Arylamide derivative with antitumor activity

Abstract

Abstract\nThe present disclosure discloses, for example, a compound represented by the general formula (6) below, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt:\n \n(6)\nwherein, 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. The compounds, salts or solutions provided by the present disclosure have high RAF / MEK complex stabilizing activity and can be used for the treatment or prevention of cell proliferation disorders, particularly cancers.

Description

Description Title of the invention Arylamide derivative with antitumor activity Technical background

[0001] The present disclosure relates to arylamide derivatives having RAF / MEK complex stabilizing activity and / or MEK inhibitory activity and useful for the treatment or prevention of cell proliferation disorders, particularly cancers, and also to RAF / MEK complex stabilizing agents or MEK inhibitory agents comprising arylamide derivatives as active ingredients. Background knowledge

[0002] MEK (mitogen-activated protein kinase kinase) is a serine / threonine kinase in the MAPK signaling pathway, which transduces signals intracellularly and is closely involved in cell proliferation (see Non-Patent Document 1). Reported MEK inhibitors include PD0325901, CH4987655, trametinib, cobimetinib and selumetinib (see Patent Document 1 and Non-Patent Document 2), and their use alone or in combination with RAF inhibitors has shown clinical effects against RAF-mutated cancers, such as BRAF-mutated malignant melanoma (see Non-Patent Documents 3 and 4).

[0003] It has also been found that the clinical efficacy of some MEK inhibitors against RAS-mutated cancers such as RAS non-small cell lung cancer is less than satisfactory. In fact, selumetinib and trametinib have been reported to have poor efficacy in clinical trials of KRAS-mutated small cell lung cancer (see Non-Patent Documents 5 and 6).

[0004] CH5126766 (see Patent Document 2 and Non-Patent Documents 7 and 8), which is known not only as a MEK inhibitor but also as a RAF / MEK complex stabilizer, has been reported to show a clinical effect against RAS-mutated non-small cell lung cancer (see Non-Patent Document 9). It has also been reported that CH5126766 stabilizes the RAF / MEK complex and prevents increased MEK phosphorylation (feedback activation of the MAPK signaling pathway) (see Non-Patent Documents 7, 8 and 10). This feedback activation is thought to be one of the reasons for the less satisfactory clinical effects of some MEK inhibitors against RAS-mutated cancers (see Non-Patent Document 10). Citation list Patent resources

[0005] Patent Document 1: WO 2006 / 011466 Patent Document 2: WO 2007 / 091736 Non-patented resources

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

[0007] Several RAF / MEK complex stabilizers or MEK inhibitors are known to be useful for the treatment or prevention of cell proliferation disorders (particularly cancers), but currently available options are still insufficient to meet the diverse needs of consumers.

[0008] The object of the present disclosure is to provide a novel compound having RAF / MEK complex stabilizing activity and / or MEK inhibitory activity and useful for the treatment or prevention of a cell proliferation disorder, particularly cancer, or a novel RAF / MEK complex stabilizing agent or MEK inhibitory agent that is useful for the treatment or prevention of a cell proliferation disorder, particularly cancer. Solution to the problem

[0009] To create such a novel combination, the present inventors focused on CH4987655 (shown below), a publicly known MEK inhibitor, and CH5126766 (shown below), a publicly known RAF / MEK complex stabilizer. [Chemical Formula 1] [Chemical Formula 2]

[0010] Compared with PD0325901, another MEK inhibitor, CH4987655 exhibits equivalent MEK inhibitory activity in a cell-free system, but exhibits slower degradation of MEK. Also, CH4987655 exhibits more potent MEK inhibitory activity (lower IC50) than PD0325901 in cynomolgus monkey peripheral blood and results in longer MEK inhibition. This is thought to be due to a unique substituent at the 5' position of the benzamide backbone of CH4987655, which contains a 3-oxo-[1,2]oxazinane ring structure (see Bioorg. Med. Chem. Lett. 2011, vol. 21, no. 6, p. 1795-1801).

[0011] CH5126766 and MEK form a complex that has a distinct structure. Specifically, binding of CH5126766 to MEK causes the activation domain of MEK to shift, placing Asn221 and Ser222 of MEK in positions that are spatially different from when PD0325089 (the PD0325901 enantiomer) binds. In the resulting complex, the sulfamide group of CH5126766 is involved in a direct hydrogen bond with Asn221 of MEK and a water-mediated hydrogen bond with Ser222. Since Ser222 is one of the two amino acids phosphorylated by RAF, the stabilizing effect of CH5126766 on the RAF / MEK complex and its inhibitory effect on increased MEK phosphorylation (feedback activation of the MAPK signaling pathway) are thought to be due to the structure of the complex (see Cancer Cell. 2014, vol. 25, no. 5, p. 697-710 (Patent Document 8)).

[0012] Binding of CH4987655 to MEK results in a spatial arrangement of Asn221 and Ser222 that is similar to that when CH5126766 is bound. CH4987655 also resembles CH5126766 in interacting with Asn221. CH4987655 has an inhibitory effect, albeit weak, on the increase in MEK phosphorylation, and this is thought to be due to the structure of the complex (see Cancer Cell. 2014, vol. 25, no. 5, p. 697-710 (Non-Patent Document 8)).

[0013] CH4987655 differs from CH5126766 in that it is distant from and does not interact with Ser222. CH4987655 also differs in that its interaction with Asn221 is a weak interaction mediated by the 3-oxo-[1,2]oxazinane ring structure. CH5126766, unlike other MEK inhibitors such as CH4987655 and PD0325901, does not interact with Lys97.

[0014] Based on the analysis described above, the present inventors formulated the following two hypotheses: (Hypothesis 1) If a chemical structure capable of hydrogen bonding with Lys97 is introduced into CH5126766, then this compound may acquire equivalent MEK inhibitory activity to CH4987655, while retaining the RAF / MEK complex stabilizing activity of CH5126766 and its inhibitory activity on increased MEK phosphorylation (feedback activation of the MAPK signaling pathway). (Hypothesis 2) If a chemical structure capable of forming strong hydrogen bonds with Asn221 and Ser222 is introduced into CH4987655, then it should be possible for the compound to achieve the RAF / MEK complex stabilizing activity and the MEK phosphorylation enhancing inhibitory activity (feedback activation of the MAPK signaling pathway) equivalent to CH5126766, while retaining the MEK inhibitory activity of CH4987655.

[0015] In the complex of MEK with CH4987655, the hydroxamate structure of CH4987655 interacts with Lys97 of MEK; therefore, based on hypothesis 1, the present inventors produced compound AA-2 below, which has the structure of CH5126766, which contains a substituent with a hydroxamate structure. [Chemical Formula 3]

[0016] In the complex of MEK with CH5126766, the sulfamide structure of CH5126766 interacts with Asn221 and Ser222 of MEK; therefore, based on hypothesis 2, the present inventors produced compound AA-1 below, which contains a sulfamide structure introduced at the end of a structure corresponding to the 5' side chain of CH4987655. [Chemical Formula 4]

[0017] The MEK1 inhibitory activity (IC50), BRAF inhibitory activity (IC50), HCT-116 growth inhibitory activity (IC50) and / or Colo-205 growth inhibitory activity (IC50) of Compound AA-2 and Compound AA-1 were measured as described in Test Example 3, 4 or 5 below (HCT-116 and Colo-205 cells were obtained from ATCC). The results are shown in Table 1 below. HCT-116 and Colo-205 cells are human cancer cells with RAS and BRAF mutations, respectively. [Table 1] Table 1 Compound No. MEK1IC50 (nM) BRAFIC50 (nM) HCT-116IC50 (nM) Colo-205IC50 (nM) AA-2 > 8000 2200 45000 ND AA-1 21 3 2 0.4 ND: Not determined

[0018] As shown in Table 1, compound AA-2 did not show the expected profile. On the other hand, compound AA-1 showed MEK1 inhibitory activity, BRAF inhibitory activity, HCT-116 growth inhibitory activity, and Colo-205 growth inhibitory activity.

[0019] The present inventors conducted intensive research using compound AA-1 as a parent compound and found that specific arylamide derivatives have RAF / MEK complex stabilizing activity and / or MEK inhibitory activity and are useful for treating or preventing cell proliferation disorders, particularly cancers.

[0020] The present disclosure provides compounds, salts or solutions according to (A1) to (A6) below. (A1) A compound represented by the general formula (1) below, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt: [Chemical formula 5] Where: Ring A is a group represented by the general formula (2), (3), (4) or (5) below (where the bonds indicated by *, ** and *** are attached to -NH-, -CONH- and -CH2-, respectively): [Chemical formula 6] X1, X2, X3, X4, X5 and X6 are each independently −CR2= or −N=; R2 is a hydrogen atom, a halogen atom or a C1-6 alkyl group; R1 is -S(=O)2-NH-R8 or -S(=O)2-R8; R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group optionally 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 optionally substituted with a C1-6 alkyl group or a C1-6 alkoxy group), or a monocyclic or bicyclic C3-6 heterocycloalkyl group; R3 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group optionally substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3-6 cycloalkyl group optionally substituted with a halogen atom or a C1-6 alkyl group) or a C1-6 alkoxy group (the C1-6 alkoxy group optionally substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group); R5 is a halogen atom or a C1-6 alkyl group; R6 is a hydrogen atom, a halogen atom or a C1-6 alkyl group and R4 is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-7 alkenyl group, a C2-7 alkynyl group, a C3-6 cycloalkyl group or a C1-6 alkylthio group, or R6 and R4 form an unsaturated 5-membered hetero ring together with the carbon atoms to which they are attached; R7 is a hydrogen atom or a C1-6 alkyl group; and R9 is a hydrogen atom, a halogen atom or a C1-6 alkyl group.

[0021] (A2) A compound, salt or solution according to (A1) wherein: Ring A is a group represented by the general formula (2) or (4); R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group optionally 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 optionally substituted with a C1-6 alkyl group); R3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C1-6 alkoxy group (the C1-6 alkoxy group optionally substituted with a hydroxy group); R6 is a hydrogen atom, a halogen atom or a C1-6 alkyl group and R4 is a halogen atom or a cyclopropyl group; and R7 is a hydrogen atom or a methyl group.

[0022] (A3) A compound, salt or solution according to (A1) wherein the compound represented by the general formula (1) is a compound represented by the formula (6) below: [Chemical Formula 7] X1, X2, X3, and X4 are each independently −CR2= or −N=; R2 is a hydrogen atom, a halogen atom or a C1-6 alkyl group; R1 is -S(=O)2-NH-R8 or -S(=O)2-R8; R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group optionally 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 optionally substituted with a C1-6 alkyl group); R3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group; R5 is a halogen atom or a C1-6 alkyl group; and R6 is a hydrogen atom, a halogen atom or a C1-6 alkyl group and R4 is a hydrogen atom or a cyclopropyl group.

[0023] (A4) A compound, salt or solution according to any one of (A1) to (A3) wherein: R2 is a hydrogen atom, a halogen atom; R8 is a C1-6 alkyl group (C1-6 alkyl group optionally substituted with a halogen atom, or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (C3-6 cycloalkyl group optionally substituted with a C1-6 alkyl group); R3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 alkoxy group optionally substituted with a hydroxy group); R5 is a halogen atom; and R6 is a hydrogen atom and R4 is a hydrogen atom, or a cyclopropyl group.

[0024] (A5) A compound, salt or solution according to any one of (A1) to (A3) wherein: R2 is a hydrogen atom, a fluorine atom; R8 is a C1-4 alkyl group (the C1-4 alkyl group optionally substituted with a fluorine atom, or a C1-4 alkoxy group), or a cyclopropyl group (the cyclopropyl group optionally substituted with a C1-4 alkyl group); R3 is a hydrogen atom, a C1-4 alkyl group, a cyclopropyl group or a C1-4 alkoxy group (the C1-4 alkoxy group optionally substituted with a hydroxy group); R5 is a fluorine atom; and R6 is a hydrogen atom and R4 is an iodine atom or a cyclopropyl group.

[0025] (A6) A compound, salt or solution according to any one of (A1) to (A3) wherein: R2 is a fluorine atom; R1 is -S(=O)2-NH-R8; R8 is a C1-4 alkyl group; R3 is a hydrogen atom or a cyclopropyl group; R5 is a fluorine atom; and R6 is a hydrogen atom and R4 is an iodine atom or a cyclopropyl group.

[0026] The present disclosure also provides agents according to (A7) to (A10) below. Compounds, salts or solutions of (A7) below include compounds, salts or solutions of (A1) to (A6). (A7) A RAF / MEK complex stabilizing agent comprising as an active ingredient a compound represented by the general formula (11) below or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt: [Chemical formula 8] Where: Ring A is a group represented by the general formula (2), (3), (4) or (5) below (where the bonds indicated by *, ** and *** are attached to -NH-, -CONH- and −X7−, respectively): [Chemical formula 9] X1, X2, X3, X4, X5, and X6 are each independently −CR2= or −N=; R2 is a hydrogen atom, a halogen atom or a C1-6 alkyl group; X7 is −(CH2)m− or −O− and m is 1, 2 or 3; R1 is -S(=O)2-NH-R8 or -S(=O)2-R8; R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group optionally 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 optionally substituted with a C1-6 alkyl group or a C1-6 alkoxy group), or a monocyclic or bicyclic C3-6 heterocycloalkyl group; R3 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group optionally substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3-6 cycloalkyl group optionally substituted with a halogen atom or a C1-6 alkyl group) or a C1-6 alkoxy group (the C1-6 alkoxy group optionally substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group); R5 is a hydrogen atom, a halogen atom or a C1-6 alkyl group; R6 is a hydrogen atom, a halogen atom or a C1-6 alkyl group and R4 is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-7 alkenyl group, a C2-7 alkynyl group, a C3-6 cycloalkyl group or a C1-6 alkylthio group, or R6 and R4 form an unsaturated 5-membered hetero ring together with the carbon atoms to which they are attached; R7 is a hydrogen atom or a C1-6 alkyl group; and R9 is a hydrogen atom, a halogen atom or a C1-6 alkyl group.

[0027] (A8) The RAF / MEK complex stabilizing agent according to (A7), wherein: Ring A is a group represented by the general formula (2) or (4); X7 is −CH2−; R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group optionally substituted with a halogen atom, a hydroxy group, a C1-6 alkoxy group), a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group optionally substituted with a C1-6 alkyl group); R3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 alkoxy group optionally substituted with a hydroxy group); R5 is a hydrogen atom or a C1-6 alkyl group; R6 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group and R4 is a hydrogen atom, a halogen atom, or a cyclopropyl group; and R7 is a hydrogen atom or a methyl group.

[0028] (A9) The RAF / MEK complex stabilizing agent according to (A7), wherein the compound represented by the general formula (11) is the compound represented by the general formula (6) below: [Chemical Formula 10] Where: X1, X2, X3, and X4 are each independently −CR2= or −N=; R2 is a hydrogen atom, a halogen atom or a C1-6 alkyl group; R1 is -S(=O)2-NH-R8 or -S(=O)2-R8; R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group optionally substituted with a halogen atom, a hydroxy group, a C1-6 alkoxy group), a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group optionally substituted with a C1-6 alkyl group); R3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 alkoxy group optionally substituted with a hydroxy group); R5 is a hydrogen atom or a C1-6 alkyl group; and R6 is a hydrogen atom, a halogen atom or a C1-6 alkyl group and R4 is a halogen atom or a cyclopropyl group.

[0029] (A10) The RAF / MEK complex stabilizing agent according to any one of (A7) to (A9), wherein: R2 is a hydrogen atom or a halogen atom; R8 is a C1-6 alkyl group (the C1-6 alkyl group optionally substituted with a halogen atom or a C1-6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group optionally substituted with a C1-6 alkyl group); R3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 alkoxy group optionally substituted with a hydroxy group); R5 is a halogen atom; and R6 is a hydrogen atom and R4 is a halogen atom or a cyclopropyl group.

[0030] The present disclosure further provides compounds, salts or solutions according to (A11) to (A15) below. Compounds, salts or solutions (A7) include compounds, salts or solutions (A11) to (A15) below. (A11) A compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solution of said compound or salt, said compound being 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), 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-1ترکیب ), N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide(A-4ترکیب ), N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (A-6ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide (A-8ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide (A-13ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-25ترکیب ), 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (A-30ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-31ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-33ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-34ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide (A-35ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-41ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide (B-1ترکیب ), 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (D-4ترکیب ), 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (E-1ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide (E-7ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide (E-13ترکیب ), 4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (I-1ترکیب ), N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (J-5ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]-N-methoxybenzamide (A-15ترکیب ), 3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-methylsulfanylanilino)benzamide (A-18ترکیب ), 2-(4-ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-20ترکیب ), 2-(4-bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-27ترکیب ), 2-(2-chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-methoxybenzamide (E-9ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxan-4-ylsulfonylamino)phenyl]methyl]benzamide (E-23ترکیب ), 2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (H-1ترکیب ), 3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (H-3ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]oxybenzamide (H-4ترکیب ), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine-3-carboxamide (J-8ترکیب ), 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 (J-10ترکیب ), 5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide (J-14ترکیب ), 5-(2-fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide (L-1ترکیب ), 5-(2-fluoro-4-iodoanilino)-8-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]imidazo[1,5-a]pyridine-6-carboxamide (M-1ترکیب ), 5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (N-1ترکیب ), 5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (N-2 compound), 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).

[0031] (A12) A compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solution of said compound or salt, said compound being selected from the following: 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 (A-1ترکیب ), N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide(A-4ترکیب ), N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (A-6ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide (A-8ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide (A-13ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-25ترکیب ), 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (A-30ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-31ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-33ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-34ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide (A-35ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-41ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide (B-1ترکیب ), 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (D-4ترکیب ), 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 (E-7 compound), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide (E-13 compound), 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).

[0032] (A13) A compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solution of said compound or salt, said compound being 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).

[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 said 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 a sodium salt or potassium salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

[0035] The compounds, salts or solutions of (A1) to (A15) exhibit high RAF / MEK complex stabilizing activity and can be used as active ingredients in therapeutic or preventive agents for cell proliferation disorders, particularly cancers (particularly, RAS mutation cancers); therefore, the present disclosure provides a pharmaceutical composition comprising the compound, salt or solution of any one of (A1) to (A15) as an active ingredient. Also, the present disclosure provides a therapeutic or preventive agent for a cell proliferation disorder, particularly cancer, which agent comprises the compound, salt or solution of any one of (A1) to (A15) as an active ingredient.

[0036] The present disclosure further provides compounds, salts or solutions according to (B1) to (B3) below and an agent according to (B4) below. (B1) A compound represented by the general formula (1) below or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt: [Chemical Formula 11] Where: Ring A is a group represented by the general formula (2), (3) or (4) below (where the bonds indicated by *, ** and *** are connected to -NH-, -CONH- and -CH2-, respectively): [Chemical Formula 12] X1, X2, X3, X4, and X5 are each independently −CR2= or −N=; R2 is a hydrogen atom, a halogen atom or a C1-4 alkyl group; R1 is -S(=O)2-NH-R8 or -S(=O)2-R8; R8 is a C1-4 alkyl group (the C1-4 alkyl group optionally 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 optionally substituted with a C1-4 alkyl group); R3 is a hydrogen atom, a C3-6 cycloalkyl group or a C1-6 alkoxy group; R5 is a halogen atom; R6 is a hydrogen atom and R4 is a hydrogen atom, a halogen atom or a C3-6 cycloalkyl group; R7 is a C1-4 alkyl group; and R9 is a hydrogen atom.

[0037] (B2) a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solution of said compound or salt, said compound being selected from: 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-1 compound), (+ / −)-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 (A-21 compound), 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 (A-30 compound), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-33 compound), 5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (A-40 ترکیب ), 3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (A-42 ترکیب ), 5-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (B-16 ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (C-3 ترکیب ), 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 (J-10 ترکیب ), 5-(2-fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide (L-1 ترکیب ), 5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (N-1 ترکیب ), 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide (P-2 compound), 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-N-methoxy-5-methyl-6-oxopyridine-3-carboxamide (P-5 compound) and N-cyclopropyl-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (P-6 compound).

[0038] (B3) A compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solution of said compound or salt, said compound being selected from: (+ / −)-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 (A-21 compound), 5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (A-40 compound), 3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (A-42 compound), 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 (C-3 compound), 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-N-methoxy-5-methyl-6-oxopyridine-3-carboxamide (P-5 compound) and N-cyclopropyl-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (P-6 compound).

[0039] (B4) A MEK inhibitor comprising the compound, salt or solution based on any one of (B1) to (B3) as an active ingredient.

[0040] The compounds, salts or solutions of (B1) to (B3) exhibit high activity in inhibiting MEK and can be used as active ingredients in therapeutic or preventive agents for cell proliferation disorders, particularly cancers (in particular, RAF mutation cancers); therefore, the present disclosure provides a pharmaceutical composition comprising the compound, salt or solution of any one of (B1) to (B3) as an active ingredient. Also, the present disclosure provides a therapeutic or preventive agent for a cell proliferation disorder, particularly cancer, which agent comprises the compound, salt or solution of any one of (B1) to (B3) as an active ingredient. Beneficial effects of the invention

[0041] According to the present disclosure, novel compounds are provided that have RAF / MEK complex stabilizing activity and / or MEK inhibitory activity and are useful for treating or preventing cell proliferative disorders, particularly cancers, or novel RAF / MEK complex stabilizing agents or MEK inhibitory agents that are useful for treating or preventing cell proliferative disorders, particularly cancers. Brief description of the shapes

[0042] Figure 1 shows a powder X-ray diffraction pattern of sample A-1a (Figure I). Figure 2 shows a powder X-ray diffraction pattern of sample A-1b. Figure 3 shows a powder X-ray diffraction pattern of sample A-1c. Figure 4 shows sensorgrams showing the amount of MEK1 binding added to the surface of the RAF1-immobilized sensor chip along with a test compound (ref-2, ref-3, ref-4, A-1, ref-1, ref-5, or B-1) over time. Figure 5 shows sensorgrams showing the amount of MEK1 binding added to the surface of the RAF1-immobilized sensor chip over time in combination with a test compound (A-2, A-25, J-1, E-1, M-1, N-1, or H-3). Figure 6 shows sensorgrams showing the amount of MEK1 binding added to the surface of the RAF1-immobilized sensor chip over time in combination with a test compound (I-2, H-4, L-1, P-1, E-7, or A-27). Figure 7 shows sensorgrams showing the amount of MEK1 binding added to the surface of the RAF1-immobilized sensor chip along with a test compound (A-33, A-18, N-2, A-20, A-8, E-13, or H-1) over time. Figure 8 shows sensorgrams showing the amount of MEK1 binding added to the surface of the RAF1-immobilized sensor chip over time in combination with a test compound (P-2, A-41, E-9, A-6, J-14, A-31, or A-34). Figure 9 shows sensorgrams showing the amount of MEK1 binding added to the surface of the RAF1-immobilized sensor chip over time in combination with a test compound (A-35, A-30, D-4, A-15, J-8, J-5, or A-4). Figure 10 shows sensorgrams showing the amount of MEK1 binding added to the surface of the RAF1-immobilized sensor chip over time in combination with a test compound (A-13, E-23, or J-10). Figure 11 shows sensorgrams showing the amount of MEK1 binding added to the surface of the RAF1-immobilized sensor chip over time in combination with a test compound (ref-4, A-1, P-2, or A-6). Figure 12 is electrophoresis images showing the results of Western blotting of proteins (p-MEK, MEK, p-ERK, and ERK) extracted from A549 cells cultured in the presence of a test compound (ref-5 or compound A-1). Figure 13 is a graph showing changes in tumor volume (mean ± SD) over time in nude mice subcutaneously transplanted with Calu-6 human lung cancer cells. Description of the incarnations

[0043] Exemplary embodiments of the present invention are described below.

[0044] As used in the present disclosure, "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0045] As used in the present disclosure, "C1-6 alkyl group" means a straight-chain or branched alkyl group of 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 2,1-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 2,1-dimethylbutyl, 3,1-dimethylbutyl, 2,2-dimethylbutyl, 3,2-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl and 2-ethylbutyl groups. It is.

[0046] As used in the present disclosure, "C2-7 alkenyl group" means a straight-chain or branched alkenyl group of 2 to 7 carbon atoms. Examples include vinyl, allyl, 1-butenyl, 2-butenyl, 3-butenyl, pentenyl, pentadienyl, hexenyl, hexadinyl, heptenyl, heptadienyl, and heptathrinyl groups.

[0047] As used in the present disclosure, "C2-7 alkynyl group" means a straight-chain or branched alkynyl group of 2 to 7 carbon atoms. Examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, pentynyl, pentadienyl, hexynyl, hexadinyl, heptynyl, heptadienyl, and heptatrienyl groups.

[0048] As used in the present disclosure, "C1-6 alkoxy group" means an alkyloxy group having a straight or branched chain alkyl group of 1 to 6 carbon atoms. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy groups.

[0049] As used in the present disclosure, "C1-6 alkylthio group" means an alkylthio group having a straight or branched chain alkyl group of 1 to 6 carbon atoms. Examples include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, s-butylthio, tert-butylthio, n-pentylthio, and n-hexylthio groups.

[0050] As used in the present disclosure, "C3-6 cycloalkyl group" means a cyclic alkyl group of 3 to 6 atoms forming a ring. While it may be monocyclic or bicyclic, it is meant to be monocyclic unless otherwise specified. Examples of monocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. Examples of bicyclic groups include bicyclo[1.1.1]pentanyl and bicyclo[2.1.1]hexyl groups.

[0051] As used in the present disclosure, a "C3-6 heterocycloalkyl group" means a C3-6 cycloalkyl group in which at least one of the carbon atoms forming the ring is replaced by a nitrogen atom, an oxygen atom, or a sulfur atom. While it may be monocyclic or bicyclic, it is meant to be monocyclic unless otherwise specified. 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] As used in the present disclosure, "unsaturated 5-membered hetero ring" means an unsaturated 5-membered ring containing at least one heteroatom selected from nitrogen, oxygen, and sulfur atoms. Examples include furan, thiophene, pyrrole, imidazole, and thiazole.

[0053] In the present disclosure, examples of pharmaceutically acceptable salts include: inorganic acid salts such as hydrochlorides, hydrobromides, hydroiodides, sulfates, and phosphates; sulfonates such as methanesulfonates, benzenesulfonates, and toluenesulfonates; carboxylates such as formates, acetates, oxalates, maleates, fumarates, citrates, malates, succinates, malonates, gluconates, mandelates, benzoates, salicylates, fluoroacetates, trifluoroacetates, tartrates, propionates, and glutarates; alkali metal salts such as lithium salts, sodium salts, potassium salts, cesium salts, and rubidium salts; Alkaline earth metal salts such as magnesium salts and calcium salts; and ammonium salts such as ammonium salts, alkyl ammonium salts, dialkyl ammonium salts, trialkyl ammonium salts and tetraalkyl ammonium salts. Among these, alkali metal salts such as lithium salts, sodium salts, potassium salts, cesium salts and rubidium salts and sodium salts and potassium salts are more preferred.

[0054] In the present disclosure, a "pharmaceutically acceptable solution" is a solution, for example with water, an alcohol (such as methanol, ethanol, 1-propanol or 2-propanol), acetone, dimethylformamide, or dimethylacetamide. The solution may be a solution with one solvent or may be a solution with several solvents. Hydrates are examples of preferred solutions.

[0055] A first aspect of the present disclosure provides a compound represented by the general formula (1) below, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt: [Chemical Formula 13] Where: Ring A is a group represented by the general formula (2) (3), (4) or (5) below (where the bonds indicated by *, ** and *** are connected to -NH-, -CONH- and CH2—, respectively): [Chemical Formula 14] X1, X2, X3, X4, X5, and X6 are each independently −CR2= or −N=; R2 is a hydrogen atom, a halogen atom or a C1-6 alkyl group; R1 is -S(=O)2-NH-R8 or -S(=O)2-R8; R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group optionally 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 optionally substituted with a C1-6 alkyl group or a C1-6 alkoxy group), or a monocyclic or bicyclic C3-6 heterocycloalkyl group; R3 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group optionally substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3-6 cycloalkyl group optionally substituted with a halogen atom or a C1-6 alkyl group) or a C1-6 alkoxy group (the C1-6 alkoxy group optionally substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group); R5 is a hydrogen atom or a C1-6 alkyl group; R6 is a hydrogen atom, a halogen atom or a C1-6 alkyl group and R4 is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-7 alkenyl group, a C2-7 alkynyl group, a C3-6 cycloalkyl group or a C1-6 alkylthio group, or R6 and R4 form an unsaturated 5-membered hetero ring together with the carbon atoms to which they are attached; R7 is a hydrogen atom or a C1-6 alkyl group; and R9 is a hydrogen atom, a halogen atom or a C1-6 alkyl group.

[0056] The compounds, salts or solutions of the first aspect exhibit high RAF / MEK complex stabilizing activity and can be used for the treatment or prevention of cell proliferation disorders, particularly cancers (in particular, RAS mutant cancers). Many of them have high MEK inhibitory activity and such compounds, salts or solutions are also suitable for RAF mutant cancers.

[0057] Ring A is preferably a group represented by the general formula (2) or (4), and more preferably a group represented by the general formula (2). R2 is preferably a hydrogen or halogen atom, more preferably a hydrogen or fluorine atom, and even more preferably a fluorine atom. R1 is preferably -S(=O)2-NH-R8. R8 is preferably a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group optionally 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 optionally substituted with a C1-6 alkyl group), preferably a C1-6 alkyl group (the C1-6 alkyl group optionally substituted with a halogen atom or a C1-6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group optionally substituted with a C1-6 alkyl group), preferably a C1-4 alkyl group (the C1-4 alkyl group optionally substituted with a fluorine atom or a C1-4 alkoxy group) or a cyclopropyl group (the cyclopropyl group optionally substituted with a C1-4 alkyl) and even more preferably a C1-4 alkyl group. R3 is preferably a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 alkoxy group optionally 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 optionally substituted with a hydroxy group), and even more preferably a hydrogen atom or a cyclopropyl group. R5 is preferably a halogen atom and more preferably a fluorine atom. R6 is preferably a hydrogen atom, a halogen atom or a C1-6 alkyl group, and more preferably a hydrogen atom. R4 is preferably a halogen atom or a cyclopropyl group, and more preferably an iodine atom or a cyclopropyl group. R7 is preferably a hydrogen atom or a methyl group.

[0058] The compound represented by general formula (1) is preferably a compound represented by general formula (6) below: [Chemical Formula 15] Where: X1, X2, X3, and X4 are each independently −CR2= or −N=; R2 is a hydrogen atom, a halogen atom or a C1-6 alkyl group; R1 is -S(=O)2-NH-R8 or -S(=O)2-R8; R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group optionally substituted with a halogen atom, a hydroxy group, a C1-6 alkoxy group), a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group optionally substituted with a C1-6 alkyl group); R3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 alkoxy group optionally substituted with a hydroxy group); R5 is a hydrogen atom or a C1-6 alkyl group; and R6 is a hydrogen atom, a halogen atom or a C1-6 alkyl group and R4 is a halogen atom or a cyclopropyl group.

[0059] Examples of compounds represented by 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 (J-1ترکیب ), 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-1ترکیب ), N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide(A-4ترکیب ), N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (A-6ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide (A-8ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide (A-13ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-25ترکیب ), 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (A-30ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-31ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-33ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-34ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide (A-35ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-41ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide (B-1ترکیب ), 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (D-4ترکیب ), 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (E-1ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide (E-7ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide (E-13ترکیب ), 4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (I-1ترکیب ), N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (J-5ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]-N-methoxybenzamide (A-15ترکیب ), 3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-methylsulfanylanilino)benzamide (A-18ترکیب ), 2-(4-ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-20ترکیب ), 2-(4-bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-27ترکیب ), 2-(2-chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-methoxybenzamide (E-9ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxan-4-ylsulfonylamino)phenyl]methyl]benzamide (E-23ترکیب ), 2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (H-1ترکیب ), 3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (H-3ترکیب ), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine-3-carboxamide (J-8ترکیب ), 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 (J-10ترکیب ), 5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide (J-14ترکیب ), 5-(2-fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide (L-1ترکیب ), 5-(2-fluoro-4-iodoanilino)-8-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]imidazo[1,5-a]pyridine-6-carboxamide (M-1ترکیب ), 5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (N-1ترکیب ), 5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (N-2ترکیب ), 4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (P-1ترکیب ) و 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide (P-2ترکیب ).

[0060] در بین این ترکیبات، N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-2ترکیب ), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (J-1ترکیب ), 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-1ترکیب ), N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide(A-4ترکیب ), N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (A-6ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide (A-8ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide (A-13ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-25ترکیب ), 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (A-30ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-31ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-33ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-34ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide (A-35ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-41ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide (B-1ترکیب ), 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (D-4ترکیب ), 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 (E-7 compound), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide (E-13 compound), 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). For example, MEK inhibitory activity, RAF inhibitory activity, cell proliferation inhibitory activity and / or metabolic stability 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) They are preferable and 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (compound A-1) It has more priority. A preferred pharmaceutically acceptable salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-1) is, for example, the sodium salt or the potassium salt.

[0061] A second aspect of the present disclosure provides a RAF / MEK complex stabilizing agent comprising, as an active ingredient, the compound represented by general formula (11) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound: [Chemical Formula 16] Where: Ring A is a group represented by the general formula (2) (3), (4) or (5) below (wherein the bonds represented by *, ** and *** are attached to -NH-, -CONH- and -X7-, respectively): [Chemical Formula 17] X1, X2, X3, X4, X5, and X6 are each independently −CR2= or −N=; R2 is a hydrogen atom, a halogen atom or a C1-6 alkyl group; X7 is −(CH2)m− or −O− and m is 1, 2 or 3; R1 is -S(=O)2-NH-R8 or -S(=O)2-R8; R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group optionally 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 optionally substituted with a C1-6 alkyl group or a C1-6 alkoxy group), or a monocyclic or bicyclic C3-6 heterocycloalkyl group; R3 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group optionally substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3-6 cycloalkyl group optionally substituted with a halogen atom or a C1-6 alkyl group) or a C1-6 alkoxy group (the C1-6 alkoxy group optionally substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group); R5 is a hydrogen atom, a halogen atom or a C1-6 alkyl group; R6 is a hydrogen atom, a halogen atom or a C1-6 alkyl group and R4 is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-7 alkenyl group, a C2-7 alkynyl group, a C3-6 cycloalkyl group or a C1-6 alkylthio group, or R6 and R4 form an unsaturated 5-membered hetero ring together with the carbon atoms to which they are attached; R7 is a hydrogen atom or a C1-6 alkyl group; and R9 is a hydrogen atom, a halogen atom or a C1-6 alkyl group.

[0062] The compounds, salts or solutions of the second aspect exhibit high RAF / MEK complex stabilizing activity and can be used for the treatment or prevention of cell proliferation disorders, particularly cancers (in particular, RAS mutant cancers). Many of them have high MEK inhibitory activity and such compounds, salts or solutions are also suitable for RAF mutant cancers.

[0063] Ring A is preferably a group represented by the general formula (2) or (4), and more preferably a group represented by the general formula (2). R2 is preferably a hydrogen or halogen atom, more preferably a hydrogen or fluorine atom, and even more preferably a fluorine atom. X7 is preferably -CH2-. R1 is preferably -S(=O)2-NH-R8. R8 is preferably a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group optionally 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 optionally substituted with a C1-6 alkyl group), preferably a C1-6 alkyl group (the C1-6 alkyl group optionally substituted with a halogen atom or a C1-6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group optionally substituted with a C1-6 alkyl group), preferably a C1-4 alkyl group (the C1-4 alkyl group optionally substituted with a fluorine atom or a C1-4 alkoxy group) or a cyclopropyl group (the cyclopropyl group optionally substituted with a C1-4 alkyl) and even more preferably a C1-4 alkyl group. R3 is preferably a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 alkoxy group optionally 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 optionally substituted with a hydroxy group), and even more preferably a hydrogen atom or a cyclopropyl group. R5 is preferably a halogen atom or a C1-6 alkyl group, more preferably a halogen atom and even more preferably a fluorine atom. R6 is preferably a hydrogen atom, a halogen atom or a C1-6 alkyl group, and more preferably a hydrogen atom. R4 is preferably a halogen atom or a cyclopropyl group, and more preferably an iodine atom or a cyclopropyl group. R7 is preferably a hydrogen atom or a methyl group.

[0064] The compound represented by the general formula (11) is preferably a compound represented by the general formula (6) below: [Chemical Formula 18] Where: X1, X2, X3 and X4 are each independently -CR2= or -N=; R2 is a hydrogen atom, a halogen atom or a C1-6 alkyl group; R1 is -S(=O)2-NH-R8 or -S(=O)2-R8; R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group optionally 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 optionally substituted with a C1-6 alkyl group); R3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C1-6 alkoxy group (the C1-6 alkoxy group is optionally substituted with a hydroxy group); R5 is a halogen atom or a C1-6 alkyl group; and R6 is a hydrogen atom, a halogen atom or a C1-6 alkyl group and R4 is a halogen atom or a cyclopropyl group.

[0065] Examples of compounds represented by formula (11) include: N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-2ترکیب ), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (J-1ترکیب ), 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-1ترکیب ), N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide(A-4ترکیب ), N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (A-6ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide (A-8ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide (A-13ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-25ترکیب ), 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (A-30ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-31ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-33ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-34ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide (A-35ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-41ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide (B-1ترکیب ), 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (D-4ترکیب ), 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (E-1ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide (E-7ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide (E-13ترکیب ), 4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (I-1ترکیب ), N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (J-5ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]-N-methoxybenzamide (A-15ترکیب ), 3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-methylsulfanylanilino)benzamide (A-18ترکیب ), 2-(4-ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-20ترکیب ), 2-(4-bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-27ترکیب ), 2-(2-chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-methoxybenzamide (E-9ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxan-4-ylsulfonylamino)phenyl]methyl]benzamide (E-23ترکیب ), 2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (H-1ترکیب ), 3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (H-3ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]oxybenzamide (H-4ترکیب ), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine-3-carboxamide (J-8ترکیب ), 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 (J-10ترکیب ), 5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide (J-14ترکیب ), 5-(2-fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide (L-1ترکیب ), 5-(2-fluoro-4-iodoanilino)-8-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]imidazo[1,5-a]pyridine-6-carboxamide (M-1ترکیب ), 5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (N-1ترکیب ), 5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (N-2ترکیب ), 4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (P-1ترکیب ) و 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide (P-2ترکیب ).

[0066] در بین این ترکیبات N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-2ترکیب ), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (J-1ترکیب ), 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-1ترکیب ), N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide(A-4ترکیب ), N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (A-6ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide (A-8ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide (A-13ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-25ترکیب ), 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (A-30ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-31ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-33ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-34ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide (A-35ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-41ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide (B-1ترکیب ), 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (D-4ترکیب ), 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (E-1ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide (E-7ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide (E-13ترکیب ), 4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (I-1ترکیب ),و 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). For example, MEK inhibitory activity, RAF inhibitory activity, cell proliferation inhibitory activity and / or metabolic stability 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) They are preferable and 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (compound A-1) It has more priority. A preferred pharmaceutically acceptable salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-1) is, for example, a sodium salt or a potassium salt.

[0067] A third aspect of the present disclosure provides a compound represented by general formula (1) below, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt: [Chemical Formula 19] Where: Ring A is a group represented by the general formula (2), (3) or (4) below (where the bonds indicated by *, ** and *** are attached to -NH-, -CONH- and -CH2-, respectively): [Chemical formula 20] X1, X2, X3, X4, and X5 are each independently −CR2= or −N=; R2 is a hydrogen atom, a halogen atom or a C1-4 alkyl group; R1 is -S(=O)2-NH-R8 or -S(=O)2-R8; R8 is a C1-4 alkyl group (the C1-4 alkyl group optionally 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 optionally substituted with a C1-4 alkyl group); R3 is a hydrogen atom, a C3-6 cycloalkyl group or a C1-6 alkoxy group; R5 is a halogen atom; R6 is a hydrogen atom and R4 is a halogen atom or a C3-6 cycloalkyl group; R7 is a C1-4 alkyl group; and R9 is a hydrogen atom. A fourth aspect of the present disclosure provides a MEK inhibitor comprising such a compound, salt or solution as an active ingredient.

[0068] The compounds, salts or solutions of the third or fourth aspect exhibit high MEK inhibitory activity and can be used to treat or prevent cell proliferation disorders, particularly cancers (in particular, RAF mutant cancers).

[0069] The following are examples of compounds of the third or fourth aspect that are preferred in terms of MEK inhibitory activity and metabolic stability: 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-1 compound), (+ / −)-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 (A-21 compound), 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 (A-30 compound), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (A-33 compound), 5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (A-40 ترکیب ), 3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (A-42 ترکیب ), 5-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (B-16 ترکیب ), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (C-3 ترکیب ), 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 (J-10 ترکیب ), 5-(2-fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide (L-1 ترکیب ), 5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (N-1 ترکیب ), 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide (P-2 compound), 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-N-methoxy-5-methyl-6-oxopyridine-3-carboxamide (P-5 compound) and N-cyclopropyl-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (P-6 compound).

[0070] The following are examples of abbreviations used in the present specification and their meanings. Boc: tert-butoxycarbonyl COMU: (1-cyano-2-ethoxy-2-oxoethylidinaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate DBU: Diazby Siklundsen DCC: N,N'-dicyclohexylcarbodiimide DCM: Dichloromethane DIPEA: N,N-diisopropylethylamine DMA: N,N-Dimethylacetamide DMF: N,N-Dimethylformamide DMSO: Dimethyl sulfoxide EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EDC·HCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EtOH: Ethanol HATU: O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetrametyluronium 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: 5,4-bis(diphenylphosphino)-9,9-dimethylxanthene

[0071] Examples of preferred methods for producing the compounds of the present disclosure will now be described. The definitions of X1, R1, R2, R3, R4, R5 and R7 are as above, unless the context indicates otherwise. Ra represents, for example, a 4-methylphenyl group or a 2-nitrophenyl group, and Rb represents, for example, a Boc group or a 4,2-dimethoxybenzyl group.

[0072] (General Production Process -1) General Production Process-1 is a preferred production process for compounds represented by the general formula (6) in which X2, X3 and X4 (which may be the same or different) are -CR2= and R6 is a hydrogen atom.

[0073] [Chemical Formula 21] [Chemical Formula 22]

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

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

[0076] Step 1-3: Hydrazenation of aldehyde derivative 1d An aldehyde derivative 1d is reacted with an arylsulfonyl hydrazide. Examples of arylsulfonyl hydrazides include methylbenzenesulfonyl hydrazides and nitrobenzenesulfonyl hydrazides, with 4-methylbenzenesulfonyl hydrazide and 2-nitrobenzenesulfonyl hydrazide being preferred. Examples of solvents include polar solvents such as alcohols, with methanol and ethanol being preferred.

[0077] Step 1-4: Coupling of hydrazone derivative 1e and arylboronic acid derivative 1f A hydrazone derivative 1e is reacted with an aryl boronic acid derivative 1f in the presence of a base. Examples of the base include salts and amines of carbonic acid, with potassium carbonate and DIPEA being preferred. Examples of the solvent include polar solvents such as 4,1-dioxane, DMF, NMP and THF, with 4,1-dioxane being preferred. The reaction temperature is preferably 80°C or higher.

[0078] Step 1-5: Deprotection of methyl benzoate derivatives 1g A methyl benzoate derivative 1g is subjected to acidic conditions to remove the protecting group Rb. Examples of the acid include sulfuric acid, hydrochloric acid, methane sulfonic acid, and trifluoroacetic acid, with trifluoroacetic acid being preferred. Examples of the solvents include alcohols and nonpolar solvents such as DCM, with DCM being preferred.

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

[0080] Step 1-7: Amidation of benzoic acid derivative 1i A benzoic acid derivative 1i is reacted with the corresponding amine or amine hydrochloride in the presence of a condensing agent. The corresponding amine or amine hydrochloride may optionally have a Boc group. Examples of the condensing agent include DCC, EDC or EDC·HCl, HATU, COMU and propylphosphonic anhydride (cyclic trimer) and for example HOOBt or HOAt may be added if necessary. For example, the use of a combination of EDC or EDC·HCl and HOOBt or the use of HATU is preferred. In some cases, for example, a base such as DIPEA or triethylamine may also be used in addition to the condensing agent, preferably DIPEA base. Examples of solvents include polar solvents such as DMF, DMA, NMP, methanol and ethanol and mixed solvents thereof, with DMF being preferred.

[0081] Step 1-8: Sulfamidation or sulfonamidation of amine derivative 1j, 1ja or 1jb Sulfamidation: An amine derivative 1j, 1ja or 1jb is reacted with the corresponding sulfamoyl chloride or 4-nitrophenylsulfamate in the presence of a base. The corresponding sulfamoyl chloride or 4-nitrophenylsulfamate may optionally have a Boc group. Examples of the base include amines, with pyridine, triethylamine, DIPEA and imidazole being preferred. Examples of the solvent include polar solvents such as DMF, DMA, NMP, THF, 4,1-dioxane, acetonitrile and pyridine, non-polar solvents such as dichloromethane and dichloroethane and mixed solvents thereof, with DMF, DMA, THF and dichloromethane being preferred.

[0082] Sulfonamidation: An 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, with pyridine, triethylamine, DIPEA and imidazole being preferred. Examples of the solvent include polar solvents such as DMF, DMA, NMP, THF, 4,1-dioxane, acetonitrile and pyridine, non-polar solvents such as dichloromethane and dichloroethane and mixed solvents thereof with dichloromethane and pyridine being preferred.

[0083] Step 1-9-1: Boc deprotection of sulfamide or sulfonamide derivative 1k1 When R1 or R3 of a sulfamide or sulfonamide derivative 1k1 has a Boc group, the Boc group is removed by placing the compound 1k1 under acidic conditions. Examples of acids include sulfuric acid, hydrochloric acid, methanesulfonic acid, and trifluoroacetic acid. Alternatively, Boc deprotection may be carried out by generating the acid with, for example, chlorotrimylsilane (TMSCl) in an alcohol. Examples of solvents include alcohols and nonpolar solvents such as DCM. The acid and solvent combination is preferably, 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 a sulfamide or sulfonamide derivative 1k1 When R4 or R5 of a sulfamide or sulfonamide derivative 1k1 is a halogen, it may be subjected to alkylation, alkenylation, alkynylation or thioetherification, for example, by the following method.

[0085] Method 1 (Alkylation or Alkenylation by Suzuki / Miyaura Cross-Coupling): Compound 1k1 is reacted with the corresponding boronic acid, boronic acid ester or borate in the presence of Pd. This can be done by the method described, for example, in Chem. Rev. 1995, vol. 95, no. 7, p. 2457 or ACC. Chem. Res., vol. 40, p. 275. Preferred examples of the base include inorganic salts such as carbonates and hydroxides and amines such as triethylamine and DIPEA, with sodium carbonate, potassium carbonate and triethylamine being preferred. Examples of the solvents include polar solvents such as THF, 4,1-dioxane, DMF, DMA, NMP, methanol, ethanol, 2-propanol and water and mixed solvents thereof, with mixed solvents of THF and 2-propanol and mixed solvents. THF and water are preferred. Examples of Pd and its ligands include those mentioned in Chem. Rev. 1995, vol. 95, no. 7, p. 2457, ACC. Chem. Res., vol. 40, p. 275 and ACC. Chem. Res., vol. 41, p. 1461, with PdCl2(PPh3)2, Pd(PPh3)4 and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride being preferred. The reaction temperature is preferably 80°C or higher.

[0086] Method 2 (Alkylation or Alkenylation by Non-Non Compound 1k1 is reacted with the corresponding organozinc reagent in the presence of Pd or Ni. This can be done by the method described, for example, in Tetrahedron.1992, vol. 48, no. 44, p. 9577 or Aldrichimica Acta. 2005, vol. 38, p. 71. Examples of solvents include polar solvents such as THF, 4,1-dioxane, DMF, DMA and NMP and mixed solvents thereof, with THF being preferred. Examples of Pd and Ni include those mentioned in Tetrahedron.1992, vol. 48, no. 44, p. 9577 or Aldrichimica Acta. 2005, vol. 38, p. 71 as well as PdCl2(PPh3)2, Pd(PPh3)4 and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, with PdCl2(PPh3)2, Pd(PPh3)4 and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride being preferred.

[0087] Method 3 (Alkynylation by Sonogashira cross-coupling): Compound 1k1 is reacted with the corresponding alkyne in the presence of Pd and Cu. This can be done by the method described in Chem. Soc. Rev. 2011, vol. 40, p. 5048. The corresponding alkyne may have a silyl group and may be, for example, trimethylsilylacetylene. Examples of the base include amines such as triethylamine, DIPEA, DBU, and piperidine, and inorganic bases such as NaOAc, with triethylamine and DIPEA being preferred. Examples of Pd catalysts include PdCl2(PPh3)2, Pd(PPh3)4, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, Pd(OAc)2 and Pd2(dba)3, with PdCl2(PPh3)2, Pd(PPh3)4 and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride being preferred. Examples of copper include copper iodide, copper bromide and copper chloride, with copper iodide being preferred. Examples of solvents include polar solvents such as THF, 4,1-dioxane, DMF, DMA, NMP, DMSO, methanol, ethanol and 2-propanol and mixed solvents thereof, with THF being preferred.

[0088] Method 4 (Thioesterification): Compound 1k1 is reacted with a mercaptan or a corresponding 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 zero-valent Pd complexes such as Pd(PPh3)4, with [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate being preferred. Examples of the solvent include polar solvents such as THF, 4,1-dioxane, DMF, DMA, NMP, DMSO, methanol, ethanol and 2-propanol and mixed solvents thereof, with 4,1-dioxane being preferred.

[0089] Step 1-10: Bromination or chlorination of amine derivative 1j When R4 or R5 of an amine derivative 1j is a halogen, compound 1j may be reacted with copper bromide or copper chloride for bromination or chlorination. Examples of the solvent include polar solvents such as THF, 4,1-dioxane, DMF, DMA and NMP, with DMF being preferred.

[0090] Step 1-11: TBS protection of amine derivative 1j When R3 is an amine derivative 1j having a hydroxy group, compound 1j may be reacted with tert-butyldimethylchlorosilane (TBSCl) in the presence of a base to protect TBS. Examples of the base include bases such as triethylamine, DIPEA and imidazole, with triethylamine being preferred. Examples of the solvent include polar solvents such as THF, 4,1-dioxane, DMF, DMA and NMP, with DMF being preferred.

[0091] Step 1-12-1: TBS deprotection of sulfamide or sulfonamide derivative 1k2 When R3 is a sulfamide or sulfonamide derivative 1k2 having a TBS group, compound 1k2 is reacted with tetrabutylammonium fluoride to remove the TBS group. Examples of solvents include polar solvents such as THF, 4,1-dioxane, and DMF, with THF being preferred.

[0092] Step 1-12-2: Desilylation of sulfamide or sulfonamide derivative 1k2 When R4 or R5 of a sulfamide or sulfonamide derivative 1k2 has a silyl group, the compound 1k2 is reacted with a base to remove the silyl group. Examples of the base include salts of carbonic acid, with potassium carbonate being preferred. Examples of the solvent include alcohols such as methanol and ethanol, with methanol being preferred.

[0093] (General Production Process-2) General production process-2 is another preferred process for producing the 1k1 compound. [Chemical Formula 23]

[0094] Step 2-1: The sulfamidation or sulfonamidation of the amine derivative 1h is carried out in a similar manner to steps 1-8. Step 2-2: Hydrolysis of the ester derivative 2a is carried out in a similar manner to steps 1-6. Step 2-3: Amidation of the benzoic acid derivative 2b is carried out in a manner similar to step 1-7. Prior to amidation, Boc deprotection, alkylation, alkenylation, alkynylation, thioetherification, bromation, or chlorination of the benzoic acid derivative 2b may also be carried out in a manner similar to steps 1-9-1, 1-9-2, or 1-10, as appropriate.

[0095] (General Production Process-3) General production process-3 is another preferred process for producing the 1k1 compound. [Chemical formula 24]

[0096] Step 3-1: Hydrazenation of an aldehyde derivative 1c may be carried out in a similar manner to steps 1–3. Step 3-2: Amidation of the benzoic acid derivative 3a is carried out in a similar manner to steps 1–7. Step 3-3: The coupling between the hydrazone derivative 3b and the arylboronic acid derivative 1f, the removal of the protecting group Rb, and the sulfamidation or sulfonamidation of the amine derivative may be carried out in a manner similar to steps 1-4, 1-5, and 1-8, respectively.

[0097] (General Production Process-4) General Production Process-4 is a preferred process for making the backbone of a compound represented by general formula (1) wherein ring A is a group represented by general formula (4), X1, -N=, X2, -CF=, and R6 and R9 are hydrogen atoms. [Chemical formula 25]

[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. For example, potassium iodide or tetrabutylammonium iodide may be added to accelerate the reaction, with tetrabutylammonium iodide being preferred as such an additive. Examples of the solvents include polar solvents such as NMP and 3,1-dimethyl-2-imidazolidinone, with 1,3-dimethyl-2-imidazolidinone being preferred. The reaction temperature is preferably 40°C or higher.

[0099] The starting compounds and reagents used to produce the compounds of the present disclosure may also form salts or solvents as long as the desired reactions are not inhibited.

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

[0101] Isolation or purification of the compounds of the present disclosure can be accomplished using distillation, recrystallization, or chromatography. When isomers (such as enantiomers, diastereomers, or structural isomers) are present, isolation or purification of the compounds can be accomplished using, for example, recrystallization, diastereomeric salt method, enzymatic separation, or chromatography (such as thin layer chromatography, column chromatography, high performance liquid chromatography, or gas chromatography).

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

[0103] In another aspect, the present disclosure provides a therapeutic or prophylactic agent for a cell proliferation disorder, particularly cancer, which agent comprises a compound, salt or solution of any one of the first to fourth aspects as an active ingredient.

[0104] The subject to whom the compound, salt, or solution of the present disclosure is to be administered is an animal, preferably a mammal (e.g., mouse, rat, rabbit, dog, monkey (e.g., cynomolgus monkey), or a human), and preferably a human. The human may be an adult (18 years or older) or a child (less than 18 years). In the case of a child, a child is preferably at least 6 months or older.

[0105] When the compound, salt or solution of the present disclosure is to be used for the treatment or prevention of a cell proliferation disorder, the dosage and dosage interval may be determined depending on, for example, the severity of symptoms, the age and body weight of the subject, the presence or absence of concomitant medication, and the appropriate route of administration. For example, when the subject is a human, a compound, salt or solution of the present disclosure is usually administered once a day to once every three weeks at a dose of 0.00001 to 5000 mg per kilogram of body weight, preferably 0.01 to 100 mg per kilogram of body weight. When the compound is administered daily, the above-mentioned dosage may be divided into 2 to 4 separate doses.

[0106] As for the route of administration to a subject, it may be, for example: systemic administration such as oral administration, rectal administration, intravenous injection, intramuscular injection, subcutaneous injection, intracisternal injection, vaginal administration, intraperitoneal administration, intravesical administration or inhalation injection; or topical administration in the form of an ointment, gel or cream. Oral administration is preferred.

[0107] A compound, salt or solution of the present disclosure is typically used in the form of a pharmaceutical formulation (dosage form). Examples of such formulations include tablets, capsules, granules, powders, fine granules, lozenges, and aqueous or non-aqueous solutions or suspensions. A solution or suspension can be filled and stored in a container suitable for dispensing into individual doses.

[0108] The various formulations mentioned above can be prepared by known methods by mixing the compounds, salts or solutions of the present disclosure with pharmaceutically acceptable additives. Examples of such additives include excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavoring agents, bases, dispersants, diluents, surfactants and emulsifiers.

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

[0110] Examples of lubricants (coating agents) include ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, and paraffin.

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

[0112] Examples of disintegrants include chemically modified starches and celluloses such as croscarmellose sodium, sodium carboxymethyl starch, and cross-linked polyvinyl pyrrolidone, as well as similar compounds mentioned as 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] Examples of flavoring agents include sweeteners, acidulants, and perfumes.

[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 stanol; animal oils; lanolin acid; petrolatum; paraffin; bentonite; glycerin; and glycol oil.

[0116] Examples of dispersants include cellulose derivatives (such as gum arabic, tragacanth, and methylcellulose), polyester stearate, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbates, and sorbitan fatty acid esters.

[0117] Examples of solvents or diluents for liquid formulations include phenol, chlorocresol, purified water, and distilled water.

[0118] Examples of surfactants or emulsifiers include polysorbate 80, polyoxyl 40 stearate, and lauromacrogel.

[0119] The preferred amount of compound, salt or solution present in the formulation varies depending on the dosage form, but will typically be 0.01% to 100% by weight based on the total weight of the formulation.

[0120] Examples of cell proliferation disorders to be treated or prevented using the compound, salt or solutions of the present disclosure include cancers, rheumatism and inflammation, among which cancers are preferred.

[0121] Examples of cancers include: blood and lymphoid cancers, such as leukemias (e.g., acute myelocytic leukemia, acute lymphocytic leukemia, chronic myelocytic leukemia, and chronic lymphocytic leukemia), malignant lymphomas (e.g., Hodgkin's disease and non-Hodgkin's lymphoma), multiple myeloma, and myelodysplastic syndrome; central nervous system cancers, such as brain tumors and gliomas; and solid cancers such as head and neck cancers (e.g., pharyngeal cancer, laryngeal cancer, and tongue cancer), esophageal cancer, gastric cancer, colorectal cancer (e.g., breast cancer, colorectal cancer, and rectal cancer), lung cancers (e.g., small cell lung cancer and non-small cell lung cancer), thyroid cancer, breast cancer, gallbladder cancer, pancreatic cancer, liver cancer, prostate cancer, ovarian cancer, uterine cancer (e.g., endometrial cancer and cervical cancer), testicular cancer, renal cell carcinoma, bladder cancer, renal pelvis cancer, ureteral cancer, malignant melanoma, and skin cancer (e.g., basal cell carcinoma, squamous cell carcinoma, extramammary Paget's disease, Merkel cell carcinoma, sweat gland carcinoma(e.g., apocrine adenocarcinoma and eccrine adenocarcinoma), sebaceous carcinoma, and trichoepithelioma).

[0122] Cancer may be a cancer with or without a gene mutation, or the presence or absence of a mutation is unknown. Examples of genes that are to be mutated include EGFR, FGFR, ALK, ROS1, PI3K, BRAF, HRAS, KRAS, and NRAS.

[0123] When a compound, salt or solution of the first or second aspect is to be used, the cancer is, for example, preferably a RAS-mutated cancer, and for example, preferably a KRAS-mutated solid cancer (particularly KRAS-mutated non-small cell lung cancer). According to one embodiment, it is used for RAF-mutated cancer, in particular for RAF-mutated and RAS-mutated cancer. When the compound, salt or solution of the third or fourth aspect is to be used, for example, the cancer is preferably a RAF-mutated cancer and preferably, for example, a BRAF-mutated solid cancer (particularly BRAF-mutated malignant melanoma). Examples

[0124] The present disclosure will now be explained in more detail based on examples (production samples and test samples), with the understanding that the invention is in no way limited to the examples.

[0125] [Production samples] NMR analysis was performed using an AVANCE III HD400 (400 MHz) from Bruker. NMR data were expressed in ppm (parts per million) (δ) and the deuterium-locked signal from the sample solvent was used as a reference.

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

[0127] High-performance liquid chromatography was performed using one of the analysis conditions A to G in Table 2 below. In Table 2, “TFA” stands for trifluoroacetic acid, “FA” for formic acid, and “AA” for ammonium acetate. [Table 2-1] Table 2 Analysis conditions Column Column temperature Detection wavelength (PDA) A Nexera UC LCMS-2020 Ascentis Express C18 2.1 mm, ID x 50 mm L, 2.7 µm 35°C 210-400 nm B Nexera UC LCMS-2020 XSelect CSH C18 2.1 mm, ID x 50 mm L, 2.5 µm 35°C 210-400 nm C Acquity SQD / SQD2 Ascentis Express C18 2.1 mm, ID x 50 mm L, 2.7 µm 35°C 210-400 nm D Acquity SQD / SQD2 Ascentis Express C18 2.1 mm, ID x 50 mm L, 2.7 µm 35°C 210-400 nm E Acquity SQD / SQD2 Ascentis Express C18 2.1 mm, ID x 50 mm L, 5 µm 35°C 210-400 nm F Acquity SQD / SQD2 Ascentis Express C18 2.1 mm, ID x 50 mm L, 2.7 µm 35°C 210-400 nm G Acquity SQD / SQD2 Ascentis Express C18 2.1 mm, ID x 50 mm L, 2.7 µm 35°C 210-400 nm [Table 2-2] Table 2 (continued) Mobile Phase Analysis Conditions Gradient Flow Rate (mL / min) Time After Injection A / B (min) AA) 0.05% TFA / CH3CN B) 0.05% TFA / H2O 0-1.5 1.5-2.0 5 / 95 → 100 / 0 100 / 0 1 BA) 0.1% FA / CH3CN B) 0.1% FA / H2O 0-1.75 1.75-2.00 5 / 95 → 100 / 0 100 / 0 1 CA) 0.1% FA / CH3CN B) 0.1% FA / H2O 0-1.0 1.0-1.4 5 / 95 → 100 / 0 100 / 0 1 DA) 0.1% FA / CH3CN B) 0.1% FA / H2O 0-1.0 1.0-1.4 40 / 60 → 0 / 100 0 / 100 1 EA) MeOH B) 10 mM AA / H2O 0-1.0 1.0-1.4 5 / 95 → 100 / 0 100 / 0 0.9 FA) 0.05% TFA / CH3CN B) 0.05% TFA / H2O 0-1.0 1.0-1.4 5 / 95 → 100 / 0 100 / 0 1 GA) 0.05% FA / CH3CN B) 0.05% FA / H2O 0-1.0 1.0-1.4 5 / 95 → 100 / 0 100 / 0 1

[0128] The microwave reaction was performed using a primer from Biotage. A shock cap reaction vial was used for the microwave reaction.

[0129] Commercially available reagents were used directly without further purification. All non-aqueous reactions were performed in anhydrous solvents. Concentration under reduced pressure and solvent distillation were performed using a rotary evaporator.

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

[0131] As used in the following production examples, "production example for compound A-1" means production example A-1-1 and "production example for compound a9" means production example a9-1.

[0132] Compound a1: Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-formylbenzoate [Chemical formula 26] A mixed 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, a 10% diazomethyltrimethylsilane hexane solution (21.8 mL, 13.1 mmol) was added, and the mixture was stirred at room temperature for 64 h. Acetic acid (0.748 mL) was added to the reaction mixture, which was then concentrated under reduced pressure. The resulting residue was purified by trituration (hexane / ethyl acetate) to give the title compound (5.01 g, 88%) as a colorless solid. LCMS m / z: 436 [M+H]+ HPLC retention time: 1.00 min (Analysis conditions D)

[0133] Compound a2: Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzoate [Chemical Formula 27] 4-Methylbenzenesulfonylhydrazide (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 h. The reaction mixture was concentrated under reduced pressure and then hexane (150 mL) was added. The mixture was cooled to 0 °C and filtered, then washed with hexane (30 mL) to give the title compound (7.05 g, quantitative) as a solid. LCMS m / z: 604 [M+H]+ HPLC retention time: 1.06 min (Analysis conditions D)

[0134] Compound a3: N-(2,4-Dimethoxybenzyl)-3-fluoro-4-iodopyridine-2-amine [Chemical Formula 28] Triethylamine (3.63 mL, 26.0 mmol) and 1-(4,2-dimethoxyphenyl)methanamine (3.26 mL, 21.7 mmol) were added to a solution of 3,2-difluoro-4-iodopyridine (2.09 g, 8.67 mmol) in NMP (32 mL), and the mixture was stirred at 100°C for 1.5 h. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with 13% brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure after filtering off the drying agent. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (3.20 g, 95%) as an oil. LCMS m / z: 389 [M+H]+ HPLC retention time: 0.94 min (Analysis conditions C)

[0135] Compound a4: [2-[(2,4-Dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid [Chemical Formula 29] A 4,1-dioxane solution (27 mL) of N-(2,4-dimethoxybenzyl)-3-fluoro-4-iodopyridine-2-amine (compound a3, 2.70 g, 6.96 mmol), the adduct of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (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 under nitrogen atmosphere for 5 h at 90 °C and then for 19 h at 110 °C. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.1% aqueous formic acid 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 min (Analysis conditions C)

[0136] Compound a5: Methyl 5-[[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate [Chemical formula 30] A 4,1-dioxane suspension (59 mL) 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) was stirred under nitrogen atmosphere for 2.5 h at 100 °C and then for 3 h at 110 °C. Ethyl acetate was added to the reaction mixture, which was then washed with water and 13% brine. The organic layer was dried over anhydrous sodium sulfate and, after filtering off the drying agent, concentrated under reduced pressure. The obtained 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 min (Analysis conditions D)

[0137] Compound a6: Methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate [Chemical Formula 31] 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 h. 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) to give the title compound (321 mg, 79%) as an oil. LCMS m / z: 532 [M+H]+ HPLC retention time: 0.55 min (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 [Chemical Formula 32] A mixed 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 h. After cooling to 0 °C, 5 M hydrochloric acid (15.1 mL) was added to the reaction mixture, and then concentrated under reduced pressure. The resulting residue was washed with water and TBME to give the title compound (4.20 g, quantitative) as a purple compound. LCMS m / z: 518 [M+H]+ HPLC retention time: 0.68 min (Analysis conditions C)

[0139] Compound a8: 5-((2-Amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide [Chemical Formula 33] An anhydrous DMF solution (3.6 mL) of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride (compound a7, 200 mg, 0.361 mmol) was cooled to 0 °C, HOOBt (67.8 mg, 0.415 mmol) and EDC·HCl (80.0 mg, 0.415 mmol) were added, and the mixture was stirred at room temperature for 1.5 h. After further addition of HOOBt (8.8 mg, 0.054 mmol) and EDC·HCl (10.4 mg, 0.054 mmol) and stirring at room temperature for 1 h, 7 M ammonia solution MeOH (0.103 mL, 0.722 mmol) and DIPEA (0.189 mL, 1.08 mmol) were added at 0 °C and the mixture was stirred at room temperature for 30 min. Water and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction mixture in a ratio of 1:1, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and, after filtering off the drying agent, concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate (1 mL) and hexane (10 mL) was added.The obtained solid was filtered 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 min (Analysis conditions C)

[0140] Compound a9: 5-((2-Amino-3-fluoropyridin-4-yl)methyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluorobenzamide [Chemical Formula 34] Example of producing 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 for 2.5 h at room temperature under a nitrogen atmosphere. Ethyl acetate (5 mL) was added to the reaction mixture, then filtered through celite and washed with ethyl acetate (3 mL). The filter was washed with water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and after filtering off the drying agent, it was concentrated under reduced pressure. Dichloromethane / hexane (1 / 10, 11 mL) was added to the obtained residue, and the solid was filtered and washed with hexane (3 mL) to give compound a9 (63.4 mg, 76%) as a colorless solid. LCMS m / z: 431 [M+H]+ HPLC retention time: 0.61 min (Analysis conditions C)

[0141] Compound r1: 4-Nitrophenyl methylsulfamate [Chemical Formula 35] 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, a dichloromethane solution (15 mL) of methylsulfamoyl chloride (5.82 g, 44.9 mmol) was added, and the mixture was stirred at −78 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure, and the 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 acetonitrile) to give the title compound (5.51 g, 66%) as a colorless solid. HPLC retention time: 0.63 min (Analysis conditions C) 1H-NMR (400 MHz, CDCl3) δ: 8.31 (2H, m), 7.46 (2H, m), 4.68 (1H, m), 3.00 (3H, d, J = 5.4 Hz).

[0142] Compound A-1: 2-(4-Cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide [Chemical Formula 36] Example of production A-1-1: After dissolving 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) 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 h. The reaction mixture was cooled to room temperature and water (24.7 mL) was added to it. After further addition of acetonitrile (3 mL) and water (19.8 mL) and stirring for 10 min, the solid was filtered. The solid obtained with water / acetonitrile (1 / 1, 49.4 mL) was washed to give compound A-1 (2.56 g, 85%) as a colorless solid. LCMS m / z: 524 [M+H]+ HPLC retention time: 1.13 min (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 [Chemical Formula 37] After dissolving 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) in anhydrous DMF (1 mL), 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 h, 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 h. The reaction mixture was purified by reverse-phase column chromatography (0.1% aqueous formic acid solution / 0.1% formic acid acetonitrile solution) to afford the title compound (103 mg, 96%) as a brown solid. LCMS m / z: 557 [M+H]+ HPLC retention time: 0.73 min (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 [Chemical Formula 38] 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 conditions similar to those in the example for the production of compound A-1. LCMS m / z: 650 [M+H]+ HPLC retention time: 1.65 min (Analysis conditions B)

[0145] Compound r2: 1-Chlorosulfonyloxy-4-nitrobenzene [Chemical Formula 39] An Et2O suspension (96 mL) of 4-nitrophenol (12.0 g, 86 mmol) and pyridine (6.98 mL, 86 mmol) was cooled to −78 °C, and then an Et2O solution (96 mL) of sulfuryl chloride (6.98 mL, 86 mmol) was added over 10 min, and the mixture was stirred at room temperature for 6.5 h. The reaction mixture was filtered and washed with Et2O (15 mL), and the filtrate was then 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 conditions C) 1H-NMR (400 MHz, CDCl3) δ: 8.41 (2H, m), 7.61 (2H, m)

[0146] Compound r3: 4-Nitrophenyl N-[(2,4-dimethoxyphenyl)methyl]sulfamate [Chemical formula 40] A DCM solution (36 mL) of 1-chlorosulfonyloxy-4-nitrobenzene (compound r2, 1.78 g, 7.48 mmol) was cooled to −78 °C, a DCM solution (53 mL) of 4,2-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 min and the mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse-phase column chromatography (0.1% aqueous formic acid solution / 0.1% acetonitrile formic acid 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 min (Analysis conditions C)

[0147] Compound r4: 4-Nitrophenyl sulfamate [Chemical formula 41] The title compound was synthesized from 4-nitrophenyl N-[(2,4-dimethoxyphenyl)methyl]sulfamate (compound r3) under conditions similar to the production example for compound a6. LCMS m / z: 217 [M−H]− HPLC retention time: 0.53 min (Analysis conditions C)

[0148] Compound r5: 4-Nitrophenyl N-ethylsulfamate [Chemical formula 42] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under conditions similar to the example for the production of compound r3. LCMS m / z: 245 [M−H]− HPLC retention time: 0.68 min (Analysis conditions C)

[0149] Compound r6: 4-Nitrophenyl N-cyclopropylsulfamate [Chemical formula 43] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under conditions similar to the example for the production of compound r3. LCMS m / z: 257 [M−H]− HPLC retention time: 0.70 min (Analysis conditions C)

[0150] Compound r7: 4-Nitrophenyl N-(2-fluoroethyl)sulfamate [Chemical formula 44] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under conditions similar to the example for the production of compound r3. LCMS m / z: 263 [M−H]− HPLC retention time: 0.65 min (Analysis conditions C)

[0151] Compound r11: 4-Nitrophenyl N-[2-[tert-butyl(dimethyl)silyl]oxypropyl]sulfamate [Chemical formula 45] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under conditions similar to the example for the production of compound r3. LCMS m / z: 389 [M−H]− HPLC retention time: 1.03 min (Analysis conditions C)

[0152] Compound r8: 4-Nitrophenyl N-(2-methoxyethyl)sulfamate [Chemical formula 46] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under conditions similar to the example for the production of compound r3. LCMS m / z: 277 [M+H]+ HPLC retention time: 0.64 min (Analysis conditions C)

[0153] Compound r9: 4-Nitrophenyl N-(1-methylcyclobutyl)sulfamate [Chemical formula 47] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under conditions similar to the example for the production of compound r3. LCMS m / z: 287 [M+H]+ HPLC retention time: 0.78 min (Analysis conditions C)

[0154] Compound r10: 4-Nitrophenyl N-[1-(methoxymethyl)cyclopropyl]sulfamate [Chemical formula 48] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under conditions similar to the example for the production of compound r3. LCMS m / z: 303 [M+H]+ HPLC retention time: 0.67 min (Analysis conditions C)

[0155] Compound r12: 4-Nitrophenyl N-propylsulfamate [Chemical formula 49] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under conditions similar to the example for the production of compound r3. LCMS m / z: 261 [M+H]+ HPLC retention time: 0.72 min (Analysis conditions C)

[0156] Compound r13: 4-Nitrophenyl N-(oxetan-3-ylmethyl)sulfamate [Chemical formula 50] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under conditions similar to the example for the production of compound r3. LCMS m / z: 289 [M+H]+ HPLC retention time: 0.59 min (Analysis conditions C)

[0157] Compound r14: 4-Nitrophenyl N-(3-oxabicyclo[3.1.0]hexan-6-yl)sulfamate [Chemical formula 51] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under conditions similar to the example for the production of compound r3. LCMS m / z: 301 [M+H]+ HPLC retention time: 0.63 min (Analysis conditions C)

[0158] Compound r15: 4-Nitrophenyl N-(1-methylcyclopropyl)sulfamate [Chemical formula 52] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under conditions similar to the example for the production of compound r3. LCMS m / z: 273 [M+H]+ HPLC retention time: 0.73 min (Analysis conditions C)

[0159] Compound r16: 4-Nitrophenyl N-[[(2R)-oxolan-2-yl]methyl]sulfamate [Chemical formula 53] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under conditions similar to the example for the production of compound r3. LCMS m / z: 303 [M+H]+ HPLC retention time: 0.67 min (Analysis conditions C)

[0160] Compound r17: 4-Nitrophenyl N-(1-methoxy-2-methylpropan-2-yl)sulfamate [Chemical formula 54] The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under conditions similar to the example for the production of compound r3. HPLC retention time: 0.76 min (Analysis conditions C) 1H-NMR (400 MHz, DMSO-d6) δ: 8.59 (1H, s), 8.34 (2H, m), 7.58 (2H, m), 3.30 (2H, s), 3.27 (3H, s), 1.28 (6H, s)

[0161] Compound A-3: N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(sulfamoylamino)pyridin-4-yl]methyl]benzamide [Chemical formula 55] 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-nitrophenylsulfamate under conditions similar to those of the example for the production of compound A-1. LCMS m / z: 636 [M+H]+ HPLC retention time: 1.58 min (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 [Chemical formula 56] 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-nitrophenylsulfamate under conditions similar to those of the example for the production of compound A-1. LCMS m / z: 664 [M+H]+ HPLC retention time: 1.70 min (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 [Chemical formula 57] 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-nitrophenylsulfamate under conditions similar to those of the example for the production of compound A-1. LCMS m / z: 676 [M+H]+ HPLC retention time: 1.70 min (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 [Chemical formula 58] 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-nitrophenylsulfamate under conditions similar to those of the example for the production of compound A-1. LCMS m / z: 682 [M+H]+ HPLC retention time: 1.66 min (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 [Chemical formula 59] 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 examples for the production of compound a10 and compound A-1. However, a 2 M THF solution of methylamine was used instead of the aminocyclopropane used in the example for the production of compound a10. LCMS m / z: 624 [M+H]+ HPLC retention time: 1.62 min (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 [Chemical formula 60] After dissolving 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) 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 for 3.5 h at room temperature. 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 for 1.5 h at room temperature. The reaction mixture was purified by reverse-phase column chromatography (0.1% aqueous formic acid solution / 0.1% formic acid acetonitrile solution) to afford the title compound (89 mg, 84%) as a colorless solid. LCMS m / z: 589 [M+H]+ HPLC retention time: 0.77 min (Analysis 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 [Chemical formula 61] 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 conditions similar to those used in the preparation of compound A-1. LCMS m / z: 682 [M+H]+ HPLC retention time: 1.69 min (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 [Chemical formula 62] 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 conditions similar to those used in the preparation of compound A-1. LCMS m / z: 726 [M+H]+ HPLC retention time: 1.71 min (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 [Chemical formula 63] 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 conditions similar to the production examples of compound a12 and compound A-1. LCMS m / z: 668 [M+H]+ HPLC retention time: 1.24 min (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 [Chemical formula 64] 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 conditions similar to those in the production examples of compound a12 and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used instead of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 712 [M+H]+ HPLC retention time: 1.26 min (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 [Chemical formula 65] 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 conditions similar to those in the production examples of compound a12 and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used instead of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 722 [M+H]+ HPLC retention time: 1.81 min (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 [Chemical formula 66] 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 conditions similar to the production examples of compound a12 and compound A-1. LCMS m / z: 640 [M+H]+ HPLC retention time: 1.16 min (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 [Chemical formula 67] 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 conditions similar to those in the production examples of compound a12 and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used instead of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 684 [M+H]+ HPLC retention time: 1.18 min (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 [Chemical formula 68] 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 conditions similar to those in the production examples of compound a12 and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used instead of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 694 [M+H]+ HPLC retention time: 1.72 min (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 [Chemical formula 69] 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 conditions similar to those in the production examples of compound a12 and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used instead of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 694 [M+H]+ HPLC retention time: 1.20 min (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 [Chemical formula 70] 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 conditions similar to those in the production examples of compound a12 and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used instead of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 768 [M+H]+ HPLC retention time: 1.12 min (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) [Chemical formula 71] After dissolving 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) in MeOH (0.4 mL), (-)-10-camphorsulfonic acid (27.2 mg, 0.117 mmol) was added and the mixture was stirred at room temperature for 1 h. 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% acetonitrile formic acid) to give the title compound (38 mg, 74%) as a colorless solid. LCMS m / z: 654 [M+H]+ HPLC retention time: 1.10 min (Analysis conditions A)

[0178] Compound a16: 5-[(2-Amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-methylsulfanylanilino)benzamide [Chemical formula 72] After dissolving 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) in anhydrous 4,1-dioxane (0.3 mL), sodium methyl mercaptan (12.2 mg, 0.174 mmol), DIPEA (30.4 μL, 0.174 mmol) and [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (11.2 mg, 0.012 mmol) were added and the mixture was stirred for 30 min at room temperature under a nitrogen atmosphere. The reaction mixture was purified by reverse-phase column chromatography (0.1% aqueous formic acid solution / 0.1% formic acid acetonitrile solution) to afford the title compound (15 mg, 59%) as a colorless solid. LCMS m / z: 437 [M+H]+ HPLC retention time: 0.60 min (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 [Chemical formula 73] 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 conditions similar to those in the production example of compound A-1. LCMS m / z: 530 [M+H]+ HPLC retention time: 1.09 min (Analysis conditions A)

[0180] Compound a17: 5-((2-Amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzamide [Chemical formula 74] After dissolving 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8, 500 mg, 0.969 mmol) in degassed 2-propanol (12 mL) and anhydrous THF (2 mL), potassium vinyl trifluoroborate (143 mg, 1.07 mmol), triethylamine (0.405 mmol, 2.91 mmol) and an adduct [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane (79.0 mg, 0.097 mmol) were added, and the mixture was stirred for 2 h at 80 °C 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% aqueous formic acid / 0.1% acetonitrile formic acid) to give the title compound (343 mg, 85%) as a colorless solid. LCMS m / z: 417 [M+H]+ HPLC retention time: 0.60 min (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 [Chemical formula 75] The title compound was synthesized from -((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzamide (compound a17) under conditions similar to those in the example for the production of compound A-1. LCMS m / z: 510 [M+H]+ HPLC retention time: 1.11 min (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 [Chemical formula 76] 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 to an anhydrous THF solution (26 mL) of 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8, 2.67 g, 5.17 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse-phase column chromatography (0.1% aqueous formic acid solution / 0.1% acetonitrile formic acid solution) to give the title compound (2.57 g, 83%) as a colorless solid. LCMS m / z: 487 [M+H]+ HPLC retention time: 0.84 min (Analysis conditions G)

[0183] Compound a19: 5-[(2-Amino-3-fluoropyridin-4-yl)methyl]-2-(4-ethynyl-2-fluoroanilino)-3,4-difluorobenzamide [Chemical formula 77] Potassium carbonate (17.0 mg, 0.123 mmol) was added to a MeOH 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) and the mixture was stirred at room temperature for 1.5 h. 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% acetonitrile formic acid) to give the title compound (14 mg, 82%) as a colorless solid. LCMS m / z: 415 [M+H]+ HPLC retention time: 0.60 min (Analysis conditions G)

[0184] Compound A-20: 2-(4-Ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide [Chemical formula 78] The title compound was synthesized from -[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-ethynyl-2-fluoroanilino)-3,4-difluorobenzamide (compound a19) and the corresponding 4-nitrophenylsulfamate under conditions similar to those in the production example of compound A-1. LCMS m / z: 536 [M+H]+ HPLC retention time: 1.18 min (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 [Chemical formula 79] 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-nitrophenylsulfamate under the same conditions as in the example for the production of compound A-1, except that imidazole was used instead of pyridine. LCMS m / z: 666 [M+H]+ HPLC retention time: 1.11 min (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 [Chemical formula 80] 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-nitrophenylsulfamate under the same conditions as in the example for the production of compound A-1, except that imidazole was used instead of pyridine. LCMS m / z: 678 [M+H]+ HPLC retention time: 1.16 min (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 [Chemical formula 81] 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-nitrophenylsulfamate under the same conditions as in the example for the production of 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 min (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 [Chemical formula 82] 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-nitrophenylsulfamate under the same conditions as in the example for the production of 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 min (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 [Chemical formula 83] After dissolving 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) in anhydrous DMA (0.1 mL), pyridine (2.3 μL, 0.029 mmol) and methylsulfamoyl chloride (2.5 μL, 0.029 mmol) were added at 0 °C and the mixture was stirred at room temperature for 1 h. The reaction mixture was purified by reverse-phase column chromatography (0.1% aqueous formic acid / 0.1% acetonitrile formic acid) to give the title compound (10.2 mg, 86%) as a colorless solid. LCMS m / z: 610 [M+H]+ HPLC retention time: 1.15 min (Analysis conditions A)

[0190] Compound s2: N-(1-Bicyclo[1.1.1]pentanyl)sulfamoyl chloride [Chemical formula 84] After dissolving sulfuryl chloride (0.102 mL, 1.25 mmol) in anhydrous acetonitrile (1.5 mL), bicyclo[1.1.1]pentan-1-amine hydrochloride (50.0 mg, 0.418 mmol) was added at 0 °C and the mixture was stirred at 80 °C for 16 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a crude product of the title compound.

[0191] Compound s3: N-(Oxan-4-yl)sulfamoyl chloride [Chemical formula 85] The title compound was synthesized from the corresponding amine under similar conditions to the example for the production of 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 [Chemical formula 86] 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 conditions similar to those of the example for the production of compound A-25. LCMS m / z: 662 [M+H]+ HPLC retention time: 1.27 min (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 [Chemical formula 87] 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 conditions similar to those of the example for the production of compound A-25. LCMS m / z: 680 [M+H]+ HPLC retention time: 1.16 min (Analysis conditions A)

[0194] Compound A-30: 5-[[2-(Cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [Chemical formula 88] 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 conditions similar to those of the example for the production of compound A-25. LCMS m / z: 636 [M+H]+ HPLC retention time: 1.21 min (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 [Chemical formula 89] 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 conditions similar to those of the example for the production of compound A-25. LCMS m / z: 638 [M+H]+ HPLC retention time: 1.24 min (Analysis conditions A)

[0196] Compound A-32: 5-[[2-(Cyclobutylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [Chemical formula 90] 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 conditions similar to those of the example for the production of compound A-25. LCMS m / z: 650 [M+H]+ HPLC retention time: 1.26 min (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 [Chemical formula 91] 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 conditions similar to those of the example for the production of compound A-25. LCMS m / z: 654 [M+H]+ HPLC retention time: 1.17 min (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 [Chemical formula 92] 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 conditions similar to those of the example for the production of compound A-25. LCMS m / z: 652 [M+H]+ HPLC retention time: 1.31 min (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 [Chemical formula 93] 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 conditions similar to those in the example for the production of compound A-25, except that the reaction was carried out at 0 °C. LCMS m / z: 664 [M+H]+ HPLC retention time: 1.30 min (Analysis conditions A)

[0200] Compound A-36: 5-[[2-(Cyclopropylmethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [Chemical formula 94] 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 conditions similar to those in the example for the production of compound A-25, except that the reaction was carried out at 0 °C. LCMS m / z: 650 [M+H]+ HPLC retention time: 1.26 min (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 [Chemical formula 95] 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 conditions similar to those in the example for the production of compound A-25, except that the reaction was carried out at 0 °C. LCMS m / z: 652 [M+H]+ HPLC retention time: 1.28 min (Analysis conditions A)

[0202] Compound A-38: 5-[[2-(Ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [Chemical formula 96] 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 conditions similar to those used in the preparation of compound A-25, except that pyridine was used as the solvent. LCMS m / z: 609 [M+H]+ HPLC retention time: 1.20 min (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 [Chemical formula 97] 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 conditions similar to those used in the preparation of compound A-25, except that pyridine was used as the solvent. LCMS m / z: 649 [M+H]+ HPLC retention time: 1.68 min (Analysis conditions B)

[0204] Compound A-40: 5-[[2-(Ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [Chemical formula 98] 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 conditions similar to those of the example for the production of compound A-25. LCMS m / z: 624 [M+H]+ HPLC retention time: 1.20 min (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 [Chemical formula 99] 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 conditions similar to those of the example for the production of compound A-25. LCMS m / z: 638 [M+H]+ HPLC retention time: 1.25 min (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 [Chemical formula 100] 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 conditions similar to those of the example for the production of compound A-25. LCMS m / z: 642 [M+H]+ HPLC retention time: 1.17 min (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 [Chemical Formula 101] After dissolving 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) in anhydrous THF (0.1 mL), triethylamine (0.100 mL, 0.717 mmol), trimethylsilylacetylene (4.1 μL, 0.033 mmol), the adduct [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane (1.2 mg, 1.6 μmol) and copper(I) iodide (0.9 mg, 5 μmol) were added and the mixture was stirred at room temperature for 24 h. The reaction mixture was purified by reverse-phase column chromatography (0.1% aqueous formic acid solution / 0.1% acetonitrile formic acid solution) to give the title compound (12.4 mg) as an oil. LCMS m / z: 580 [M+H]+ HPLC retention time: 0.95 min (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 [Chemical formula 102] After dissolving 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) 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 h. The reaction mixture was purified by reverse-phase column chromatography (0.1% aqueous formic acid / 0.1% acetonitrile formic acid) to give the title compound (5.0 mg, 52%) as a solid. LCMS m / z: 508 [M+H]+ HPLC retention time: 1.05 min (Analysis conditions A)

[0209] Compound a21: 5-[(2-Amino-3-fluoropyridin-4-yl)methyl]-2-(4-bromo-2-fluoroanilino)-3,4-difluorobenzamide [Chemical formula 103] After dissolving 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) 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 h. The reaction mixture was purified by preparative HPLC (5 μm TSK-gel ODS 80TS, 250 × 20 mm column (TOSOH), 0.1% aqueous formic acid solution / 0.1% acetonitrile formic acid solution) to give the title compound (35.6 mg) as a solid. LCMS m / z: 469 [M+H]+ HPLC retention time: 0.61 min (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 [Chemical formula 104] 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 conditions similar to those in the example for the production of compound A-25. LCMS m / z: 562 [M+H]+ HPLC retention time: 1.13 min (Analysis conditions C)

[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 [Chemical formula 105] After dissolving 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8, 102 mg, 0.198 mmol) in anhydrous THF (2 mL), pyridine (0.160 mL, 1.98 mmol) and methanesulfinic acid chloride (0.100 mL, 0.717 mmol) were added at 0 °C under nitrogen atmosphere. After adding tert-butyl hypochlorite (44.6 μL, 0.395 mmol) to the solution at 0 °C and stirring for 1 min, more tert-butyl hypochlorite (44.6 μL, 0.395 mmol) was added. Then, a 2 M solution of methylamine in THF (1.98 mL, 3.95 mmol) was added and the reaction mixture was stirred and purified by reverse phase column chromatography (0.1% aqueous formic acid / 0.1% acetonitrile formic acid) to give the title compound (45.9 mg, 38%) as a colorless solid. LCMS m / z: 608 [M+H]+ HPLC retention time: 1.00 min (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 [Chemical formula 106] After dissolving 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) in THF (16.8 mL) and water (8.4 mL), lithium hydroxide monohydrate (415 mg, 9.88 mmol) was added at 0 °C and the mixture was stirred at room temperature for 2 h. 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 min (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 [Chemical formula 107] 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 conditions similar to those used for the preparation of compound A12. LCMS m / z: 577 [M+H]+ HPLC retention time: 0.58 min (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 [Chemical formula 108] After dissolving 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) in anhydrous DMF (3 mL), triethylamine (0.116 mL, 0.833 mmol) and tert-butyldimethylchlorosilane (0.100 mL, 0.717 mmol) were added at 0 °C and the mixture was stirred at room temperature for 16 h. Then, triethylamine (0.116 mL, 0.833 mmol) and tert-butyldimethylchlorosilane (0.100 mL, 0.717 mmol) were added and stirring was continued for 7 h. The reaction mixture was purified by reverse phase column chromatography (10 mM aqueous ammonium acetate / methanol) to give the title compound (302 mg, 79%) as a yellow solid. LCMS m / z: 691 [M+H]+ HPLC retention time: 0.98 min (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 [Chemical formula 109] 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 conditions similar to those in the example for the production of compound A-25. LCMS m / z: 798 [M+H]+ HPLC retention time: 1.11 min (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 [Chemical formula 110] After dissolving 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) in anhydrous THF (0.2 mL), a 1 M THF solution of tetrabutylammonium fluoride (27 μL, 0.27 mmol) was added at 0 °C and the mixture was stirred for 2 h. The reaction mixture was purified by reverse-phase column chromatography (0.1% aqueous formic acid / 0.1% acetonitrile formic acid) to give the title compound (14 mg, 91%) as a yellow solid. LCMS m / z: 684 [M+H]+ HPLC retention time: 0.79 min (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 [Chemical formula 111] 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 conditions similar to those used for the production of compound A-25. LCMS m / z: 698 [M+H]+ HPLC retention time: 0.83 min (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 [Chemical formula 112] 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-nitrophenylsulfamate under conditions similar to those of the example for the production of compound A-1. LCMS m / z: 578 [M+H]+ HPLC retention time: 0.89 min (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 [Chemical formula 113] 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-nitrophenylsulfamate under conditions similar to those of the production example of compound A-1. LCMS m / z: 704 [M+H]+ HPLC retention time: 0.97 min (Analysis conditions C)

[0220] Compound a26: 5-Bromo-2,3,4-trifluorobenzoic acid [Chemical formula 114] A reaction vessel containing water (81 mL) was cooled to an external temperature of 0 °C and concentrated sulfuric acid (162 mL) was added. Then, 4,3,2-trifluorobenzoic acid (27.0 g, 153 mmol) and potassium sulfate (401 mg, 2.30 mmol) were added and the mixture was heated to an external temperature of 55 °C. An aqueous solution prepared from sodium bromate (25.4 g, 169 mmol) and water (108 mL) was added dropwise over 2.5 h and the mixture was stirred for 2.5 h. The reaction mixture was cooled to 0 °C and then an aqueous solution prepared from sodium sulfite (24.3 g, 161 mmol) and water (324 mL) was added. The crystals were filtered, washed with water (162 mL), and dried under ventilation to give the title compound (27.9 g, 71%) as a colorless solid. LCMS m / z: 253 [MH]- HPLC retention time: 0.66 min (Analysis conditions C)

[0221] Compound a27: 5-Bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzoic acid [Chemical formula 115] A reaction vessel containing a 1 M lithium bis(trimethylsilyl)amide THF solution (206 mL, 206 mmol) was cooled to an external temperature of −15 °C, and a THF solution (30 mL) of 4-cyclopropyl-2-fluoroaniline (11.6 g, 76.5 mmol) was added dropwise. A THF solution (120 mL) of 5-bromo-4,3,2-trifluorobenzoic acid (compound a26, 15.0 g, 58.8 mmol) was added dropwise over 30 min, and the mixture was stirred for 30 min. After adding 5 M hydrochloric acid (118 mL) to the reaction mixture, it was 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 concentrated under reduced pressure. Acetone (120 mL) was added to the resulting concentrated residue, and after heating until dissolved, water (45 mL) and seed crystals (150 mg) were added to precipitate crystals. Water (45 mL) was added to the resulting slurry and the crystals were filtered.After washing with a liquid mixture of acetone / water (2 / 1), they were dried at an external temperature of 40 °C under reduced pressure to give the title compound (19.4 g, 85%). LCMS m / z: 386 [M+H]+ HPLC retention time: 0.62 min (Analysis conditions C)

[0222] Compound a28: 5-Bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide [Chemical formula 116] 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 h. After adding 28% aqueous ammonia (13 mL) to the reaction mixture, it was stirred at room temperature for 30 min and then water (117 mL) was added over 1 h. The crystals were filtered and washed with water and then dried at an external temperature of 40 °C under reduced pressure to give the title compound (12.0 g, 93%). LCMS m / z: 385 [M+H]+ HPLC retention time: 0.52 min (Analysis conditions C)

[0223] Compound a30: N-[3-Fluoro-4-(hydroxymethyl)pyridin-2-yl]acetamide methanesulfonate [Chemical formula 117] (1) Synthesis of N-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-fluoropyridin-2-yl]acetamide After adding tert-butyl-[(2-chloro-3-fluoropyridin-4-yl)methoxy]-dimethylsilane (180 g, 653 mmol), xanthophos (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) to the reaction vessel, it was deaerated in vacuo and exchanged with nitrogen. After adding tris(dibenzylideneacetone)dipalladium(0) (14.9 g, 16.3 mmol) and toluene (540 mL), deaerated in vacuo and exchanged with nitrogen were repeated. The mixture was heated to an external temperature of 120 °C under a nitrogen atmosphere and stirred for 7 h. 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 h. The reaction mixture was then filtered and washed twice with toluene (270 mL the first time and 180 mL the second time) to obtain the crude product N-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-fluoropyridin-2-yl]acetamide as a toluene solution. LCMS m / z: 299 [M+H]+ HPLC retention time: 0.81 min (Analysis conditions C)

[0224] (2) Synthesis of compound a30: The toluene solution of N-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-fluoropyridin-2-yl]acetamide obtained, toluene (175 mL) and methanol (195 mL) were added to the reaction vessel and deaerated in vacuo and exchanged with nitrogen. After adding methane sulfonic acid (188 g, 1.96 mol) dropwise at an external temperature of 10 °C, the mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to an external temperature of 0 °C and stirred for 3 h. The precipitate was filtered and washed with a cooled liquid mixture of toluene (312 mL) and methanol (78 mL). The solid was filtered and a liquid mixture of toluene (1.1 L) and ethanol (492 mL) was added to the reaction vessel and the mixture was stirred for 1 h at an external temperature of 0 °C. The solid was filtered and washed with a liquid mixture of toluene (281 mL) and ethanol (117 mL) and then dried at an external temperature of 40 °C under reduced pressure to give compound a30 (149 g, 81%). LCMS m / z: 185 [M+H]+ HPLC retention time: 0.30 min (Analysis conditions E)

[0225] Compound a31: (2-Acetamide-3-fluoropyridin-4-yl)methyl methylcarbonate [Chemical formula 118] 4-Dimethylaminopyridine (52.3 g, 428 mmol) was added at room temperature 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). The external temperature was cooled to 0 °C, methyl chloroformate (21.9 g, 232 mmol) was added, and the mixture was warmed to room temperature and stirred. The precipitated solid was filtered, 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 to dissolve at room temperature, and then DIPEA (31.2 mL, 178 mmol), heptane (150 mL) and seed crystals were added. After confirming the precipitation of crystals, heptane (1 L) was added. The slurry was cooled to an external temperature of 0 °C, and then the crystals were filtered and washed with a liquid mixture of ethyl acetate / heptane (7 / 2). These were dried at an external temperature of 40 °C under reduced pressure to give the title compound (31.3 g, 72%) as a colorless solid. LCMS m / z: 243 [M+H]+ HPLC retention time: 0.37 min (Analysis conditions C)

[0226] Compound a32: 5-[(2-Acetamide-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide [Chemical formula 119] After adding 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) were added to the reaction vessel, the vessel was vacuum deaerated and nitrogen exchanged. Then, (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 vacuum deaeration and nitrogen exchange were repeated. The mixture was heated to an external temperature of 80 °C under a nitrogen atmosphere and stirred for 6 h. The external temperature was cooled to room temperature, potassium carbonate (10.8 g, 77.9 mmol) was added, and the mixture was deaerated in vacuo and exchanged with nitrogen. After addition of (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (1.1 g, 1.3 mmol) and further deaeration in vacuo and nitrogen exchange, a solution of (2-acetamide-3-fluoropyridin-4-yl)methyl methylcarbonate (compound a31, 12.6 g, 51.9 mmol) in 2-methyltetrahydrofuran (150 mL) was added. The mixture was heated to an external temperature of 70 °C under nitrogen atmosphere and after addition of water (935 μL, 51.9 mmol) three times at 20 min intervals, the mixture was stirred for 20 min. More water (7.0 mL) was added dropwise, the mixture was stirred for 2 h, a solution prepared from N-acetylcysteine ​​(847 mg, 5.2 mmol) and water (150 mL) was added and the mixture was stirred for 1 h. After cooling to an external temperature of 40°C, the aqueous layer was drained. The organic layer was washed with 15% aqueous sodium chloride solution (150 mL), the insoluble part was filtered, and concentration was carried out under reduced pressure. Acetonitrile (500 mL) was added to the resulting concentrated residue, and the mixture was heated at an external temperature of 100°C to dissolve, and then cooled to room temperature.The crystals were filtered and washed with acetonitrile (200 mL) and then dried at an external temperature of 40°C under reduced pressure to give the title compound (8.34 g, 68%). LCMS m / z: 471 [MH]- HPLC retention time: 0.74 min (Analysis conditions C)

[0227] Compound a9: 5-[(2-Amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide [Chemical formula 120] Example of producing 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-acetamide-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 for 6 h at an external temperature of 50 °C. The reaction mixture was cooled to room temperature and a 2 M aqueous solution of sodium hydroxide (1.1 mL, 2.1 mmol) was added. Water (0.5 mL) was added to the resulting slurry and the crystals were filtered. After washing with a methanol / water (2 / 3) liquid mixture, they were dried at an external temperature of 40 °C under reduced pressure to obtain compound a9 (77.7 mg, 85%) as a colorless solid. LCMS m / z: 431 [M+H]+ HPLC retention time: 0.61 min (Analysis conditions C)

[0228] Compound A-1: 2-(4-Cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide [Chemical formula 121] Example of production A-1-2: After dissolving 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (compound a9, 100 mg, 0.232 mmol) in anhydrous DMA (1 mL), pyridine (56.4 μL, 0.697 mmol) was added. After cooling to 0 °C, methylsulfamoyl chloride (30.2 μL, 0.349 mmol) was added and the mixture was stirred for 1 h. Acetonitrile (0.6 mL), water (0.3 mL) and seed crystals (1 mg) were added to the reaction mixture, the temperature was raised to room temperature, and then water (0.7 mL) and acetonitrile (0.4 mL) were added. The mixture was stirred for 20 h. The precipitate was filtered and washed with acetonitrile / water (1 / 1) to give compound A-1 (93.1 mg, 77%) as a colorless solid. LCMS m / z: 524 [M+H]+ HPLC retention time: 1.13 min (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 [Chemical formula 122] (1) Preparation of sample A-1a (Figure I) Acetone (10.6 mL) and DMSO (1.51 mL) were added to 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-1, 3.03 g), dissolve it at room temperature. A 20% ethanol solution of sodium ethoxide (3.03 mL) and seed crystals of the sodium salt of Compound A-1 (Sample A-1b mentioned below) were added to the solution and the mixture was stirred at room temperature for 1 h, after which ethanol (15.1 mL) was added and the mixture was stirred at room temperature for 4 h. Then, ethanol (15.1 mL) was added and the mixture was stirred for 4 h at room temperature to obtain a sodium salt of compound A-1 (2.74 g) as a powdered crystal (Sample A-1a (Figure I)).

[0230] (2) Preparation of Sample A-1b A 20% ethanol solution of sodium ethoxide (0.054 mL) and methyl isobutyl ketone (0.161 mL) was added to compound A-1 (53.6 mg), the mixture was stirred for 30 min at room temperature, and then methyl isobutyl ketone (0.161 mL) was added and stirring was continued for 4 days at 60°C. Then DMSO (0.054 mL) was added and the mixture was stirred for 5 h at 60°C 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). The solution was freeze-dried at −20 °C for 4 days and then dried under reduced pressure at room temperature for 3 days. After adding 1-pentanol (10.0 mL) to the obtained solid, the mixture was stirred at 80 °C for 10 min. It was then stirred at room temperature for 6 h to obtain a sodium salt of compound A-1 (0.966 g) as powdery crystals (sample A-1c).

[0232] (4) Powder X-ray diffraction analysis Sample A-1a (Form I), sample A-1b, and sample A-1c were subjected to powder X-ray diffraction analysis under the following conditions. Device: SmartLab, D / Tex Ultra detector (Rigaku company) Anticathode: Copper Tube voltage: 45 kV Tube current: 200 mA Sampling width: 0.02 degrees

[0233] The results of powder X-ray diffraction analysis are shown in Figures 1 to 3. Figure 1 shows the powder X-ray diffraction pattern of Sample A-1a (Figure 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 When the ratio of sodium ion in the crystals was measured by ion chromatography for sample A-1a (Figure I), the molar ratio of sodium ion to compound A-1 was 0.99. This confirmed that sample A-1a was a monosodium salt. Ion chromatography was performed under the following conditions. Device: Dionex ICS-1600, AS to AP (Thermo Fisher Scientific) Column: Dionex IonPac CG16 (50 × 5 mm) / CS16 (250 × 5 mm) (Thermo Fisher Scientific) Detergent: 30 mmol / L methane sulfonic acid solution Stopper: Dionex CERS-500 4 mm, 88 mA (Thermo Fisher Scientific) Column temperature: 40°C Detergent liquid flow rate: 1.00 ml / min Sample injection volume: 10 microliters Detector: Electrical conductivity detector Sample treatment: Sample A-1a was suspended in a 20 mmol / L methane sulfonic acid solution at a concentration of 0.5 mg / mL, and the suspension was shaken and stirred for 17 hours, the sodium ion was extracted, 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 [Chemical formula 123] 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 conditions similar to those used for the preparation of compound A-25, except that anhydrous NMP was used instead of anhydrous DMA. LCMS m / z: 436 [M+H]+ HPLC retention time: 1.00 min (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 [Chemical formula 124] A mixed 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 h. After adding 2 M hydrochloric acid to the reaction mixture, extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, it was concentrated under reduced pressure to give the title compound (161 mg) as a foam. LCMS m / z: 611 [M+H]+ HPLC retention time: 0.67 min (Analysis 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 [Chemical formula 125] 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 conditions similar to those of the production example of compound a8. LCMS m / z: 670 [M+H]+ HPLC retention time: 1.07 min (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 [Chemical formula 126] 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 conditions similar to those of the production example of compound a8. LCMS m / z: 684 [M+H]+ HPLC retention time: 1.56 min (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 [Chemical formula 127] 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 conditions similar to those of the production example of compound a8. LCMS m / z: 664 [M+H]+ HPLC retention time: 1.70 min and 1.72 min (Analysis conditions 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 (racemate) [Chemical formula 128] 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 conditions similar to those of the production example of compound a12. LCMS m / z: 686 [M+H]+ HPLC retention time: 1.69 min (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 (racemate) [Chemical formula 129] B-5 compound: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(1R,2R)-(+ / −)-2-methylcyclopropyl]benzamide (racemate) [Chemical formula 130] 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 (5 μm YMC Triart C18 plus, 150 × 4.6 mm column, 0.1% TFA aqueous solution / 0.1% TFA acetonitrile solution) to give compound B-4 (14.7 mg) and compound B-5 (41 mg) as separate solids. Compound B-4 LCMS m / z: 664 [M+H]+ HPLC retention time: 1.70 min (Analysis conditions B) Compound B-5 LCMS m / z: 664 [M+H]+ HPLC retention time: 1.72 min (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 [Chemical formula 131] The title compound was synthesized from the corresponding methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate under the same conditions as in the examples for the production of compound A-25, compound b2, and compound a8. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, as used in the example for the production of compound A-25. LCMS m / z: 623 [M+H]+ HPLC retention time: 1.63 min (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 [Chemical formula 132] 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 examples for the production of compound A-25, compound b2, and compound a8. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, as used in the example for the production of compound A-25. LCMS m / z: 640 [M+H]+ HPLC retention time: 1.06 min (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 [Chemical formula 133] 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 examples for the production of compound A-25 and compound b2. However, anhydrous NMP was used instead of anhydrous DMA as used in the example for the production of compound A-25. LCMS m / z: 697 [M+H]+ HPLC retention time: 0.71 min (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 [Chemical formula 134] 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 h. The reaction mixture was purified by reverse phase column chromatography (0.1% aqueous formic acid / 0.1% acetonitrile formic acid) to afford the title compound (75.0 mg, 67%) as a foam. LCMS m / z: 597 [M+H]+ HPLC retention time: 0.60 min (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 [Chemical formula 135] 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 conditions similar to those used in the preparation of compound a12. LCMS m / z: 596 [M+H]+ HPLC retention time: 1.11 min (Analysis conditions A)

[0247] Compound b10: 2-(2-Chloro-4-iodoanilino)-3,4-difluoro-5-formylbenzoic acid [Chemical formula 136] A 2 M LDA THF solution (6.53 mL, 13.1 mmol) was cooled to -78 °C and slowly added to a THF solution (6 mL) of 4,3,2-trifluorobenzoic acid (1.00 g, 5.68 mmol) under nitrogen atmosphere. After stirring at -78 °C for 50 min, DMF (0.484 mL, 6.25 mmol) was slowly added and stirring was continued for 2 h at -10 °C. 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, a 1 M THF solution of lithium bis(trimethylsilyl)amide (13.6 mL, 13.6 mmol) was added dropwise, and the mixture was stirred for 30 min. After stirring, the previous reaction mixture was added, and the resulting mixture was stirred at room temperature for 20 h. After adding water and 2 M hydrochloric acid to the reaction mixture, extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and after filtering off the drying agent, it was concentrated under reduced pressure to obtain the crude product of the title compound (1.2 g). LCMS m / z: 438 [M+H]+ HPLC retention time: 0.91 min (Analysis conditions G)

[0248] Compound b12: Methyl 2-(2-chloro-4-iodoanilino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzoate [Chemical formula 137] The title compound was synthesized from 2-(2-chloro-4-iodoanilino)-3,4-difluoro-5-formylbenzoic acid (compound b10) under conditions similar to the production examples for compound a1 and compound a2. LCMS m / z: 620 [M+H]+ HPLC retention time: 1.09 min (Analysis conditions G)

[0249] Compound b14: Methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate [Chemical formula 138] 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 similar conditions to the production examples of compound a5 and compound a6. However, DIPEA was used instead of potassium carbonate used in the production example of compound a5. LCMS m / z: 548 [M+H]+ HPLC retention time: 0.89 min (Analysis conditions C)

[0250] Compound B-11: 2-(2-Chloro-4-iodoanilino)-5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluorobenzamide [Chemical formula 139] 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-nitrophenylsulfamate under conditions similar to the examples for the production of compound A-1, compound b2, and compound a8. LCMS m / z: 652 [M+H]+ HPLC retention time: 1.67 min (Analysis conditions B)

[0251] Composition B-12: 2-(2-Chloro-4-iodoanilino)-N-cyclopropyl-5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluorobenzamide [Chemical formula 140] 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-nitrophenylsulfamate under similar conditions to the examples for the production of compound A-1, compound b2, and compound a8. However, the corresponding amine was used instead of the 7 M ammonia MeOH solution used in the example for the production of compound a8. LCMS m / z: 692 [M+H]+ HPLC retention time: 1.78 min (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 [Chemical formula 141] 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-nitrophenylsulfamate under similar conditions to the examples for the production of compound A-1, compound b2, and compound a8. However, the corresponding amine was used instead of the 7 M ammonia MeOH solution used in the example for the production of compound a8. LCMS m / z: 724 [M+H]+ HPLC retention time: 1.81 min (Analysis conditions B)

[0253] Compound B-14: N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methanesulfonamide)pyridin-4-yl]methyl]benzamide [Chemical formula 142] 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 of compound A-25, compound b2 and compound a12. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, which were used in the production example for compound A-25, 1 M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate, which was used in the production example for compound b2, and the corresponding amine was used instead of tert-butoxyamine hydrochloride, which was used in the production example for compound a12. LCMS m / z: 635 [M+H]+ HPLC retention time: 0.87 min (Analysis conditions C)

[0254] Compound B-15: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methanesulfonamide)pyridin-4-yl]methyl]-N-methoxybenzamide [Chemical formula 143] 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 of compound A-25, compound b2 and compound a12. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, which were used in the production example for compound A-25, 1 M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate, which was used in the production example for compound b2, and the corresponding amine was used instead of tert-butoxyamine hydrochloride, which was used in the production example for compound a12. LCMS m / z: 625 [M+H]+ HPLC retention time: 0.80 min (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 [Chemical formula 144] 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 of compound A-25, compound b2 and compound a12. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, which were used in the production example for compound A-25, 1 M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate, which was used in the production example for compound b2, and the corresponding amine was used instead of tert-butoxyamine hydrochloride, which was used in the production example for compound a12. LCMS m / z: 639 [M+H]+ HPLC retention time: 0.83 min (Analysis conditions C)

[0256] Compound c1: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzamide [Chemical formula 145] After adding 4-methylbenzenesulfonylhydrazide (2.21 g, 11.9 mmol) to an anhydrous DMF solution (59 mL) of 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-formylbenzoic acid (5.00 g, 11.9 mmol), the mixture was stirred for 30 min at room temperature. Then, HOOBt (1.94 g, 11.9 mmol) and EDC·HCl (2.28 g, 11.9 mmol) were added and the mixture was stirred for 1.5 h at room temperature. 7 M ammonia solution MeOH (3.39 mL, 23.8 mmol) was added to the reaction mixture and stirring was continued for 30 min at room temperature, then the solid was filtered and washed with DMF (30 mL). Acetonitrile (90 mL) and 0.1 M hydrochloric acid (90 mL) were added to the filtrate, and the resulting solid was washed with acetonitrile / water liquid mixture to give the title compound (6.27 g, 90%) as a colorless solid. LCMS m / z: 598 [M+H]+ HPLC retention time: 0.90 min (Analysis conditions C)

[0257] Compound c2: [2-[(2,4-Dimethoxyphenyl)methylamino]pyridin-4-yl]boronic acid [Chemical formula 146] The title compound was synthesized from 4-bromo-2-fluoropyridine under conditions similar to the production examples for compound a3 and compound a4. LCMS m / z: 298 [M+H]+ HPLC retention time: 0.38 min (Analysis conditions C)

[0258] Compound c4: 5-[(2-Aminopyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [Chemical formula 147] The title compound was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzamide (compound c1) under similar conditions to the production examples of compound a5 and compound a6. However, [2-[(2,4-dimethoxyphenyl)methylamino]pyridin-4-yl]boronic acid (compound c2) was used instead of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4) used in the production example of compound a5. LCMS m / z: 649 [M+H]+ HPLC retention time: 0.71 min (Analysis conditions C)

[0259] Compound C-1: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(sulfamoylamino)pyridin-4-yl]methyl]benzamide [Chemical formula 148] 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 conditions similar to those of the example for the production of compound A-1. LCMS m / z: 578 [M+H]+ HPLC retention time: 1.42 min (Analysis conditions B)

[0260] Compound C-2: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide [Chemical formula 149] 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 conditions similar to those used in the example for the production of compound A-1, except that imidazole was used instead of pyridine. LCMS m / z: 636 [M+H]+ HPLC retention time: 1.10 min (Analysis conditions A)

[0261] Compound C-3: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide [Chemical formula 150] 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 conditions similar to those of the example for the production of compound A-25. LCMS m / z: 592 [M+H]+ HPLC retention time: 1.08 min (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 [Chemical formula 151] 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 conditions similar to those of the example for the production of compound A-43. LCMS m / z: 590 [M+H]+ HPLC retention time: 0.92 min (Analysis conditions A)

[0263] Compound c5: 5-Ethenyl-3,4-difluoro-2-(4-iodo-2-methylanilino)benzoic acid [Chemical formula 152] An anhydrous THF solution (1.8 mL) of 4-iodo-2-methylaniline (636 mg, 2.73 mmol) was cooled to −78 °C, and then a 1.3 M THF solution of lithium bis(trimethylsilyl)amide (5.08 mL, 6.60 mmol) was added over 1 h, and the mixture was stirred for 1 h. Then an anhydrous THF solution (3.9 mL) of 4,3,2-trifluoro-5-vinylbenzoic acid (460 mg, 2.28 mmol) was added, and the mixture was stirred for 2 h at 0 °C. Water and 2 M hydrochloric acid were added to the reaction mixture, and extraction was performed twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and after filtering off the drying agent, 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 min (Analysis conditions E)

[0264] Compound c6: 3,4-Difluoro-5-formyl-2-(4-iodo-2-methylanilino)benzoic acid [Chemical formula 153] After adding 1 M aqueous sodium hydrogen carbonate solution (3.02 mL, 3.02 mmol), sodium periodate (1.29 g, 6.03 mmol) and microencapsulated osmium(VIII) oxide (38.3 mg, 0.015 mmol) to an anhydrous THF solution (6.3 mL) of 5-ethenyl-3,4-difluoro-2-(4-iodo-2-methylanilino)benzoic acid (compound c5, 626 mg, 1.51 mmol), the mixture was stirred at room temperature for 6 h. After ethyl acetate was added to the reaction mixture, it was washed with 1 M hydrochloric acid and 0.2 M aqueous sodium thiosulfate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure after filtering off the drying agent. The resulting residue was suspended and washed with ethyl acetate / hexane (25.1, 42 mL) and the solid was filtered. 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 min (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 [Chemical formula 154] The title compound was synthesized from 3,4-difluoro-5-formyl-2-(4-iodo-2-methylanilino)benzoic acid (compound c6) under similar conditions to the production examples of compound c1, compound a5, compound a6 and compound A-1. LCMS m / z: 606 [M+H]+ HPLC retention time: 1.20 min (Analysis conditions A)

[0266] Compound C-6: N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-(methylsulfamoylamino)phenyl]methyl]benzamide [Chemical formula 155] The title compound was synthesized from 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-formylbenzoic acid under conditions similar to 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 min (Analysis conditions B)

[0267] Compound d1: Methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate [Chemical formula 156] 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 conditions similar to those used in the preparation of compound a5, except that (3-amino-2-fluorophenyl)boronic acid hydrochloride was used instead of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4). LCMS m / z: 531 [M+H]+ HPLC retention time: 0.96 min (Analysis conditions D)

[0268] Compound d2: 5-[(3-Amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid [Chemical formula 157] 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 similar conditions to the production example of compound a7. LCMS m / z: 517 [M+H]+ HPLC retention time: 0.95 min (Analysis conditions C)

[0269] Compound D-1: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(2-methoxyethylsulfamoylamino)phenyl]methyl]benzamide [Chemical formula 158] 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 similar conditions to the production examples of compound a8 and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used instead of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 653 [M+H]+ HPLC retention time: 1.24 min (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 [Chemical formula 159] 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 similar conditions to the production examples of compound a8 and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used instead of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 681 [M+H]+ HPLC retention time: 1.35 min (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 [Chemical formula 160] 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 similar conditions to the production examples of compound a8 and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used instead of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 679 [M+H]+ HPLC retention time: 1.27 min (Analysis conditions A)

[0272] Compound D-4: 5-[[3-(Ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [Chemical formula 161] 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 the production examples for compound a8 and compound A-25. However, the corresponding sulfonyl chloride was used instead of methylsulfamoyl chloride used in the production example for compound A-25. Pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 608 [M+H]+ HPLC retention time: 1.26 min (Analysis conditions A)

[0273] Compound D-5: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(2-methoxyethylsulfonylamino)phenyl]methyl]benzamide [Chemical formula 162] 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 the production examples for compound a8 and compound A-25. However, the corresponding sulfonyl chloride was used instead of methylsulfamoyl chloride used in the production example for compound A-25. Pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 638 [M+H]+ HPLC retention time: 1.67 min (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 [Chemical formula 163] 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 conditions similar to the production examples for compound a8 and compound A-1. LCMS m / z: 649 [M+H]+ HPLC retention time: 1.71 min (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 [Chemical formula 164] 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 similar conditions to the production examples of compound a8 and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used instead of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 635 [M+H]+ HPLC retention time: 1.65 min (Analysis conditions B)

[0276] Compound D-8: N-Cyclopropyl-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [Chemical formula 165] 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 the production examples for compound a8 and compound A-25. However, the corresponding sulfonyl chloride was used instead of methylsulfamoyl chloride used in the production example for compound A-25. Pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 648 [M+H]+ HPLC retention time: 1.77 min (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 [Chemical formula 166] 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 similar conditions to the production examples of compound a8 and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used instead of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 663 [M+H]+ HPLC retention time: 1.95 min (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 [Chemical formula 167] 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 similar conditions to the production examples of compound a8 and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used instead of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 703 [M+H]+ HPLC retention time: 1.01 min (Analysis conditions C)

[0279] Compound D-11: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]-N-methoxybenzamide [Chemical formula 168] 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 examples of compound a8 and compound A-1. However, instead of DIPEA, triethylamine was used, which was used in the production example of compound a8. LCMS m / z: 639 [M+H]+ HPLC retention time: 1.62 min (Analysis conditions B)

[0280] Compound D-12: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(sulfamoylamino)phenyl]methyl]-N-methoxybenzamide [Chemical formula 169] 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 similar conditions to the production examples of compound a8 and compound A-1. However, DIPEA was used instead of triethylamine as used in the production example of compound a8 and the corresponding 4-nitrophenylsulfamate was used instead of 4-nitrophenylmethylsulfamate as used in the production example for compound A-1. LCMS m / z: 625 [M+H]+ HPLC retention time: 0.81 min (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 [Chemical formula 170] 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 similar conditions to the production examples of compound a8 and compound A-1. However, DIPEA was used instead of triethylamine as used in the production example of compound a8 and the corresponding 4-nitrophenylsulfamate was used instead of 4-nitrophenylmethylsulfamate as used in the production example for compound A-1. LCMS m / z: 693 [M+H]+ HPLC retention time: 0.95 min (Analysis conditions C)

[0282] Compound D-14: 2-(4-Cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide [Chemical formula 171] 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 examples for the production of compound a9, compound a7, compound a8, and compound A-25. However, a 1 M aqueous solution of sodium hydroxide was used instead of lithium hydroxide monohydrate used in the example for the production of compound a7. LCMS m / z: 523 [M+H]+ HPLC retention time: 1.58 min (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 [Chemical formula 172] 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 examples for the production of compound a9, compound a7, compound a8, and compound A-25. However, a 1 M aqueous sodium hydroxide solution was used instead of the lithium hydroxide monohydrate used in the example for the production of compound a7, and the corresponding amine was used instead of the 7 M ammonia MeOH solution used in the example for the production of compound a8. LCMS m / z: 563 [M+H]+ HPLC retention time: 1.68 min (Analysis conditions B)

[0284] Compound D-16: 2-(4-Cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]-N-methoxybenzamide [Chemical formula 173] 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 examples for the production of compound a9, compound a7, compound a8, and compound A-25. However, a 1 M aqueous sodium hydroxide solution was used instead of the lithium hydroxide monohydrate used in the example for the production of compound a7, and the corresponding amine was used instead of the 7 M ammonia MeOH solution used in the example for the production of compound a8. LCMS m / z: 551 [MH]- HPLC retention time: 0.85 min (Analysis conditions C)

[0285] Compound E-1: 5-[[3-(Ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide [Chemical formula 174] 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 the production examples of compound A-25, compound b2 and compound a12. However, pyridine was used as the solvent in the sulfonamidation step. The corresponding amine was also used instead of tert-butoxyamine hydrochloride, which was used in the production example for compound a12. LCMS m / z: 638 [M+H]+ HPLC retention time: 1.68 min (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 [Chemical formula 175] 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 similar conditions to the examples for the production of 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 min (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 [Chemical formula 176] 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 the production examples of compound A-25, compound b2 and compound a12. However, pyridine was used as the solvent in the sulfonamidation step. The corresponding amine was also used instead of tert-butoxyamine hydrochloride, which was used in the production example for compound a12. LCMS m / z: 694 [M+H]+ HPLC retention time: 1.74 min (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 [Chemical formula 177] 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 similar conditions to the examples for the production of 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 min (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 [Chemical formula 178] 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 the production examples of compound A-25, compound b2 and compound a12. However, pyridine was used as the solvent in the sulfonamidation step. The corresponding amine was also used instead of tert-butoxyamine hydrochloride, which was used in the production example for compound a12. LCMS m / z: 664 [M+H]+ HPLC retention time: 1.73 min (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 [Chemical formula 179] 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 similar conditions to the examples for the production of 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 min (Analysis conditions B)

[0291] Compound E-7: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide [Chemical formula 180] 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 the production examples of compound A-25, compound b2 and compound a12. However, pyridine was used as the solvent in the sulfonamidation step. The corresponding amine was also used instead of tert-butoxyamine hydrochloride, which was used in the production example for compound a12. LCMS m / z: 609 [M+H]+ HPLC retention time: 1.23 min (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 [Chemical formula 181] 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 the production examples of compound A-25, compound b2 and compound a12. However, pyridine was used as the solvent in the sulfonamidation step. The corresponding amine was also used instead of tert-butoxyamine hydrochloride, which was used in the production example for compound a12. LCMS m / z: 695 [M+H]+ HPLC retention time: 0.74 min (Analysis conditions D)

[0293] Compound E-8: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(sulfamoylamino)phenyl]methyl]benzamide [Chemical formula 182] 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 conditions similar to those used for the preparation of compound b9. LCMS m / z: 595 [M+H]+ HPLC retention time: 1.17 min (Analysis conditions A)

[0294] Compound E-9: 2-(2-Chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-methoxybenzamide [Chemical formula 183] 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 the production examples of compound A-25, compound b2, and compound a12. However, pyridine was used as the solvent in the sulfonamidation step. The corresponding amine was also used instead of tert-butoxyamine hydrochloride, which was used in the production example for compound a12. LCMS m / z: 654 [M+H]+ HPLC retention time: 1.75 min (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 [Chemical formula 184] 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 the production examples of compound A-25, compound b2, and compound a12. However, pyridine was used as the solvent in the sulfonamidation step. The corresponding amine was also used instead of tert-butoxyamine hydrochloride, which was used in the production example for compound a12. LCMS m / z: 696 [M+H]+ HPLC retention time: 1.87 min (Analysis conditions B)

[0296] Compound E-11: 2-(2-Chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluorobenzamide [Chemical formula 185] 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 the production examples of compound A-25, compound b2, and compound a12. However, pyridine was used as the solvent in the sulfonamidation step. The corresponding amine was also used instead of tert-butoxyamine hydrochloride, which was used in the production example for compound a12. LCMS m / z: 624 [M+H]+ HPLC retention time: 1.73 min (Analysis conditions B)

[0297] Compound e17: Methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate [Chemical formula 186] 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 similar conditions to the example for the production of compound a5, except that (3-amino-2-fluorophenyl)boronic acid hydrochloride was used instead of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4) and DIPEA was used instead of potassium carbonate. LCMS m / z: 547 [M+H]+ HPLC retention time: 1.13 min (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 [Chemical formula 187] 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-nitrophenylsulfamate under similar conditions to the production samples of compound A-1, compound b2, and compound a12. LCMS m / z: 723 [M+H]+ HPLC retention time: 1.87 min (Analysis conditions B)

[0299] Compound e20: Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzoate [Chemical formula 188] 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 conditions similar to those used for the preparation of compound A-25, except that pyridine was used as the solvent. LCMS m / z: 609 [M+H]+ HPLC retention time: 1.01 min (Analysis conditions C)

[0300] Compound E-13: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide [Chemical formula 189] Lithium hydroxide monohydrate (7.9 mg, 0.19 mmol) was added to a mixed solution of methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzoate (compound e20, 23.0 mg, 0.038 mmol) in THF (0.7 mL) and water (0.3 mL), and the mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated under reduced pressure, and then 1 M hydrochloric acid (0.76 mL) was added, and the mixture was further concentrated under reduced pressure. After adding HOOBt (9.3 mg, 0.057 mmol) and EDC·HCl (10.9 mg, 0.057 mmol) to the anhydrous DMF solution (0.3 mL) of the resulting mixture, the resulting mixture was stirred for 3 h at room temperature. After adding 7 M ammonia MeOH solution (22 μL, 0.15 mmol) at 0 °C, stirring was continued for 30 min. A 10% aqueous trifluoroacetic acid solution (1 mL) was added to the reaction mixture, which was then purified by reverse-phase column chromatography (0.1% aqueous formic acid / 0.1% acetonitrile formic acid) to give the title compound (19.7 mg, 97%) was obtained as a colorless solid. LCMS m / z: 594 [M+H]+ HPLC retention time: 1.61 min (Analysis conditions B)

[0301] Compound E-14: 5-[[3-(Cyclopropylmethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [Chemical formula 190] 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 conditions similar to 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 min (Analysis conditions B)

[0302] Compound E-15: 3,4-Difluoro-5-[[2-fluoro-3-(3-fluoropropylsulfonylamino)phenyl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide [Chemical formula 191] 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 the production examples for compound A-25 and compound E-13. However, pyridine was used as the solvent in the sulfonamidation step. However, anhydrous DCM was used instead of anhydrous DMA used in the production example for compound A-25. LCMS m / z: 640 [M+H]+ HPLC retention time: 1.67 min (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 [Chemical formula 192] 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 conditions similar to 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 min (Analysis conditions B)

[0304] Compound E-17: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(2-methylpropylsulfonylamino)phenyl]methyl]benzamide [Chemical formula 193] 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 conditions similar to 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 min (Analysis conditions B)

[0305] Compound E-18: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(propylsulfonylamino)phenyl]methyl]benzamide [Chemical formula 194] 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 conditions similar to 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 min (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 [Chemical formula 195] 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 conditions similar to 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 min (Analysis conditions B)

[0307] Compound E-20: 5-[[3-(Cyclobutylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [Chemical formula 196] 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 conditions similar to 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 min (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 [Chemical formula 197] 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 conditions similar to 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 min (Analysis conditions B)

[0309] Compound E-22: 5-[[3-(Cyclopropylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [Chemical formula 198] 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 conditions similar to 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 min (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 [Chemical formula 199] 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 conditions similar to the production examples for compound A-25 and compound E-13. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, which were used in the production example for compound A-25. LCMS m / z: 664 [M+H]+ HPLC retention time: 1.65 min (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 [Chemical formula 200] 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 conditions similar to 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 min (Analysis conditions B)

[0312] Compound E-25: N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide [Chemical formula 201] The title compound was synthesized from methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzoate (compound e20) under similar conditions to the examples for the production of compound b2 and compound a12. However, the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the example for the production of compound a12. LCMS m / z: 634 [M+H]+ HPLC retention time: 0.92 min (Analysis conditions C)

[0313] Compound E-26: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]-N-methoxybenzamide [Chemical formula 202] The title compound was synthesized from methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzoate (compound e20) under similar conditions to the examples for the production of compound b2 and compound a12. However, the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the example for the production of compound a12. LCMS m / z: 624 [M+H]+ HPLC retention time: 0.86 min (Analysis conditions C)

[0314] Compound F-1: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-(methylsulfamoylamino)phenyl]methyl]benzamide [Chemical formula 203] The title compound was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzamide (compound c1) under conditions similar to those in the production examples of compound a5 and compound A-25. However, 3-aminophenylboronic acid was used instead of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4) which was used in the production example for compound a5. LCMS m / z: 591 [M+H]+ HPLC retention time: 0.84 min (Analysis conditions C)

[0315] Compound F-2: 5-[[3-(Ethylsulfonylamino)phenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [Chemical formula 204] 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 similar conditions to the production examples of compound a5 and compound A-25, however, 3-aminophenylboronic acid was used instead of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4) which was used in the production example for compound a5. Pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 590 [M+H]+ HPLC retention time: 1.26 min (Analysis conditions A)

[0316] Compound F-3: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-(2-methoxyethylsulfonylamino)phenyl]methyl]benzamide [Chemical formula 205] 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 similar conditions to the production examples of compound a5 and compound A-25, however, 3-aminophenylboronic acid was used instead of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4) which was used in the production example for compound a5. Pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 620 [M+H]+ HPLC retention time: 1.65 min (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 [Chemical formula 206] 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 conditions similar to the production examples of compound a9 and compound A-1. LCMS m / z: 525 [M+H]+ HPLC retention time: 0.83 min (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 [Chemical formula 207] 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 conditions similar to those used in the preparation of compound a10. LCMS m / z: 564 [M+H]+ HPLC retention time: 1.61 min (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 [Chemical formula 208] After adding 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) to an anhydrous DMF solution (0.2 mL) of 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), the mixture was stirred at room temperature for 16 h. The reaction mixture was purified by reverse-phase column chromatography (0.1% aqueous formic acid solution / 0.1% acetonitrile formic acid solution) to afford the title compound (14 mg, 66%) as a colorless solid. LCMS m / z: 554 [M+H]+ HPLC retention time: 1.53 min (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 [Chemical formula 209] 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 similar conditions to the examples for the production of compound a21, compound A-1, and compound G-2. LCMS m / z: 592 [M+H]+ HPLC retention time: 1.52 min (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 [Chemical formula 210] 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 similar conditions to the production examples of compound a21, compound A-1, and compound G-2. However, copper(I) chloride was used instead of copper(I) bromide, which was used in the production example for compound a21. LCMS m / z: 548 [M+H]+ HPLC retention time: 1.50 min (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 [Chemical formula 211] 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 examples of compound a9, compound a7, compound a12 and compound A-1. However, instead of lithium hydroxide monohydrate used in the production example for compound a7, 1 M aqueous sodium hydroxide solution was used, and instead of DIPEA used in the production example for compound a12, triethylamine was used. Also, the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the production example for compound a12, and the corresponding 4-nitrophenylsulfamate was used instead of 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 618 [M+H]+ HPLC retention time: 0.95 min (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 [Chemical formula 212] 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 examples of compound a9, compound a7, compound a12 and compound A-1. However, instead of lithium hydroxide monohydrate used in the production example for compound a7, 1 M aqueous sodium hydroxide solution was used, and instead of DIPEA used in the production example for compound a12, triethylamine was used. Also, the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the production example for compound a12, and the corresponding 4-nitrophenylsulfamate was used instead of 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 608 [M+H]+ HPLC retention time: 0.90 min (Analysis conditions C)

[0324] Composition G-7: N-Cyclopropyl-2-(4-cyclopropyl-2-fluoroanilino)-5-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluorobenzamide [Chemical formula 213] 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 of compound A-25, compound a9, compound a7 and compound a12. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, which were used in the production example for compound A-25, and 1 M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate, which was used in the production example for compound a7. Also, the corresponding amine was used instead of tert-butoxyamine hydrochloride, which was used in the production example for compound a12. LCMS m / z: 563 [M+H]+ HPLC retention time: 0.88 min (Analysis conditions C)

[0325] Composition G-8: 2-(4-Cyclopropyl-2-fluoroanilino)-5-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-N-methoxybenzamide [Chemical formula 214] 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 of compound A-25, compound a9, compound a7 and compound a12. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, which were used in the production example for compound A-25, and 1 M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate, which was used in the production example for compound a7. Also, the corresponding amine was used instead of tert-butoxyamine hydrochloride, which was used in the production example for compound a12. LCMS m / z: 553 [M+H]+ HPLC retention time: 0.82 min (Analysis conditions C)

[0326] Compound G-9: 2-(4-Cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methanesulfonamide)pyridin-4-yl]methyl]-N-methoxybenzamide [Chemical formula 215] 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 of compound A-25, compound a9, compound a7 and compound a12. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA, respectively, which were used in the production example for compound A-25, and 1 M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate, which was used in the production example for compound a7. Also, the corresponding amine was used instead of tert-butoxyamine hydrochloride, which was used in the production example for compound a12. LCMS m / z: 539 [M+H]+ HPLC retention time: 0.79 min (Analysis conditions C)

[0327] Compound h1: Methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-[3-(2-ethylhexaoxy)-3-oxopropyl]sulfanyl-2-fluoroanilino]-3,4-difluorobenzoate [Chemical formula 216] 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), xanthophos (109 mg, 0.188 mmol), tris(dibenzylideneacetone)dipalladium(0) (86 mg, 0.094 mmol) and DIPEA (0.492 mL, 2.82 mmol) in 4,1-dioxane (17 mL) was stirred at 110 °C for 1 h. After adding acetonitrile to the reaction mixture, it was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase column chromatography (0.1% aqueous formic acid solution / 0.1% formic acid acetonitrile solution) to obtain the title compound (584 mg, quant.) as a yellow viscous oil. LCMS m / z: 622 [M+H]+ HPLC retention time: 1.14 min (Analysis conditions G)

[0328] Compound h2: Methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluorobenzoate [Chemical formula 217] A methanol solution (9 mL) of methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-[3-(2-ethylhexaoxy)-3-oxopropyl]sulfanyl-2-fluoroanilino]-3,4-difluorobenzoate (compound h1, 584 mg, 0.939 mmol) was cooled to 0 °C, and then a 25% methanol solution of sodium methoxide (1.29 mL, 5.64 mmol) was added, and the mixture was stirred at room temperature for 3 h. Diethyl (bromodifluoromethyl)phosphonate (1.00 g, 3.76 mmol) was then added at 0 °C, and the mixture was stirred at room temperature for 10 min. The reaction mixture was cooled to 0°C, a 25% methanol solution of sodium methoxide (1.29 mL, 5.64 mmol) and diethyl (bromodifluoromethyl)phosphonate (1.51 g, 5.64 mmol) were added, and the mixture was stirred at room temperature for 20 min. The reaction mixture was cooled to 0°C, formic acid (0.213 mL, 5.64 mmol) was added, and the mixture was concentrated under reduced pressure. The residue obtained was purified by reverse phase column chromatography (0.1% aqueous formic acid / 0.1% acetonitrile formic acid).1%) was purified to give the title compound (195 mg, 43%) as a colorless solid. LCMS m / z: 488 [M+H]+ HPLC retention time: 0.81 min (Analysis conditions G)

[0329] Compound h3: 5-[(2-Amino-3-fluoropyridin-4-yl)methyl]-2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluorobenzamide [Chemical formula 218] 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 a 7 M ammonia MeOH solution (1.80 mL, 12.6 mmol) was stirred for 6 h at 85 °C in a sealed tube 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) to give the title compound (53.2 g, 91%) as a yellow oil. LCMS m / z: 473 [M+H]+ HPLC retention time: 0.63 min (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 [Chemical formula 219] 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 conditions similar to those in the production example of compound A-1. LCMS m / z: 566 [M+H]+ HPLC retention time: 1.49 min (Analysis conditions B)

[0331] Compound h4: 2-(1-Benzothiophen-5-ylamino)-3,4-difluoro-5-formylbenzoic acid [Chemical formula 220] An anhydrous THF solution (30 mL) of 6,6,2,2-tetramethylpiperidine (2.53 g, 17.9 mmol) was cooled to −78 °C. A 1.6 M hexane solution of n-butyllithium (11.2 mL, 17.9 mmol) was added under nitrogen and the mixture was stirred for 5 min. The reaction mixture was added to a THF solution (9.0 mL) of 4,3,2-trifluorobenzoic acid (1.50 g, 8.52 mmol) at −78 °C and the mixture was stirred for 10 min. Then anhydrous DMF (0.759 mL, 9.80 mmol) was added and stirring was continued for 2 h at 0 °C. 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 then a 1.3 M THF solution of lithium bis(trimethylsilyl)amide (15.1 mL, 19.6 mmol) and the previous reaction mixture were added, and the resulting mixture was stirred at room temperature for 24 h. After adding 2 M hydrochloric acid to the reaction mixture and stirring for 24 h, water and 2 M hydrochloric acid were added, and extraction was performed with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and after filtering off the drying agent, concentrated under reduced pressure. The obtained residue was purified by reverse phase column chromatography (0.1% aqueous formic acid solution / 0.1% acetonitrile formic acid solution) to give the title compound (609 mg, 21%) as a gray solid. LCMS m / z: 334 [M+H]+ HPLC retention time: 0.80 min (Analysis conditions C)

[0332] Compound h5: 2-(1-Benzothiophen-5-ylamino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzamide [Chemical formula 221] After adding HOOBt (595 mg, 3.65 mmol) and EDC·HCl (699 mg, 3.65 mmol) to an anhydrous DMF suspension (9.1 mL) of 2-(1-benzothiophen-5-ylamino)-3,4-difluoro-5-formylbenzoic acid (compound h4, 608 mg, 1.82 mmol), the mixture was stirred for 1.5 h at room temperature. Then, 7 M ammonia solution MeOH (0.912 mL, 6.38 mmol) was added at 0 °C and stirring was continued for 30 min. 4-methylbenzenesulfonylhydrazide (340 mg, 1.82 mmol) was added at 0 °C and stirring was continued for 16 h at room temperature. After filtering the reaction mixture, acetonitrile (14 mL) and 0.1 M hydrochloric acid (100 mL) were added to the filtrate. The solid was filtered and then washed with water to give the title compound (412 mg, 45%) as a light brown solid. LCMS m / z: 501 [M+H]+ HPLC retention time: 0.83 min (Analysis conditions C)

[0333] Compound h7: 5-[(2-Amino-3-fluoropyridin-4-yl)methyl]-2-(1-benzothiophen-5-ylamino)-3,4-difluorobenzamide [Chemical formula 222] The title compound was synthesized from 2-(1-benzothiophen-5-ylamino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzamide (compound h5) under conditions similar to those in the examples for the production of compound a5 and compound a6. LCMS m / z: 429 [M+H]+ HPLC retention time: 0.57 min (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 [Chemical formula 223] 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 conditions similar to those in the production example of compound A-1. LCMS m / z: 522 [M+H]+ HPLC retention time: 1.06 min (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 [Chemical formula 224] An anhydrous acetonitrile solution (0.3 mL) of 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(1-benzothiophen-5-ylamino)-3,4-difluorobenzamide (compound h7, 22 mg, 0.051 mmol) was cooled to 0 °C, and then N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (9.5 mg, 0.027 mmol) was added and the mixture was stirred for 2.5 h. Then N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (8.0 mg, 0.023 mmol) was added and the mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by reverse phase column chromatography (0.05% aqueous trifluoroacetic acid solution / 0.05% acetonitrile trifluoroacetic acid solution) to give the title compound (8.0 mg, 35%) as a brown solid. LCMS m / z: 447 [M+H]+ HPLC retention time: 0.61 min (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 [Chemical formula 225] 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 conditions similar to those in the production example of compound A-1. LCMS m / z: 540 [M+H]+ HPLC retention time: 1.10 min (Analysis conditions A)

[0337] Compound h9: 1,2,3-Trifluoro-4-[(4-methoxyphenyl)methoxy]benzene [Chemical formula 226] Potassium carbonate (9.90 g, 71.6 mmol) and 4-methoxybenzyl chloride (5.55 mL, 40.9 mmol) were added to an anhydrous acetone solution (101 mL) of 4,3,2-trifluorophenol (5.01 mmol, 34.1 mmol) and the mixture was stirred at 70 °C for 8 h. Water (150 mL) was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and after filtering off the drying agent, concentrated under reduced pressure. DMSO (15 mL) and water (100 mL) were added to the obtained residue and the obtained solid was washed to give the title compound (8.72 g, 95%) as a gray solid. LCMS m / z: 267 [MH]- HPLC retention time: 0.92 min (Analysis conditions C)

[0338] Compound h10: 2,3,4-Trifluoro-5-[(4-methoxyphenyl)methoxy]benzoic acid [Chemical formula 227] An anhydrous THF solution (15 mL) of 6,6,2,2-tetramethylpiperidine (4.15 mL, 24.6 mmol) was cooled to −78 °C, and then a 1.6 M hexane solution of lithium bis(trimethylsilyl)amide (15.4 mL, 24.6 mmol) was added under a nitrogen atmosphere, and the mixture was stirred for 10 min. The reaction mixture was added to an anhydrous THF solution (15 mL) of 1,2,3-trifluoro-4-[(4-methoxyphenyl)methoxy]benzene (compound h9, 3.00 g, 11.2 mmol) at −78 °C, and the mixture was then stirred for 3 h and another 30 min while carbon dioxide gas was bubbled in. After adding 1 M hydrochloric acid (60 mL) to the reaction mixture, extraction was performed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and after filtering off the drying agent, concentrated under reduced pressure. The obtained residue was purified by reverse phase column chromatography (0.1% aqueous formic acid solution / 0.1% formic acid acetonitrile solution) to give the title compound (1.32 g, 34%) as a gray solid. LCMS m / z: 311 [MH]- HPLC retention time: 0.80 min (Analysis conditions C)

[0339] Compound h13: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-methyl hydroxybenzoate [Chemical formula 228] The title compound was synthesized from 2,3,4-trifluoro-5-[(4-methoxyphenyl)methoxy]benzoic acid (compound h10) under conditions similar to those in the production examples for compound c5, compound a1, and compound a6. However, 2-fluoro-4-iodoaniline was used instead of 4-iodo-2-metylaniline used in the production example for compound c5, and anhydrous THF was used instead of toluene used in the production example for compound a1. LCMS m / z: 424 [M+H]+ HPLC retention time: 0.91 min (Analysis conditions C)

[0340] Compound h14: Methyl 5-[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]oxy-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate [Chemical formula 229] After adding [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) to a DCM solution (15 mL) of 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-methyl hydroxybenzoate (compound h13, 375 mg, 0.886 mmol), the mixture was stirred at room temperature for 2.5 h. Then [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4, 231 mg, 0.753 mmol) was added and the mixture was stirred for 4 h. After N-acetylcysteine ​​(434 mg, 2.66 mmol) was added to the reaction mixture, stirring was continued for 3 h. The solid was filtered and washed with DCM (10 mL), and the filtrate was concentrated under reduced pressure. The residue obtained was purified by reverse-phase column chromatography (0.1% aqueous formic acid / 0.1% acetonitrile formic acid).1%) was purified to give the title compound (168 mg, 28%) as a foam. LCMS m / z: 684 [M+H]+ HPLC retention time: 1.07 min (Analysis conditions C)

[0341] Compound H-4: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]oxybenzamide [Chemical formula 230] 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 conditions similar to those used for the production of compound a6, compound E-13, and compound A-1. LCMS m / z: 612 [M+H]+ HPLC retention time: 1.55 min (Analysis conditions C)

[0342] Compound h17: 5-[[6-[bis[(4-Methoxyphenyl)methyl]amino]pyridin-2-yl]-hydroxymethyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid [Chemical formula 231] An anhydrous THF solution (12 mL) of 6-bromo-N,N-bis(4-methoxybenzyl)pyridine-2-amine (1.22 g, 2.95 mmol) was cooled to −40 °C, and then a 1.6 M solution of lithium bis(trimethylsilyl)amide in THF (1.85 mL, 2.95 mmol) was added under nitrogen atmosphere and the mixture was stirred for 30 min. The reaction mixture was added to an anhydrous THF solution (2.4 mL) of 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-formylbenzoic acid (414 mg, 0.984 mmol) at −78 °C and stirring was continued for 20 min. After adding 1 M hydrochloric acid (2 mL) to the reaction mixture, it was concentrated under reduced pressure. The obtained residue was purified by reverse phase column chromatography (10 mM aqueous ammonium acetate / methanol) to give the title compound (192 mg, 26%) as a yellow solid. LCMS m / z: 756 [M+H]+ HPLC retention time: 1.06 min (Analysis conditions E)

[0343] Compound h18: 5-[(6-Aminopyridin-2-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid [Chemical formula 232] 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 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) and the mixture was stirred at room temperature for 1 h. Then triethylsilane (0.129 mL, 0.810 mmol) and trifluoromethanesulfonic acid (14 μL, 0.162 mmol) were added and stirring was continued for 5 h at room temperature. The reaction mixture was purified by reverse phase column chromatography (0.1% aqueous formic acid / 0.1% acetonitrile formic acid) to give the title compound (72.7 mg, 90%) as a pink solid. LCMS m / z: 500 [M+H]+ HPLC retention time: 1.61 min (Analysis conditions C)

[0344] Compound H-5: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[6-(methylsulfamoylamino)pyridin-2-yl]methyl]benzamide [Chemical formula 233] 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 similar conditions to the examples for the production of compound a8 and compound A-1. LCMS m / z: 592 [M+H]+ HPLC retention time: 1.19 min (Analysis conditions A)

[0345] Compound I-1: 4-Fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide [Chemical formula 234] The title compound was synthesized from 2,4-difluoro-5-vinylbenzoic acid under conditions similar to those in the production examples for compound c5, compound c6, and compound c1, compound a5, compound a6, and compound A-1. However, 2-fluoro-4-iodoaniline was used instead of 4-iodo-2-metylaniline, which was used in the production example for compound c5. LCMS m / z: 592 [M+H]+ HPLC retention time: 1.17 min (Analysis conditions A)

[0346] Compound I-2: 5-[[2-(Ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-4-fluoro-2-(2-fluoro-4-iodoanilino)benzamide [Chemical formula 235] The title compound was synthesized from 2,4-difluoro-5-vinylbenzoic acid under conditions similar to those in the production examples for compound c5, compound c6 and compound c1, compound a5, compound a6 and compound A-1. However, 2-fluoro-4-iodoaniline was used instead of 4-iodo-2-metylaniline used in the production example for compound c5 and the corresponding 4-nitrophenylsulfamate was used instead of 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 606 [M+H]+ HPLC retention time: 1.62 min (Analysis conditions B)

[0347] Compound I-3: 5-[[2-(Cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-4-fluoro-2-(2-fluoro-4-iodoanilino)benzamide [Chemical formula 236] The title compound was synthesized from 2,4-difluoro-5-vinylbenzoic acid under conditions similar to those in the production examples for compound c5, compound c6 and compound c1, compound a5, compound a6 and compound A-1. However, 2-fluoro-4-iodoaniline was used instead of 4-iodo-2-metylaniline used in the production example for compound c5 and the corresponding 4-nitrophenylsulfamate was used instead of 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 618 [M+H]+ HPLC retention time: 1.64 min (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 [Chemical formula 237] The title compound was synthesized from 2,4-difluoro-5-vinylbenzoic acid under conditions similar to those in the production examples for compound c5, compound c6 and compound c1, compound a5, compound a6 and compound A-1. However, 2-fluoro-4-iodoaniline was used instead of 4-iodo-2-metylaniline used in the production example for compound c5 and the corresponding 4-nitrophenylsulfamate was used instead of 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 636 [M+H]+ HPLC retention time: 1.19 min (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 [Chemical formula 238] Thionyl chloride (10.6 mL, 145 mmol) was added to a DCM (91 mL) suspension of methanol (2-amino-3-fluoropyridin-4-yl) (10.3 g, 72.7 mmol) over 10 min, and the mixture was stirred at room temperature for 65 min. After filtering the reaction mixture, the resulting solid was dissolved in ethyl acetate and washed with aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and after filtering off the drying agent, it was concentrated under reduced pressure to give the crude product 2-amino-4-(chloromethyl)-3-fluoropyridine (10.3 g).

[0350] The crude product 2-amino-4-(chloromethyl)-3-fluoropyridine (3.47 g) and tripotassium phosphate (5.00 g, 23.6 mmol) were added to a solution of 3,1-dimethyl-2-imidazolidinone (39 mL) of methyl 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (7.90 g, 19.7 mmol) and tetrabutylammonium iodide (0.726 g, 1.97 mmol) and the mixture was stirred at 50° C. for 4 h. Water was added to the reaction mixture and the resulting solid was filtered and washed with acetonitrile / water mixture to give the title compound (10.3 g, 60%). LCMS m / z: 527 [M+H]+ HPLC retention time: 0.63 min (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 [Chemical formula 239] 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 conditions similar to those used in the preparation of compound a7. LCMS m / z: 513 [M+H]+ HPLC retention time: 0.76 min (Analysis conditions E)

[0352] Compound j3: 5-[(2-Amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide [Chemical formula 240] 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 conditions similar to those in the example for the production of compound a8. LCMS m / z: 512 [M+H]+ HPLC retention time: 0.84 min (Analysis conditions 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 [Chemical formula 241] 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-carboxamide (compound j3) under conditions similar to those of the example for the production of compound A-25. LCMS m / z: 605 [M+H]+ HPLC retention time: 0.95 min (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 [Chemical formula 242] 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 conditions similar to those in the production examples of compound a8 and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used instead of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 649 [M+H]+ HPLC retention time: 0.97 min (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 [Chemical formula 243] 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 conditions similar to those in the examples for the production of compound a8 and compound A-1. LCMS m / z: 645 [M+H]+ HPLC retention time: 1.40 min (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 [Chemical formula 244] 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 conditions similar to those in the production examples of compound a8 and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used instead of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 671 [M+H]+ HPLC retention time: 1.47 min (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 [Chemical formula 245] 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 conditions similar to those in the production examples of compound a8 and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used instead of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 689 [M+H]+ HPLC retention time: 1.43 min (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 [Chemical formula 246] 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 conditions similar to the production examples of compound a12 and compound A-1. LCMS m / z: 635 [M+H]+ HPLC retention time: 1.29 min (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 [Chemical formula 247] 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 conditions similar to those in the production examples of compound a12 and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used in place of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 679 [M+H]+ HPLC retention time: 1.31 min (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 [Chemical formula 248] 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 conditions similar to the production examples of compound a12 and compound A-1. LCMS m / z: 677 [M+H]+ HPLC retention time: 1.46 min (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 [Chemical formula 249] 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 conditions similar to those in the production examples of compound a12 and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used in place of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 703 [M+H]+ HPLC retention time: 1.52 min (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 [Chemical formula 250] 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 conditions similar to those in the production examples of compound a8 and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used in place of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 631 [M+H]+ HPLC retention time: 1.37 min (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 [Chemical formula 251] 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 conditions similar to those in the production examples of compound a8 and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used in place of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 619 [M+H]+ HPLC retention time: 1.35 min (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 [Chemical formula 252] 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 conditions similar to those in the production examples of compound a8 and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used in place of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 659 [M+H]+ HPLC retention time: 0.77 min (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 [Chemical formula 253] 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-carboxamide (compound j3) under conditions similar to those in the examples for the production of compound a9 and compound A-1. LCMS m / z: 519 [M+H]+ HPLC retention time: 1.31 min (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 [Chemical formula 254] 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-carboxamide (compound j3) and the corresponding amine under conditions similar to those in the production examples of compound a9 and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used in place of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 545 [M+H]+ HPLC retention time: 1.37 min (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 [Chemical formula 255] The title compound was synthesized from 2-amino-4-(hydroxymethyl)pyridine under the same conditions as in the production examples of compound j1, compound A-25 and compound a7. However, the corresponding sulfonyl chloride was used instead of methylsulfamoyl chloride used in the production example of compound A-25. Pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 587 [M+H]+ HPLC retention time: 0.64 min (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 [Chemical formula 256] 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 then HATU (13.0 mg, 0.034 mmol) and DIPEA (17.9 μL, 0.102 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was purified by reverse-phase column chromatography (0.1% aqueous formic acid / 0.1% acetonitrile formic acid) to afford the title compound (7.2 mg, 29%) as a colorless solid. LCMS m / z: 586 [M+H]+ HPLC retention time: 1.24 min (Analysis conditions B)

[0369] Compound k1: Methyl 2-(2-fluoro-4-iodoanilino)-5-formyl-1-methyl-6-oxopyridine-3-carboxylate [Chemical formula 257] After adding (chloromethylene)dimethylminium chloride (168 mg, 1.31 mmol) to an acetonitrile 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), the mixture was stirred at room temperature for 1.5 h. Water was added to the reaction mixture, stirring was continued for 30 min, and then the solid was filtered to give the title compound (108 mg, 76%). LCMS m / z: 431 [M+H]+ HPLC retention time: 1.80 min (Analysis conditions C)

[0370] Compound k4: Methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate [Chemical formula 258] The title compound was synthesized from methyl 2-(2-fluoro-4-iodoanilino)-5-formyl-1-methyl-6-oxopyridine-3-carboxylate (compound k1) under similar conditions to the production examples of compound a2, compound a5, and compound a6. However, 2-nitrobenzene-1-sulfonohydrazide was used instead of 4-methylbenzenesulfonyl hydrazide used in the production example for compound a2. Also, [2-fluoro-3-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4) and potassium carbonate were used instead of [2-fluoro-3-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]boronic acid and DIPEA, respectively, which were used in the production example for compound a5. LCMS m / z: 526 [M+H]+ HPLC retention time: 0.90 min (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 [Chemical formula 259] 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 conditions similar to those in the examples for the production of compound b2, compound a8, and compound A-1. LCMS m / z: 604 [M+H]+ HPLC retention time: 1.37 min (Analysis conditions B)

[0372] Compound K-2: 5-[[3-(Ethylsulfamoylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide [Chemical formula 260] The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (compound k4) under the same conditions as the production examples of compound b2, compound a8, and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used instead of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 618 [M+H]+ HPLC retention time: 1.41 min (Analysis conditions B)

[0373] Compound K-3: 5-[[3-(Cyclopropylsulfamoylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide [Chemical formula 261] The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (compound k4) under the same conditions as the production examples of compound b2, compound a8, and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used instead of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 630 [M+H]+ HPLC retention time: 1.43 min (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 [Chemical formula 262] 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 similar conditions to the examples for the production of compound b2, compound a10, and compound A-1. LCMS m / z: 644 [M+H]+ HPLC retention time: 1.48 min (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 [Chemical formula 263] The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (compound k4) under the same conditions as the production examples of compound b2, compound a10, and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used instead of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 670 [M+H]+ HPLC retention time: 1.53 min (Analysis conditions B)

[0376] Composition K-13: N-Cyclopropyl-5-[[3-(ethylsulfamoylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide [Chemical formula 264] The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (compound k4) under the same conditions as the production examples of compound b2, compound a10, and compound A-1. However, the corresponding 4-nitrophenylsulfamate was used instead of the 4-nitrophenylmethylsulfamate used in the production example for compound A-1. LCMS m / z: 658 [M+H]+ HPLC retention time: 1.52 min (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 [Chemical formula 265] 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 similar conditions to the examples for the production of 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 min (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 [Chemical formula 266] 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 of compound A-25, compound b2, and compound a8. However, pyridine was used as the solvent in the sulfonamidation step. Also, the corresponding amine was used instead of tert-butoxyamine hydrochloride, which was used in the production example for compound a12. LCMS m / z: 659 [M+H]+ HPLC retention time: 1.47 min (Analysis conditions B)

[0379] Composition K-11: N-Cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclopropyl)sulfonylamino]phenyl]methyl]-1-methyl-6-oxopyridine-3-carboxamide [Chemical formula 267] 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 examples for the production of compound A-25, compound b2, and compound a8. However, pyridine was used as the solvent in the sulfonamidation step. The corresponding amine was used instead of the 7 M ammonia solution in MeOH used in the example for the production of compound a8. LCMS m / z: 669 [M+H]+ HPLC retention time: 1.59 min (Analysis conditions B)

[0380] K-12 Composition: 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 [Chemical formula 268] 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 similar conditions to the examples for the production of 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 min (Analysis conditions B)

[0381] Composition k11: 5-[[3-(Ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid [Chemical formula 269] 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 similar conditions to the examples for the production of 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 min (Analysis conditions C)

[0382] Composition K-8: N-Cyclopropyl-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide [Chemical formula 270] 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 conditions similar to those used for the production of compound a10. LCMS m / z: 643 [M+H]+ HPLC retention time: 1.53 min (Analysis conditions B)

[0383] K-9 Composition: 5-[[3-(Ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide [Chemical formula 271] 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 conditions similar to those used for the production of compound a12. LCMS m / z: 675 [M+H]+ HPLC retention time: 1.57 min (Analysis conditions B)

[0384] Composition K-10: 5-[[3-(Ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide [Chemical formula 272] After adding HOOBt (8.92 mg, 0.055 mmol) and EDC·HCl (10.5 mg, 0.055 mmol) 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), the mixture was stirred at room temperature for 3 h. After adding 7 M ammonia MeOH solution (20.8 μL, 0.146 mmol) at 0 °C, stirring was continued for 1 h. The reaction mixture was purified by reverse-phase column chromatography (0.1% aqueous formic acid solution / 0.1% formic acid acetonitrile solution) to afford the title compound (15.8 mg, 72%) as a colorless solid. LCMS m / z: 603 [M+H]+ HPLC retention time: 1.42 min (Analysis conditions B)

[0385] Compound l2: Methyl 2-bromo-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate [Chemical formula 273] The title compound was synthesized from 2-bromo-5-fluoropyridine-4-carboxylic acid under the same conditions as in the production examples for compound c5 and compound a1. However, 2-fluoro-4-trimethylsilylaniline was used instead of 4-iodo-2-methylaniline, which was used in the production example for compound c5. LCMS m / z: 397 [M+H]+ HPLC retention time: 1.17 min (Analysis conditions G)

[0386] Compound l3a: Methyl 5-(2-fluoro-4-trimethylsilylanilino)-2-formylpyridine-4-carboxylate [Chemical formula 274] l3b combination: 5-(2-Fluoro-4-trimethylsilylanilino)-4-methoxycarbonylpyridine-2-carboxylic acid [Chemical formula 275] After adding an anhydrous DMF solution (63 mL) of triethylsilane (2.01 mL, 12.6 mmol) to an anhydrous DMF suspension (63 mL) of methyl 2-bromo-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate (compound l2, 2.5 g, 6.29 mmol), 1,1,3-trioxo-1,2-benzothiazole-2-carbaldehyde (2.66 g, 612.6 mmol), xanthophos (728 mg, 1.26 mmol), palladium acetate (141 mg, 0.629 mmol) and sodium carbonate (1.67 g, 15.7 mmol), the mixture was stirred for 10 min at room temperature and then for 2.5 h at 75 °C. The reaction mixture was purified by reverse-phase column chromatography (0.1% aqueous formic acid / 0.1% formic acid acetonitrile) to afford compound l3a (0.4 g, 18%) and compound l3b (1.4 g, 61%) each as a yellow solid. L3A combination LCMS m / z: 347 [M+H]+ HPLC retention time: 1.06 min (Analysis conditions G) l3b combination LCMS m / z: 363 [M+H]+ HPLC retention time: 0.92 min (Analysis conditions G)

[0387] Compound l4: Methyl 5-(2-fluoro-4-trimethylsilylanilino)-2-(hydroxymethyl)pyridine-4-carboxylate [Chemical formula 276] After adding a 1 M THF solution of borane-tetrahydrofuran complex (4.33 mL, 4.33 mmol) to an anhydrous THF solution (14 mL) of methyl 5-(2-fluoro-4-trimethylsilylanilino)-2-formylpyridine-4-carboxylate (compound l3a, 500 mg, 1.44 mmol), the mixture was stirred at room temperature for 1 h. Acetic acid (0.496 mL, 8.66 mmol) was added to the reaction mixture, which was then concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% aqueous formic acid / 0.1% acetonitrile formic acid) to give the title compound (360 mg, 72%) as a light yellow solid. LCMS m / z: 349 [M+H]+ HPLC retention time: 0.91 min (Analysis conditions G)

[0388] Compound l4: Methyl 5-(2-fluoro-4-trimethylsilylanilino)-2-(hydroxymethyl)pyridine-4-carboxylate [Chemical formula 277] After adding borane-dimethyl sulfide complex (0.747 mL, 7.86 mmol) to an anhydrous THF solution (16 mL) of 5-(2-fluoro-4-trimethylsilylanilino)-4-methoxycarbonylpyridine-2-carboxylic acid (compound l3b, 570 mg, 1.57 mmol), the mixture was stirred at room temperature for 2 h. Acetic acid (1.58 mL, 27.6 mmol) was added to the reaction mixture, which was then concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% aqueous formic acid / 0.1% acetonitrile formic acid) to give the title compound (350 mg, 64%) as a light yellow solid. LCMS m / z: 349 [M+H]+ HPLC retention time: 0.91 min (Analysis conditions G)

[0389] Compound l5: Methyl 2-(chloromethyl)-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate [Chemical formula 278] After adding thionyl chloride (0.168 mL, 2.30 mmol) to a DCM solution (12 mL) of methyl 5-(2-fluoro-4-trimethylsilylanilino)-2-(hydroxymethyl)pyridine-4-carboxylate (compound l4, 400 mg, 1.15 mmol), the mixture was stirred at room temperature for 50 min. The reaction mixture was concentrated under reduced pressure to give the crude product of the title compound (400 mg). LCMS m / z: 367 [M+H]+ HPLC retention time: 1.11 min (Analysis conditions G)

[0390] Compound l6: Methyl 2-[[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]methyl]-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate [Chemical formula 279] A 4,1-dioxane suspension (17 mL) 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) was stirred for 2 h at 110 °C. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and after filtering off the drying agent, concentrated under reduced pressure. The obtained 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 min (Analysis conditions G)

[0391] Compound l7: Methyl 2-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate [Chemical formula 280] The title compound was synthesized from methyl 2-[[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]methyl]-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate (compound l6) under conditions similar to those used for the preparation of compound a6. LCMS m / z: 443 [M+H]+ HPLC retention time: 0.83 min (Analysis conditions G)

[0392] Compound l8: Methyl 2-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)pyridine-4-carboxylate [Chemical formula 281] An anhydrous DCM solution (14 mL) of methyl 2-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate (compound l7, 300 mg, 0.678 mmol) was cooled to 0 °C, iodine monochloride (220 mg, 1.36 mmol) was added, and the mixture was stirred at 0 °C for 30 min and then at room temperature for 3 h. 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 min (Analysis conditions G)

[0393] Compound L-1: 5-(2-Fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide [Chemical formula 282] The title compound was synthesized from methyl 2-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)pyridine-4-carboxylate (compound l8) under conditions similar to those in the examples for the production of compound a7, compound K-10, and compound A-1. LCMS m / z: 575 [M+H]+ HPLC retention time: 1.36 min (Analysis conditions B)

[0394] Compound m1: Methyl 2-amino-6-(aminomethyl)pyridine-3-carboxylate diacetate [Chemical formula 283] After adding a palladium catalyst on activated carbon powder (10% palladium) (933 mg, 0.877 mmol) to a mixed solution of methyl 2-amino-6-cyanopyridine-3-carboxylate (9.14 g, 51.6 mmol) in acetic acid (100 mL) and methanol (100 mL), the mixture was stirred for 4 hours at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the crude product of the title compound (15.3 g). LCMS m / z: 182 [M+H]+ HPLC retention time: 0.26 min (Analysis conditions G)

[0395] Composition m2: Methyl 2-amino-6-(formamidemethyl)pyridine-3-carboxylate [Chemical formula 284] Acetic anhydride (115 mL, 1.22 mol) was added 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) over 30 min, and the mixture was stirred overnight at 70 °C. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and after filtering off the drying agent, concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (hexane / DCM) to give the title compound (8.16 g, 80%) as a yellow solid. LCMS m / z: 210 [M+H]+ HPLC retention time: 0.29 min (Analysis conditions G)

[0396] Composition m3: Methyl 2-amino-5-bromo-6-(formamidemethyl)pyridine-3-carboxylate [Chemical formula 285] After adding N-bromosuccinimide (7.87 g, 44.2 mmol) to an anhydrous acetonitrile solution (400 mL) of methyl 2-amino-6-(formamidemethyl)pyridine-3-carboxylate (compound m2, 9.25 g, 44.2 mmol) in several portions, the mixture was stirred at room temperature for 1 h. 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 min (Analysis conditions G)

[0397] Compound m4: Methyl 5-amino-8-bromoimidazo[1,5-a]pyridine-6-carboxylate [Chemical formula 286] After adding phosphoryl chloride (17.5 mL, 187 mmol) to an anhydrous toluene suspension (200 mL) of methyl 2-amino-5-bromo-6-(formamidemethyl)pyridine-3-carboxylate (compound m3, 12.0 g, 41.7 mmol), the mixture was stirred at 95 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogen carbonate and water were added to the resulting residue. The resulting solid was washed with water and dissolved in DCM, and then dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure to give the title compound (10.5 g, 93%) as a light brown solid. LCMS m / z: 270 [M+H]+ HPLC retention time: 0.65 min (Analysis conditions G)

[0398] Compound m5: Methyl 5-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-8-bromoimidazo[1,5-a]pyridine-6-carboxylate [Chemical formula 287] After adding 4-dimethylaminopyridine (143 mg, 1.17 mmol) to an anhydrous DCM solution (50 mL) 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) the mixture was stirred at room temperature for 2 h. 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 min (Analysis conditions G)

[0399] Compound m6: Methyl 5-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-8-ethenylimidazo[1,5-a]pyridine-6-carboxylate [Chemical formula 288] A mixed 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 vinyl trifluoroborate (1.07 g, 7.97 mmol), palladium tetrakistriphenylphosphine (614 mg, 0.532 mmol), cesium carbonate (5.20 mmol, 16 mmol, 16 mmol) and water (10 mL) was stirred at 100 °C for 2 h. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the mixture was concentrated under reduced pressure, and the obtained 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 min (Analysis conditions G)

[0400] m8 composition: Methyl 5-amino-8-formylimidazo[1,5-a]pyridine-6-carboxylate trifluoroacetate [Chemical formula 289] 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 conditions similar to those in the examples for the production of compound c6 and compound a6. LCMS m / z: 220 [M+H]+ HPLC retention time: 0.48 min (Analysis conditions G)

[0401] Compound m9: Methyl 5-amino-8-(5,5-dimethyl-1,3-dioxan-2-yl)imidazo[1,5-a]pyridine-6-carboxylate [Chemical formula 290] A toluene suspension (30 mL) 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-3,1-propanediol (742 mg, 7.13 mmol) was stirred overnight at 110 °C. DIPEA (1 mL) was added to the reaction mixture, which was then concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography to give the title compound (340 mg, 78%) as a red solid. LCMS m / z: 306 [M+H]+ HPLC retention time: 0.66 min (Analysis conditions G)

[0402] Compound m10: Methyl 5-chloro-8-(5,5-dimethyl-1,3-dioxan-2-yl)imidazo[1,5-a]pyridine-6-carboxylate [Chemical formula 291] An acetonitrile suspension (15 mL) 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) was cooled to 0 °C, and then copper (I) chloride (165 mg, 1.67 mmol) and copper (II) chloride (225 mg, 1.67 mmol) were added. After addition of tert-butyl nitrite (172 mg, 1.67 mmol), the mixture was stirred at room temperature for 30 min. 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 min (Analysis conditions 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 [Chemical formula 292] A DMA suspension (4 mL) 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) was stirred overnight at 50 °C. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure after filtering off the drying agent. The obtained 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 min (Analysis conditions G)

[0404] Compound m12: Methyl 5-(2-fluoro-4-iodoanilino)-8-formylimidazo[1,5-a]pyridine-6-carboxylate [Chemical formula 293] A mixed 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 for 1 h at room temperature. 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% acetonitrile formic acid) to give the title compound (168 mg, 96%) as a yellow solid. LCMS m / z: 440 [M+H]+ HPLC retention time: 1.84 min (Analysis conditions 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 [Chemical formula 294] The title compound was synthesized from methyl 5-(2-fluoro-4-iodoanilino)-8-formylimidazo[1,5-a]pyridine-6-carboxylate (compound m12) under similar conditions to the production examples of compound a2, compound a5, and compound a6. However, MeOH was used instead of EtOH used in the production example for compound a2. LCMS m / z: 536 [M+H]+ HPLC retention time: 0.54 min (Analysis conditions F)

[0406] Composition m16: 8-[(2-Amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylic acid trifluoroacetate [Chemical formula 295] A mixed 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 overnight at 50 °C. The reaction mixture was acidified by addition of formic acid and concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (0.1% aqueous TFA / 0.1% acetonitrile TFA) to give the title compound (42 mg, 72%) as a yellow solid. LCMS m / z: 522 [M+H]+ HPLC retention time: 0.45 min (Analysis conditions 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 [Chemical formula 296] 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 then 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 the mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse-phase column chromatography (0.1% aqueous TFA solution / 0.1% acetonitrile TFA solution) to give the title compound (25 mg, 60%) as a yellow solid. LCMS m / z: 521 [M+H]+ HPLC retention time: 0.41 min (Analysis 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 [Chemical formula 297] 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 conditions similar to those in the example for the production of compound A-1. LCMS m / z: 614 [M+H]+ HPLC retention time: 1.18 min (Analysis conditions B)

[0409] Compound n1: 6-Chloro-5-fluoro-4-(2-fluoro-4-iodoanilino)pyridine-3-carboxylic acid [Chemical formula 298] An anhydrous THF solution (8 mL) of 2-fluoro-4-iodoaniline (2.26 g, 9.52 mmol) was cooled to −78 °C, and then a 2 M LDA solution of THF / heptane / ethylbenzene (7.14 mL, 14.3 mmol) was added and the mixture was stirred for 30 min. An anhydrous THF solution (8 mL) of 4,6-dichloro-5-fluoropyridine-3-carboxylic acid (1.00 g, 4.76 mmol) was added and the mixture was stirred for 30 min at −78 °C. Then, water and 6 M hydrochloric acid were added to the reaction mixture to adjust the pH to between 1 and 2, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and, after filtering off the drying agent, concentrated under reduced pressure. Recrystallization (DCM) of the obtained residue was carried out to give the title compound (850 mg, 44%) as a light brown solid. LCMS m / z: 411 [M+H]+ HPLC retention time: 0.85 min (Analysis conditions G)

[0410] Compound n2: Methyl 6-chloro-5-fluoro-4-(2-fluoro-4-iodoanilino)pyridine-3-carboxylate [Chemical formula 299] The title compound was synthesized from 6-chloro-5-fluoro-4-(2-fluoro-4-iodoanilino)pyridine-3-carboxylic acid (compound n1) under conditions similar to those used in the preparation of compound a1. LCMS m / z: 425 [M+H]+ HPLC retention time: 1.04 min (Analysis conditions G)

[0411] Compound n3: Methyl 5-fluoro-4-(2-fluoro-4-iodoanilino)-6-hydroxypyridine-3-carboxylate [Chemical formula 300] 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 h. Water was added to the reaction mixture and the resulting solid was washed with water and DCM to give the title compound (281 mg, 84%) as a light brown solid. LCMS m / z: 407 [M+H]+ HPLC retention time: 0.72 min (Analysis conditions G)

[0412] Compound n4: N-[4-(Bromomethyl)-3-fluoropyridin-2-yl]-1,1-diphenylmethaneimine [Chemical formula 301] DIPEA (3.93 mL, 22.5 mmol) and methanesulfonic anhydride (2.07 g, 11.3 mmol) were added to an anhydrous DCM solution (37.5 mL) of [2-(benzhydrylideneamino)-3-fluoropyridin-4-yl]methanol (2.30 g, 7.51 mmol) and the mixture was stirred for 30 min at room temperature. Then, an anhydrous THF solution (0.5 mL) of lithium bromide (3.26 g, 37.5 mmol) was added and the mixture was stirred for 2 h at room temperature. Water was added to the reaction mixture and extraction was performed with DCM. The organic layer was dried over anhydrous sodium sulfate and, after filtering off the drying agent, concentrated under reduced pressure. The obtained 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 min (Analysis conditions G)

[0413] Compound n5: Methyl 1-[[2-(benzhydrylideneamino)-3-fluoropyridin-4-yl]methyl]-5-fluoro-4-(2-fluoro-4-iodoanilino)-6-oxopyridine-3-carboxylate [فرمول شیمیایی 302] Lithium hydride (1.85 mg, 0.222 mmol) was added to an anhydrous DMF solution (0.739 mL) of methyl 5-fluoro-4-(2-fluoro-4-iodoanilino)-6-hydroxypyridine-3-carboxylate (compound n3, 30 mg, 0.074 mmol) and the mixture was stirred for 30 min at room temperature. Then an anhydrous THF solution (0.5 mL) of N-[4-(bromomethyl)-3-fluoropyridin-2-yl]-1,1-diphenylmethaneimine (compound n4, 82 mg, 0.222 mmol) was added and the resulting mixture was stirred for 1 h at room temperature. Then, an anhydrous THF solution (0.5 mL) of lithium hydride (1 mg, 0.126 mmol) and compound n4 (25 mg, 0.068 mmol) was added and stirring was continued for 1 h at room temperature. The reaction mixture was cooled to 0 °C, acetic acid (21.1 μL) and water were added, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and after filtering off the drying agent, it was concentrated under reduced pressure.The obtained 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 min (Analysis conditions G)

[0414] Compound n8: 1-[(2-Amino-3-fluoropyridin-4-yl)methyl]-5-fluoro-4-(2-fluoro-4-iodoanilino)-6-oxopyridine-3-carboxamide [Chemical formula 303] 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 conditions similar to those in the examples for the production of compound a6, compound a7, and compound K-10. However, 4 M hydrochloric acid was added in the initial step, where the reaction was carried out under conditions similar to those in the example for the production of compound a6. LCMS m / z: 516 [M+H]+ HPLC retention time: 0.52 min (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 [Chemical formula 304] The title compound was synthesized from 1-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-fluoro-4-(2-fluor...

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