] Compound J-7: N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid hydrochloride (Compound j2) and the corresponding amine under the same conditions as in the preparation example for Compound a8 and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 689 [M+H] ＋ HPLC retention time: 1.43 minutes (Analysis conditions B)

[0358] Compound J-8: 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine-3-carboxamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid hydrochloride (Compound j2) and the corresponding amine under the same conditions as in the production example for Compound a12 and Compound A-1. LCMS m / z: 635 [M+H] ＋ HPLC retention time: 1.29 minutes (Analysis conditions B)

[0359] Compound J-9: 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine-3-carboxamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid hydrochloride (Compound j2) and the corresponding amine under the same conditions as in the preparation example for Compound a12 and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 679 [M+H] ＋ HPLC retention time: 1.31 minutes (Analysis conditions B)

[0360] Compound J-10: 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid hydrochloride (Compound j2) under the same conditions as in the production example for Compound a12 and Compound A-1. LCMS m / z: 677 [M+H] ＋ HPLC retention time: 1.46 minutes (Analysis conditions B)

[0361] Compound J-11: 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid hydrochloride (Compound j2) under the same conditions as in the preparation example for Compound a12 and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 703 [M+H] ＋ HPLC retention time: 1.52 minutes (Analysis conditions B)

[0362] Compound J-13: 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid hydrochloride (Compound j2) under the same conditions as in the preparation example for Compound a8 and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 631 [M+H] ＋ HPLC retention time: 1.37 minutes (Analysis conditions B)

[0363] Compound J-14: 5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid hydrochloride (Compound j2) under the same conditions as in the preparation example for Compound a8 and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 619 [M+H] ＋ HPLC retention time: 1.35 minutes (Analysis conditions B)

[0364] Compound J-15: 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid hydrochloride (Compound j2) under the same conditions as in the preparation example for Compound a8 and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 659 [M+H] ＋ HPLC retention time: 0.77 minutes (Analysis conditions C)

[0365] Compound J-3: 2-(4-cyclopropyl-2-fluoroanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide (Compound j3) under the same conditions as in the production example for Compound a9 and Compound A-1. LCMS m / z: 519 [M+H] ＋ HPLC retention time: 1.31 minutes (Analysis conditions B)

[0366] Compound J-4: 2-(4-cyclopropyl-2-fluoroanilino)-5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide (Compound j3) under the same conditions as in the preparation example for Compound a9 and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 545 [M+H] ＋ HPLC retention time: 1.37 minutes (Analysis conditions B)

[0367] Compound j12: 5-[[2-(ethylsulfonylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid 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 in place 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 minutes (Analysis conditions C)

[0368] Compound J-12: 5-[[2-(ethylsulfonylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide A DMF solution (85 μL) of 5-[[2-(ethylsulfonylamino)pyridin-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) was cooled to 0° C., and HATU (13.0 mg, 0.034 mmol) and DIPEA (17.9 μL, 0.102 mmol) were added, followed by stirring at room temperature overnight. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give the title compound (7.2 mg, 29%) as a colorless solid. LCMS m / z: 586 [M+H] ＋ HPLC retention time: 1.24 minutes (Analysis conditions B)

[0369] Compound k1: methyl 2-(2-fluoro-4-iodoanilino)-5-formyl-1-methyl-6-oxopyridine-3-carboxylate To a solution (2.7 mL) of methyl 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (132 mg, 0.328 mmol), (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 the mixture was stirred for 30 minutes. The solid was then collected by filtration to give the title compound (108 mg, 76%). LCMS m / z: 431 [M+H] ＋ HPLC retention time: 0.80 minutes (Analysis conditions C)

[0370] Compound k4: methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate The title compound was synthesized from methyl 2-(2-fluoro-4-iodoanilino)-5-formyl-1-methyl-6-oxopyridine-3-carboxylate (Compound k1) under the same conditions as in the preparation examples for Compound a2, Compound a5, and Compound a6. However, 2-nitrobenzene-1-sulfonohydrazide was used in place of 4-methylbenzenesulfonylhydrazide used in the preparation example for Compound a2. Furthermore, [2-fluoro-3-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]boronic acid and DIPEA were used in place of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (Compound a4) and potassium carbonate used in the preparation example for Compound a5, respectively. LCMS m / z: 526 [M+H] ＋ HPLC retention time: 0.90 minutes (Analysis conditions C)

[0371] Compound K-1: 2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]-1-methyl-6-oxopyridine-3-carboxamide 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 production examples for Compound b2, Compound a8, and Compound A-1. LCMS m / z: 604 [M+H] ＋ HPLC retention time: 1.37 minutes (Analysis conditions B)

[0372] Compound K-2: 5-[[3-(ethylsulfamoylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide 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 example for Compound b2, Compound a8, and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 618 [M+H] ＋ HPLC retention time: 1.41 minutes (Analysis conditions B)

[0373] Compound K-3: 5-[[3-(cyclopropylsulfamoylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide 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 example for Compound b2, Compound a8, and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 630 [M+H] ＋ HPLC retention time: 1.43 minutes (Analysis conditions B)

[0374] Compound K-4: N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]-1-methyl-6-oxopyridine-3-carboxamide 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 production examples for Compound b2, Compound a10, and Compound A-1. LCMS m / z: 644 [M+H] ＋ HPLC retention time: 1.48 minutes (Analysis conditions B)

[0375] Compound K-5: N-cyclopropyl-5-[[3-(cyclopropylsulfamoylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide 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 for Compound b2, Compound a10, and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 670 [M+H] ＋ HPLC retention time: 1.53 minutes (Analysis conditions B)

[0376] Compound K-13: N-cyclopropyl-5-[[3-(ethylsulfamoylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide 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 for Compound b2, Compound a10, and Compound A-1. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 658 [M+H] ＋ HPLC retention time: 1.52 minutes (Analysis conditions B)

[0377] Compound K-6: 2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclopropyl)sulfonylamino]phenyl]methyl]-1-methyl-6-oxopyridine-3-carboxamide 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 production examples for Compound A-25, Compound b2, and Compound 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 conditions B)

[0378] 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 The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (Compound k4) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for Compound A-25, Compound b2, and Compound a12. However, pyridine was used as a solvent in the sulfonamidation step. Furthermore, the corresponding amine was used in place of tert-butoxyamine hydrochloride used in the preparation example for Compound a12. LCMS m / z: 659 [M+H] ＋ HPLC retention time: 1.47 minutes (Analysis conditions B)

[0379] 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 The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (Compound k4) and the corresponding sulfonyl chloride under the same conditions as in the preparation examples for Compound A-25, Compound b2, and Compound a8. However, pyridine was used as the solvent in the sulfonamidation step. Furthermore, the corresponding amine was used instead of the 7M ammonia MeOH solution used in the preparation example for Compound a8. LCMS m / z: 669 [M+H] ＋ HPLC retention time: 1.59 minutes (Analysis conditions B)

[0380] 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 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 production examples for Compound A-25, Compound b2, and Compound 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 conditions B)

[0381] Compound k11: 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid 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 production examples for Compound A-25 and Compound b2. However, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 604 [M+H]＋ HPLC retention time: 0.77 minutes (Analysis conditions C)

[0382] Compound K-8: N-cyclopropyl-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide The title compound was synthesized from 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid (Compound k11) under the same conditions as in the production example for Compound a10. LCMS m / z: 643 [M+H] ＋ HPLC retention time: 1.53 minutes (Analysis conditions B)

[0383] Compound K-9: 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide The title compound was synthesized from 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid (Compound k11) under the same conditions as in the production example for Compound a12. LCMS m / z: 675 [M+H] ＋ HPLC retention time: 1.57 minutes (Analysis conditions B)

[0384] Compound K-10: 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide HOOBt (8.92 mg, 0.055 mmol) and EDC.HCl (10.5 mg, 0.055 mmol) were added to an anhydrous DMF solution (0.264 mL) of 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid (Compound k11, 22.0 mg, 0.036 mmol), and the mixture was stirred at room temperature for 3 hours. Then, 7M ammonia in MeOH (20.8 μL, 0.146 mmol) was added at 0° C., and the mixture was stirred for 1 hour. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to obtain the title compound (15.8 mg, 72%) as a colorless solid. LCMS m / z: 603 [M+H] ＋ HPLC retention time: 1.42 minutes (Analysis conditions B)

[0385] Compound 12: Methyl 2-bromo-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate The title compound was obtained from 2-bromo-5-fluoropyridine-4-carboxylic acid under the same conditions as in the preparation example for Compound c5 and Compound a1. However, 2-fluoro-4-trimethylsilylaniline was used in place of 4-iodo-2-methylaniline used in the preparation example for Compound c5. LCMS m / z: 397 [M+H] ＋ HPLC retention time: 1.17 minutes (analysis condition G)

[0386] Compound l3a: methyl 5-(2-fluoro-4-trimethylsilylanilino)-2-formylpyridine-4-carboxylate Compound 13b: 5-(2-fluoro-4-trimethylsilylanilino)-4-methoxycarbonylpyridine-2-carboxylic acid A solution of triethylsilane (2.01 mL, 12.6 mmol) in anhydrous DMF (63 mL) was added to a suspension of methyl 2-bromo-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate (Compound 12, 2.5 g, 6.29 mmol), 1,1,3-trioxo-1,2-benzothiazole-2-carbaldehyde (2.66 g, 612.6 mmol), Xantphos (728 mg, 1.26 mmol), palladium acetate (141 mg, 0.629 mmol), and sodium carbonate (1.67 g, 15.7 mmol) in anhydrous DMF (63 mL), and the mixture was stirred at room temperature for 10 minutes and then at 75° C. for 2.5 hours. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give compound 13a (0.4 g, 18%) and compound 13b (1.4 g, 61%), each as a yellow solid. Compound 13a LCMS m / z: 347 [M+H] ＋ HPLC retention time: 1.06 minutes (Analysis conditions G) Compound l3b LCMS m / z: 363 [M+H] ＋ HPLC retention time: 0.92 minutes (analysis condition G)

[0387] Compound 14: Methyl 5-(2-fluoro-4-trimethylsilylanilino)-2-(hydroxymethyl)pyridine-4-carboxylate To a solution (14 mL) of methyl 5-(2-fluoro-4-trimethylsilylanilino)-2-formylpyridine-4-carboxylate (Compound 13a, 500 mg, 1.44 mmol) in anhydrous THF, a 1 M solution of borane tetrahydrofuran complex in THF (4.33 mL, 4.33 mmol) was added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, acetic acid (0.496 mL, 8.66 mmol) was added, and the mixture was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give the title compound (360 mg, 72%) as a pale yellow solid. LCMS m / z: 349 [M+H] ＋ HPLC retention time: 0.91 minutes (analysis condition G)

[0388] Compound 14: Methyl 5-(2-fluoro-4-trimethylsilylanilino)-2-(hydroxymethyl)pyridine-4-carboxylate Borane dimethyl sulfide complex (0.747 mL, 7.86 mmol) was added to a solution (16 mL) of 5-(2-fluoro-4-trimethylsilylanilino)-4-methoxycarbonylpyridine-2-carboxylic acid (Compound 13b, 570 mg, 1.57 mmol) in anhydrous THF, and the mixture was stirred at room temperature for 2 hours. Acetic acid (1.58 mL, 27.6 mmol) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give the title compound (350 mg, 64%) as a pale yellow solid. LCMS m / z: 349 [M+H] ＋ HPLC retention time: 0.91 minutes (analysis condition G)

[0389] Compound 15: methyl 2-(chloromethyl)-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate Thionyl chloride (0.168 mL, 2.30 mmol) was added to a DCM solution (12 mL) of methyl 5-(2-fluoro-4-trimethylsilylanilino)-2-(hydroxymethyl)pyridine-4-carboxylate (Compound 14, 400 mg, 1.15 mmol), and the mixture was stirred at room temperature for 50 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (400 mg) as a crude product. LCMS m / z: 367 [M+H] ＋ HPLC retention time: 1.11 minutes (analysis condition G)

[0390] Compound 16: Methyl 2-[[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]methyl]-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate A suspension of methyl 2-(chloromethyl)-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate (Compound l5, 584 mg, 1.59 mmol), [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (Compound a4, 731 mg, 2.39 mmol), tetrakistriphenylphosphine palladium (184 mg, 0.159 mmol), and potassium carbonate (660 mg, 4.78 mmol) in 1,4-dioxane (17 mL) was stirred at 110°C for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was removed by filtration. The mixture was then concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound (583 mg, 62%) as a yellow solid. LCMS m / z: 593 [M+H] ＋ HPLC retention time: 1.13 minutes (analysis condition G)

[0391] Compound 17: methyl 2-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate The title compound was synthesized from methyl 2-[[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]methyl]-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate (Compound 16) under the same conditions as in the preparation example for Compound a6. LCMS m / z: 443 [M+H] ＋ HPLC retention time: 0.83 minutes (analysis condition G)

[0392] Compound 18: methyl 2-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)pyridine-4-carboxylate A solution of methyl 2-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate (Compound 17, 300 mg, 0.678 mmol) in anhydrous DCM (14 mL) was cooled to 0°C, and iodine monochloride (220 mg, 1.36 mmol) was added. The mixture was stirred at 0°C for 30 minutes and then at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography to give the title compound (320 mg, 95%) as a yellow solid. LCMS m / z: 497 [M+H] ＋ HPLC retention time: 0.69 minutes (analysis condition G)

[0393] Compound L-1: 5-(2-fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide The title compound was synthesized from methyl 2-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)pyridine-4-carboxylate (Compound 18) under the same conditions as in the production examples for Compound a7, Compound K-10, and Compound A-1. LCMS m / z: 575 [M+H] ＋ HPLC retention time: 1.36 minutes (Analysis conditions B)

[0394] Compound m1: methyl 2-amino-6-(aminomethyl)pyridine-3-carboxylate diacetate Palladium-supported activated carbon powder catalyst (10% palladium) (933 mg, 0.877 mmol) was added to a solution of methyl 2-amino-6-cyanopyridine-3-carboxylate (9.14 g, 51.6 mmol) in a mixture of acetic acid (100 mL) and methanol (100 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound as a crude product (15.3 g). LCMS m / z: 182 [M+H] ＋ HPLC retention time: 0.26 minutes (analysis condition G)

[0395] Compound m2: methyl 2-amino-6-(formamidomethyl)pyridine-3-carboxylate Acetic anhydride (115 mL, 1.22 mol) was added over 30 minutes to a formic acid solution (230 mL) of methyl 2-amino-6-(aminomethyl)pyridine-3-carboxylate diacetate (Compound m1, 14.7 g, 48.8 mmol), and the mixture was stirred at 70°C overnight. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography to give the title compound (8.16 g, 80%) as a yellow solid. LCMS m / z: 210 [M+H] ＋ HPLC retention time: 0.29 minutes (analysis condition G)

[0396] Compound m3: methyl 2-amino-5-bromo-6-(formamidomethyl)pyridine-3-carboxylate N-Bromosuccinimide (7.87 g, 44.2 mmol) was added in several portions to a solution of methyl 2-amino-6-(formamidomethyl)pyridine-3-carboxylate (Compound m2, 9.25 g, 44.2 mmol) in anhydrous acetonitrile (400 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and water was added to the resulting residue. The resulting solid was washed with water to give the title compound (12.0 g, 94%) as a yellow solid. LCMS m / z: 288 [M+H] ＋ HPLC retention time: 0.52 minutes (analysis condition G)

[0397] Compound m4: methyl 5-amino-8-bromoimidazo[1,5-a]pyridine-6-carboxylate Phosphoryl chloride (17.5 mL, 187 mmol) was added to a suspension of methyl 2-amino-5-bromo-6-(formamidomethyl)pyridine-3-carboxylate (Compound m3, 12.0 g, 41.7 mmol) in anhydrous toluene (200 mL), and the mixture was stirred at 95°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution and water were added to the resulting residue. The resulting solid was washed with water, dissolved in DCM, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the mixture was concentrated under reduced pressure to give the title compound (10.5 g, 93%) as a pale brown solid. LCMS m / z: 270 [M+H] ＋ HPLC retention time: 0.65 minutes (analysis condition G)

[0398] Compound m5: methyl 5-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-8-bromoimidazo[1,5-a]pyridine-6-carboxylate 4-Dimethylaminopyridine (143 mg, 1.17 mmol) was added to a solution of methyl 5-amino-8-bromoimidazo[1,5-a]pyridine-6-carboxylate (Compound m4, 1.58 g, 5.85 mmol) and di-tert-butyl dicarbonate (3.19 g, 14.6 mmol) in anhydrous DCM (50 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (2.5 g, 91%) as a yellow solid. LCMS m / z: 470 [M+H] ＋ HPLC retention time: 0.95 minutes (analysis condition G)

[0399] Compound m6: methyl 5-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-8-ethenylimidazo[1,5-a]pyridine-6-carboxylate A suspension of methyl 5-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-8-bromoimidazo[1,5-a]pyridine-6-carboxylate (Compound m5, 2.5 g, 5.32 mmol), potassium vinyltrifluoroborate (1.07 g, 7.97 mmol), tetrakistriphenylphosphine palladium (614 mg, 0.532 mmol), and cesium carbonate (5.20 g, 16.0 mmol) in 1,4-dioxane (40 mL) and water (10 mL) was stirred at 100°C for 2 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (1.68 g, 76%) as a yellow solid. LCMS m / z: 418 [M+H] ＋ HPLC retention time: 0.89 minutes (analysis condition G)

[0400] Compound m8: methyl 5-amino-8-formylimidazo[1,5-a]pyridine-6-carboxylate trifluoroacetate The title compound was synthesized from methyl 5-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-8-ethenylimidazo[1,5-a]pyridine-6-carboxylate (Compound m6) under the same conditions as in the preparation example for Compound c6 and Compound a6. LCMS m / z: 220 [M+H] ＋ HPLC retention time: 0.48 minutes (analysis condition G)

[0401] Compound m9: methyl 5-amino-8-(5,5-dimethyl-1,3-dioxan-2-yl)imidazo[1,5-a]pyridine-6-carboxylate A suspension of methyl 5-amino-8-formylimidazo[1,5-a]pyridine-6-carboxylate trifluoroacetate (Compound m8, 475 mg, 1.43 mmol), p-toluenesulfonic acid monohydrate (54.2 mg, 0.285 mmol), and 2,2-dimethyl-1,3-propanediol (742 mg, 7.13 mmol) in toluene (30 mL) was stirred at 110° C. overnight. DIPEA (1 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography to give the title compound (340 mg, 78%) as a red solid. LCMS m / z: 306 [M+H] ＋ HPLC retention time: 0.66 minutes (analysis condition G)

[0402] Compound m10: methyl 5-chloro-8-(5,5-dimethyl-1,3-dioxan-2-yl)imidazo[1,5-a]pyridine-6-carboxylate A suspension of methyl 5-amino-8-(5,5-dimethyl-1,3-dioxan-2-yl)imidazo[1,5-a]pyridine-6-carboxylate (Compound m9, 340 mg, 1.11 mmol) in acetonitrile (15 mL) was cooled to 0° C., and copper(I) chloride (165 mg, 1.67 mmol) and copper(II) chloride (225 mg, 1.67 mmol) were added. Then, tert-butyl nitrite (172 mg, 1.67 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography to give the title compound (237 mg, 66%) as a red solid. LCMS m / z: 325 [M+H] ＋ HPLC retention time: 0.77 minutes (analysis condition G)

[0403] Compound m11: methyl 8-(5,5-dimethyl-1,3-dioxan-2-yl)-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylate A suspension of methyl 5-chloro-8-(5,5-dimethyl-1,3-dioxan-2-yl)imidazo[1,5-a]pyridine-6-carboxylate (Compound m10, 237 mg, 0.730 mmol), cesium carbonate (713 mg, 2.19 mmol), and 2-fluoro-4-iodoaniline (346 mg, 1.46 mmol) in DMA (4 mL) was stirred at 50°C overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the drying agent was removed by filtration. The mixture was then concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography to give the title compound (210 mg, 55%) as a yellow solid. LCMS m / z: 526 [M+H] ＋ HPLC retention time: 1.02 minutes (analysis condition G)

[0404] Compound m12: methyl 5-(2-fluoro-4-iodoanilino)-8-formylimidazo[1,5-a]pyridine-6-carboxylate A suspension of methyl 8-(5,5-dimethyl-1,3-dioxan-2-yl)-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylate (Compound m11, 210 mg, 0.400 mmol) in water (2 mL) and TFA (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give the title compound (168 mg, 96%) as a yellow solid. LCMS m / z: 440 [M+H] ＋ HPLC retention time: 0.84 minutes (analysis condition G)

[0405] Compound m15: methyl 8-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylate trifluoroacetate The title compound was synthesized from methyl 5-(2-fluoro-4-iodoanilino)-8-formylimidazo[1,5-a]pyridine-6-carboxylate (Compound m12) under the same conditions as in the preparation examples for Compound a2, Compound a5, and Compound a6. However, MeOH was used instead of EtOH used in the preparation example for Compound a2. LCMS m / z: 536 [M+H] ＋ HPLC retention time: 0.54 minutes (analysis condition F)

[0406] Compound m16: 8-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylic acid trifluoroacetate A suspension of methyl 8-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylate trifluoroacetate (Compound m15, 60 mg, 0.092 mmol) and lithium hydroxide monohydrate (78 mg, 1.85 mmol) in THF (3 mL) and water (2 mL) was stirred at 50° C. overnight. The reaction mixture was acidified with formic acid and then concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% TFA aqueous solution / 0.1% TFA acetonitrile solution) to give the title compound (42 mg, 72%) as a yellow solid. LCMS m / z: 522 [M+H] ＋ HPLC retention time: 0.45 minutes (analysis condition F)

[0407] Compound m17: 8-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxamide trifluoroacetate A DMF solution (1.6 mL) of 8-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylic acid trifluoroacetate (Compound m16, 42 mg, 0.066 mmol) was cooled to 0°C, and HATU (390 mg, 1.03 mmol), ammonium chloride (67.2 mg, 1.26 mmol), and DIPEA (0.253 mL, 1.45 mmol) were added and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.1% TFA aqueous solution / 0.1% TFA acetonitrile solution) to give the title compound (25 mg, 60%) as a yellow solid. LCMS m / z: 521 [M+H] ＋ HPLC retention time: 0.41 minutes (Analysis conditions F)

[0408] Compound M-1: 5-(2-fluoro-4-iodoanilino)-8-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]imidazo[1,5-a]pyridine-6-carboxamide The title compound was synthesized from 8-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxamide trifluoroacetate (Compound m17) under the same conditions as in the production example for Compound A-1. LCMS m / z: 614 [M+H] ＋ HPLC retention time: 1.18 minutes (Analysis conditions B)

[0409] Compound n1: 6-chloro-5-fluoro-4-(2-fluoro-4-iodoanilino)pyridine-3-carboxylic acid A solution of 2-fluoro-4-iodoaniline (2.26 g, 9.52 mmol) in anhydrous THF (8 mL) was cooled to -78°C, and 2M LDA solution in THF / heptane / ethylbenzene (7.14 mL, 14.3 mmol) was added, followed by stirring for 30 minutes. Next, a solution of 4,6-dichloro-5-fluoropyridine-3-carboxylic acid (1.00 g, 4.76 mmol) in anhydrous THF (8 mL) was added, followed by stirring at -78°C for 30 minutes. Water and 6M hydrochloric acid were then added to the reaction mixture to adjust the pH to 1 to 2, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the mixture was concentrated under reduced pressure. The resulting residue was recrystallized (DCM) to give the title compound (850 mg, 44%) as a pale brown solid. LCMS m / z: 411 [M+H] ＋ HPLC retention time: 0.85 minutes (Analysis conditions G)

[0410] Compound n2: methyl 6-chloro-5-fluoro-4-(2-fluoro-4-iodoanilino)pyridine-3-carboxylate The title compound was synthesized from 6-chloro-5-fluoro-4-(2-fluoro-4-iodoanilino)pyridine-3-carboxylic acid (Compound n1) under the same conditions as in the preparation example for Compound a1. LCMS m / z: 425 [M+H] ＋ HPLC retention time: 1.04 minutes (analysis condition G)

[0411] Compound n3: methyl 5-fluoro-4-(2-fluoro-4-iodoanilino)-6-hydroxypyridine-3-carboxylate Potassium carbonate (570 mg, 4.12 mmol) and N-hydroxyacetamide (186 mg, 2.47 mmol) were added to a DMSO solution (2.75 mL) of methyl 6-chloro-5-fluoro-4-(2-fluoro-4-iodoanilino)pyridine-3-carboxylate (compound n2, 350 mg, 0.824 mmol), and the mixture was stirred at 100° C. for 1 hour. Water was added to the reaction mixture, and the resulting solid was washed with water and DCM to give the title compound (281 mg, 84%) as a pale brown solid. LCMS m / z: 407 [M+H] ＋ HPLC retention time: 0.72 minutes (analysis condition G)

[0412] Compound n4: N-[4-(bromomethyl)-3-fluoropyridin-2-yl]-1,1-diphenylmethanimine DIPEA (3.93 mL, 22.5 mmol) and methanesulfonic anhydride (2.07 g, 11.3 mmol) were added to a solution of [2-(benzhydrylideneamino)-3-fluoropyridin-4-yl]methanol (2.30 g, 7.51 mmol) in anhydrous DCM (37.5 mL), and the mixture was stirred at room temperature for 30 minutes. Subsequently, a solution of lithium bromide (3.26 g, 37.5 mmol) in anhydrous THF (0.5 mL) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was then extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, and the drying agent was removed by filtration. The mixture was then concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography to give the title compound (990 mg, 34%) as a yellow semi-solid. LCMS m / z: 369 [M+H] ＋ HPLC retention time: 0.94 minutes (analysis condition G)

[0413] Compound n5: methyl 1-[[2-(benzhydrylideneamino)-3-fluoropyridin-4-yl]methyl]-5-fluoro-4-(2-fluoro-4-iodoanilino)-6-oxopyridine-3-carboxylate Lithium hydride (1.85 mg, 0.222 mmol) was added to a solution (0.739 mL) of methyl 5-fluoro-4-(2-fluoro-4-iodoanilino)-6-hydroxypyridine-3-carboxylate (compound n3, 30 mg, 0.074 mmol) in anhydrous DMF, and the mixture was stirred at room temperature for 30 minutes. Next, a solution (0.5 mL) of N-[4-(bromomethyl)-3-fluoropyridin-2-yl]-1,1-diphenylmethanimine (compound n4, 82 mg, 0.222 mmol) in anhydrous THF was added, and the mixture was stirred at room temperature for 1 hour. Lithium hydride (1 mg, 0.126 mmol) and a solution (0.5 mL) of compound n4 (25 mg, 0.068 mmol) in anhydrous THF were then added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, and acetic acid (21.1 μL) and water were added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (19 mg, 37%) as a colorless solid. LCMS m / z: 695 [M+H] ＋ HPLC retention time: 1.05 minutes (analysis condition G)

[0414] Compound n8: 1-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-fluoro-4-(2-fluoro-4-iodoanilino)-6-oxopyridine-3-carboxamide The title compound was synthesized from methyl 1-[[2-(benzhydrylideneamino)-3-fluoropyridin-4-yl]methyl]-5-fluoro-4-(2-fluoro-4-iodoanilino)-6-oxopyridine-3-carboxylate (Compound n5) under the same conditions as in the preparation examples for Compound a6, Compound a7, and Compound K-10. However, in the first step, where the reaction was carried out under the same conditions as in the preparation example for Compound a6, 4M hydrochloric acid was added. LCMS m / z: 516 [M+H] ＋ HPLC retention time: 0.52 minutes (Analysis conditions C)

[0415] Compound N-1: 5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide The title compound was synthesized from 1-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-fluoro-4-(2-fluoro-4-iodoanilino)-6-oxopyridine-3-carboxamide (Compound n8) under the same conditions as in the production example for Compound A-1. LCMS m / z: 609 [M+H] ＋ HPLC retention time: 0.94 minutes (Analysis conditions A)

[0416] Compound N-2: 5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide The title compound was synthesized from 1-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-fluoro-4-(2-fluoro-4-iodoanilino)-6-oxopyridine-3-carboxamide (Compound n8) and the corresponding 4-nitrophenyl sulfamate under the same conditions as in the preparation example for Compound A-1. LCMS m / z: 637 [M+H] ＋ HPLC retention time: 1.04 minutes (Analysis conditions A)

[0417] Compound N-3: 5-fluoro-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-4-(2-fluoro-4-methylsulfanylanilino)-6-oxopyridine-3-carboxamide The title compound was synthesized from 1-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-fluoro-4-(2-fluoro-4-iodoanilino)-6-oxopyridine-3-carboxamide (Compound n8) under the same conditions as in the production example for Compound a16 and Compound A-1. LCMS m / z: 529 [M+H] ＋ HPLC retention time: 0.88 minutes (Analysis conditions A)

[0418] Compound p3: methyl 4-(2-fluoro-4-iodoanilino)-6-hydroxy-5-methylpyridine-3-carboxylate The title compound was synthesized from 4,6-dichloro-5-methylpyridine-3-carboxylic acid under the same conditions as in the preparation examples for Compound c5, Compound a1, and Compound n3. However, 2-fluoro-4-iodoaniline was used instead of 4-iodo-2-methylaniline used in the preparation example for Compound c5. LCMS m / z: 403 [M+H] ＋ HPLC retention time: 0.76 minutes (analysis condition G)

[0419] Compound P-1: 4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide The title compound was synthesized from methyl 4-(2-fluoro-4-iodoanilino)-6-hydroxy-5-methylpyridine-3-carboxylate (Compound p3) under the same conditions as in the preparation examples for Compound n4, Compound b2, Compound m17, Compound a6, and Compound A-1. However, 2M aqueous sodium hydroxide solution was used in place of lithium hydroxide monohydrate used in the preparation example for Compound b2, and 4M hydrogen chloride 1,4-dioxane solution was used in place of trifluoroacetic acid used in the preparation example for Compound a6. LCMS m / z: 605 [M+H] ＋ HPLC retention time: 0.66 minutes (Analysis conditions C)

[0420] Compound P-3: 4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide The title compound was synthesized from methyl 4-(2-fluoro-4-iodoanilino)-6-hydroxy-5-methylpyridine-3-carboxylate (Compound p3) under the same conditions as in the preparation examples for Compound n4, Compound b2, Compound m17, Compound a6, and Compound A-1. However, 2M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate used in the preparation example for Compound b2, 4M hydrogen chloride 1,4-dioxane solution was used instead of trifluoroacetic acid used in the preparation example for Compound a6, and the corresponding 4-nitrophenyl sulfamate was used instead of 4-nitrophenyl methylsulfamate used in the preparation example for Compound A-1. LCMS m / z: 659 [M+H] ＋ HPLC retention time: 0.76 minutes (Analysis conditions C)

[0421] Compound p9: methyl 4-(2-fluoro-4-iodoanilino)-6-hydroxy-5-methylpyridine-3-carboxylate The title compound was synthesized from methyl 4-(2-fluoro-4-iodoanilino)-6-hydroxy-5-methylpyridine-3-carboxylate (Compound p3) under the same conditions as in the preparation examples for Compound n4 and Compound a6. However, di-tert-butyl 2-[4-(bromomethyl)-3-fluoropyridin-2-yl]iminopropanedioate was used in place of N-[4-(bromomethyl)-3-fluoropyridin-2-yl]-1,1-diphenylmethanimine used in the preparation example for Compound n4, and 4 M hydrogen chloride in 1,4-dioxane was used in place of trifluoroacetic acid used in the preparation example for Compound a6. LCMS m / z: 527 [M+H] ＋ HPLC retention time: 0.72 minutes (analysis condition G)

[0422] Compound p10: methyl 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxylate The title compound was synthesized from methyl 4-(2-fluoro-4-iodoanilino)-6-hydroxy-5-methylpyridine-3-carboxylate (Compound p9) and ethylsulfonyl chloride under the same conditions as in the preparation example for Compound A-25. However, DIPEA was used instead of pyridine, and anhydrous DCM was used instead of anhydrous DMA. LCMS m / z: 619 [M+H] ＋ HPLC retention time: 0.87 minutes (analysis condition G)

[0423] Compound P-2: 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide The title compound was synthesized from methyl 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxylate (Compound p10) under the same conditions as in the preparation examples for Compound b2 and Compound K-10. However, 1 M aqueous sodium hydroxide solution was used in place of lithium hydroxide monohydrate used in the preparation example for Compound b2. LCMS m / z: 604 [M+H] ＋ HPLC retention time: 0.67 minutes (Analysis conditions C)

[0424] Compound P-4: N-cyclopropyl-1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide The title compound was synthesized from methyl 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxylate (Compound p10) under the same conditions as in the preparation examples for Compound b2 and Compound K-10. However, 1M aqueous sodium hydroxide solution was used in place of lithium hydroxide monohydrate used in the preparation example for Compound b2, and the corresponding amine was used in place of 7M ammonia MeOH solution used in the preparation example for Compound K-10. LCMS m / z: 644 [M+H] ＋HPLC retention time: 0.74 minutes (Analysis conditions C)

[0425] Compound P-5: 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-N-methoxy-5-methyl-6-oxopyridine-3-carboxamide The title compound was synthesized from methyl 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxylate (Compound p10) under the same conditions as in the preparation examples for Compound b2 and Compound K-10. However, 1M aqueous sodium hydroxide solution was used in place of lithium hydroxide monohydrate used in the preparation example for Compound b2, and the corresponding amine was used in place of 7M ammonia MeOH solution used in the preparation example for Compound K-10. LCMS m / z: 634 [M+H] ＋ HPLC retention time: 0.67 minutes (Analysis conditions C)

[0426] Compound P-6: N-cyclopropyl-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide The title compound was synthesized from methyl 1-[(2-amino-3-fluoropyridin-4-yl)methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxylate (Compound p9) under the same conditions as in the preparation examples for Compound b2, Compound a12, and Compound A-25. However, the corresponding amine was used in place of tert-butoxyamine hydrochloride used in the preparation example for Compound a12. LCMS m / z: 645 [M+H] ＋ HPLC retention time: 0.73 minutes (Analysis conditions C)

[0427] Compound P-7: 4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxy-5-methyl-6-oxopyridine-3-carboxamide The title compound was synthesized from methyl 1-[(2-amino-3-fluoropyridin-4-yl)methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxylate (Compound p9) under the same conditions as in the preparation examples for Compound b2, Compound a12, and Compound A-25. However, the corresponding amine was use...

Claims

1. A compound represented by the following general formula (1) or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate of said compound or salt: X １ , X ２ , X ３ , X ４ , X ５ and X ６ Each independently represents -CR ２ = or -N=, R ２ is a hydrogen atom, a halogen atom or a C1-6 alkyl group; R １ is -S(=O) ２ -NH-R ８ Or -S(=O) ２ -R ８ And R ８ is a hydrogen atom, a C1-6 alkyl group (which may be substituted with a halogen atom, a hydroxy 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 (which 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 is a hydrogen atom, a C1-6 alkyl group (which may be substituted with a halogen atom, a hydroxy group, or a C1-6 alkoxy group), a C3-6 cycloalkyl group (which may be substituted with a halogen atom or a C1-6 alkyl group), or a C1-6 alkoxy group (which may be substituted with a halogen atom, a hydroxy group, or a C1-6 alkoxy group), R ５ is a halogen atom or a C1-6 alkyl group; R ６ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, R 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 form an unsaturated 5-membered heterocyclic ring together with the carbon atom to which they are attached, R ７ is a hydrogen atom or a C1-6 alkyl group; R ９ is a hydrogen atom, a halogen atom, or a C1-6 alkyl group.

2. Ring A is a group represented by general formula (2) or (4), R ８ is a hydrogen atom, a C1-6 alkyl group (which may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (which may be substituted with a C1-6 alkyl group), R ３ 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 hydroxy group), R ６ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, R ４ is a halogen atom or a cyclopropyl group; R ７ The compound, salt or solvate according to claim 1 , wherein is a hydrogen atom or a methyl group.

3. The compound, salt or solvate according to claim 1, wherein the compound represented by general formula (1) is a compound represented by the following general formula (6): [In the formula, X １ , X ２ , X ３ and X ４ Each independently represents -CR ２ = or -N=, R ２ is a hydrogen atom, a halogen atom or a C1-6 alkyl group; R １ is -S(=O) ２ -NH-R ８ Or -S(=O) ２ -R ８ And R ８ is a hydrogen atom, a C1-6 alkyl group (which may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (which may be substituted with a C1-6 alkyl group), R ３ 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 hydroxy group), R ５ is a halogen atom or a C1-6 alkyl group; R ６ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, R ４ is a halogen atom or a cyclopropyl group.

4. R ２ is a hydrogen atom or a halogen atom, R ８ is a C1-6 alkyl group (which may be substituted with a halogen atom or a C1-6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (which may be substituted with a C1-6 alkyl group), R ３ 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 hydroxy group), R ５ is a halogen atom; R ６ is a hydrogen atom, R ４ The compound, salt or solvate according to any one of claims 1 to 3, wherein is a halogen atom or a cyclopropyl group.

5. R ２ is a hydrogen atom or a fluorine atom, R ８ is a C1-4 alkyl group (which may be substituted with a fluorine atom or a C1-4 alkoxy group) or a cyclopropyl group (which may be substituted with a C1-4 alkyl group); R ３ 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 hydroxy group), R ５ is a fluorine atom, R ６ is a hydrogen atom, R ４ The compound, salt or solvate according to any one of claims 1 to 3, wherein is an iodine atom or a cyclopropyl group.

6. R ２ is a fluorine atom, R １ is -S(=O) ２ -NH-R ８ And R ８ is a C1-4 alkyl group; R ３ is a hydrogen atom or a cyclopropyl group; R ５ is a fluorine atom, R ６ is a hydrogen atom, R ４ The compound, salt or solvate according to any one of claims 1 to 3, wherein is an iodine atom or a cyclopropyl group.

7. A stabilizer for a RAF / MEK complex comprising, as an active ingredient, a compound represented by the following general formula (11) or a pharma- ceutically acceptable salt thereof, or a pharma- ceutical acceptable solvate of said compound or salt: X １ , X ２ , X ３ , X ４ , X ５ and X ６ Each independently represents -CR ２ = or -N=, R ２ is a hydrogen atom, a halogen atom or a C1-6 alkyl group; ７ Ha-(CH ２ ) ｍ - or -O-, m is 1, 2 or 3; R １ is -S(=O) ２ -NH-R ８ Or -S(=O) ２ -R ８ And R ８ is a hydrogen atom, a C1-6 alkyl group (which may be substituted with a halogen atom, a hydroxy 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 (which 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 is a hydrogen atom, a C1-6 alkyl group (which may be substituted with a halogen atom, a hydroxy group, or a C1-6 alkoxy group), a C3-6 cycloalkyl group (which may be substituted with a halogen atom or a C1-6 alkyl group), or a C1-6 alkoxy group (which may be substituted with a halogen atom, a hydroxy group, or a C1-6 alkoxy group), R ５ is a hydrogen atom, a halogen atom or a C1-6 alkyl group; R ６ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, R 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 form an unsaturated 5-membered heterocyclic ring together with the carbon atom to which they are attached, R ７ is a hydrogen atom or a C1-6 alkyl group; R ９ is a hydrogen atom, a halogen atom, or a C1-6 alkyl group.

8. Ring A is a group represented by general formula (2) or (4), ７ Ha-CH ２ - and R ８ is a hydrogen atom, a C1-6 alkyl group (which may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (which may be substituted with a C1-6 alkyl group), R ３ 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 hydroxy group), R ５ is a halogen atom or a C1-6 alkyl group; R ６ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, R ４ is a halogen atom or a cyclopropyl group; R ７ The stabilizer for a RAF / MEK complex according to claim 7 , wherein is a hydrogen atom or a methyl group.

9. The stabilizer for RAF / MEK complex according to claim 7, wherein the compound represented by general formula (11) is a compound represented by the following general formula (6): [In the formula, X １ , X ２ , X ３ and X ４ Each independently represents -CR ２ = or -N=, R ２ is a hydrogen atom, a halogen atom or a C1-6 alkyl group; R １ is -S(=O) ２ -NH-R ８ Or -S(=O) ２ -R ８ And R ８ is a hydrogen atom, a C1-6 alkyl group (which may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (which may be substituted with a C1-6 alkyl group), R ３ 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 hydroxy group), R ５ is a halogen atom or a C1-6 alkyl group; R ６ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, R ４ is a halogen atom or a cyclopropyl group.

10. R ２ is a hydrogen atom or a halogen atom, R ８ is a C1-6 alkyl group (which may be substituted with a halogen atom or a C1-6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (which may be substituted with a C1-6 alkyl group), R ３ 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 hydroxy group), R ５ is a halogen atom; R ６ is a hydrogen atom, R ４ The stabilizer for a RAF / MEK complex according to any one of claims 7 to 9, wherein is a halogen atom or a cyclopropyl group.

11. N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide, 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide, 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide, N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide, N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide, 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide, 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide, 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzamide, 4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide, N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]-N-methoxybenzamide, 3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-methylsulfanylanilino)benzamide, 2-(4-ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide, 2-(4-bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide, 2-(2-chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-methoxybenzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxan-4-ylsulfonylamino)phenyl]methyl]benzamide, 2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide, 3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]oxybenzamide, 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine-3-carboxamide, 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide, 5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide, 5-(2-fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide, 5-(2-fluoro-4-iodoanilino)-8-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]imidazo[1,5-a]pyridine-6-carboxamide, 5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide, 5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide, 4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide, and A compound selected from the group consisting of 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide, or a pharma- ceutically acceptable salt thereof, or a pharma-ceutically acceptable solvate of said compound or salt.

12. N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide, 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide, 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide, N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide, N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide, 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide, 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide, 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide, A compound selected from 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzamide, 4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide, and N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide, or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate of said compound or salt.

13. A compound selected from N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide, 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide, and 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide, or a pharma-ceutically acceptable salt thereof, or a pharma-ceutically acceptable solvate of said compound or salt.

14. 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate of said compound or salt.

15. 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide or its sodium salt or potassium salt, or a pharma- ceutically acceptable solvate of said compound or salt.

16. A pharmaceutical composition comprising as an active ingredient the compound, salt or solvate according to any one of claims 1 to 15.

17. A therapeutic or preventive agent for a cell proliferative disease, comprising as an active ingredient the compound, salt or solvate according to any one of claims 1 to 15.

18. The therapeutic or preventive agent for a cell proliferative disease according to claim 17, wherein the cell proliferative disease is cancer.

Images