Aryl amide derivatives having antitumor activity

Abstract

The present invention provides a novel compound having RAF / MEK complex stabilizing activity and / or MEK inhibitory activity and useful for treating or preventing cell proliferative diseases, or a novel RAF / MEK complex stabilizer or MEK inhibitor useful for treating or preventing cell proliferative diseases. [Solution] For example, a compound represented by the following general formula (6) [wherein X1, X2, X3, and X4 each independently represent -CR2= or -N=, R2 is, for example, a halogen atom, R1 is, for example, -S(=O)2-NH-R8, R8 is, for example, a C1-6 alkyl group, R3 is, for example, a hydrogen atom, R5 is, for example, a halogen atom, R6 is, for example, a hydrogen atom, and R4 is, for example, a cyclopropyl group] or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt, or an RAF / MEK complex stabilizer containing the compound, salt, or solvate as an active ingredient. TIFF2022023958000351.tif37149

Description

Technical Field

[0001] The present disclosure relates to arylamide derivatives having RAF / MEK complex stabilization activity and / or MEK inhibitory activity, which are useful for the treatment or prevention of cell proliferative diseases, particularly cancer, and RAF / MEK complex stabilizers or MEK inhibitors containing such arylamide derivatives as an active ingredient.

Background Art

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

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

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

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0006]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Summary of the Invention

Problems to be Solved by the Invention

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

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

Means for Solving the Problems

[0009] In order to create the novel compound as described above, the present inventor focused on the following CH4987655, which is a known MEK inhibitor, and the following CH5126766, which is a known RAF / MEK complex stabilizer.

Chemical Formula

Chemical Formula

[0010] Compared with PD0325901, another MEK inhibitor, CH4987655 shows comparable MEK inhibitory activity in cell-free systems but exhibits slower dissociation from MEK. And in cynomolgus monkey peripheral blood, it shows stronger MEK inhibitory activity than PD0325901 (IC 50 is low), achieving more persistent MEK inhibition. These are considered to be due to the characteristic substituents containing a 3-oxo-[1,2]oxazinane ring structure present at the 5'-position of the benzamide skeleton of CH4987655 (see Bioorg. Med. Chem. Lett. 2011, vol. 21, no. 6, p. 1795-1801).

[0011] CH5126766 forms a complex with MEK having a characteristic structure. That is, when CH5126766 binds to MEK, the MEK activation segment moves, and accordingly, Asn221 and Ser222 of MEK are arranged in spatially different positions from those when PD0325089 (the enantiomer of PD0325901) binds. In the complex, the sulfamide group of CH5126766 forms a hydrogen bond directly with Asn221 of MEK and with Ser222 via water. Since Ser222 is one of the two amino acids phosphorylated by RAF, the RAF / MEK complex stabilizing effect and the inhibitory effect on the enhancement of MEK phosphorylation (feedback activation of the MAPK signaling pathway) of CH5126766 are considered to be due to such a complex structure (see Cancer Cell. 2014, vol. 25, no. 5, p. 697-710 (Non-Patent Document 8)).

[0012] When CH4987655 binds to MEK, it results in a spatial arrangement of Asn221 and Ser222 similar to that of CH5126766. Also, it is similar to CH5126766 in terms of the points interacting with Asn221. CH4987655 has a weak inhibitory effect on the enhancement of MEK phosphorylation, which is considered to be due to such a complex structure (see Cancer Cell. 2014, vol. 25, no. 5, p. 697-710 (Non-Patent Document 8)).

[0013] CH4987655 is at a distance from Ser222 and does not interact with it. Also, the interaction between CH4987655 and Asn221 is weak via the 3-oxo-[1,2]oxazinane ring structure, which is different from CH5126766. On the other hand, CH5126766 does not interact with Lys97, unlike MEK inhibitors such as CH4987655 and PD0325901.

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

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

Chemical formula

[0016] In the complex of CH5126766 and MEK, the sulfamide structure of CH5126766 interacts with Asn221 and Ser222 of MEK. Therefore, based on Hypothesis 2, the following compound AA-1 was produced by introducing a sulfamide structure into the terminal part of the structure corresponding to the 5'-side chain of CH4987655.

Chemical formula

[0017] For compounds AA-2 and AA-1, the MEK1 inhibitory activity (IC 50 ), BRAF inhibitory activity (IC 50 ), HCT-116 growth inhibitory activity (IC 50 ), and / or Colo-205 growth inhibitory activity (IC 50 ) were measured in the same manner as in Test Examples 3, 4, or 5 described below (HCT-116 and Colo-205 were obtained from ATCC). The results are shown in Table 1 below. Note that HCT-116 and Colo-205 are human cancer cells having RAS mutation and BRAF mutation, respectively. [Table 1]

[0018] As is clear from Table 1, compound AA-2 did not acquire the expected profile. On the other hand, compound AA-1 showed significant MEK1 inhibitory activity, BRAF inhibitory activity, HCT-116 growth inhibitory activity, and Colo-205 growth inhibitory activity.

[0019] As a result of intensive studies with compound AA-1 as a lead compound, the present inventors have found that a specific arylamide derivative has RAF / MEK complex stabilization activity and / or MEK inhibitory activity and is useful for the treatment or prevention of cell proliferative diseases, particularly cancer.

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

[0021] (A2) 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 may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group). R3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxy group). R6 is a hydrogen atom, a halogen atom or a C1-6 alkyl group, R4 is a halogen atom or a cyclopropyl group, R7 is a hydrogen atom or a methyl group, The compound, salt or solvate according to (A1).

[0022] (A3) The compound represented by the general formula (1) is the compound represented by the following general formula (6), the compound, salt or solvate according to (A1).

Chemical formula

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

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

[0025] (A6) 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, R6 is a hydrogen atom, R4 is an iodine atom or a cyclopropyl group, A compound, salt or solvate according to any one of (A1) to (A3).

[0026] The present disclosure also provides an agent described in the following (A7) to (A10). The compound, salt or solvate described in the following (A7) includes the compound, salt or solvate described in (A1) to (A6). (A7) A stabilizer of the RAF / MEK complex containing, as an active ingredient, a compound represented by the following general formula (11), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt. [Chemical formula] [In the formula, Ring A is a group represented by the following general formula (2), (3), (4) or (5) (wherein the bonds marked with *, ** and *** are bonded to -NH-, -CONH- and -X7- respectively). [Chemical formula] 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-, m is 1, 2 or 3, R1 is -S(=O)2-NH-R8 or -S(=O)2-R8, R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group, a C1-6 alkoxy group, a C3-6 cycloalkyl group or a C3-6 heterocycloalkyl group), a monocyclic or bicyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group or a C1-6 alkoxy group) or a monocyclic or bicyclic C3-6 heterocycloalkyl group, R3 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group) or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), 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, R4 is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-7 alkenyl group, a C2-7 alkynyl group, a C3-6 cycloalkyl group or a C1-6 alkylthio group, or R6 and R4 together with the carbon atom to which they are attached form an unsaturated hetero 5-membered ring, R7 is a hydrogen atom or a C1-6 alkyl group, R9 is a hydrogen atom, a halogen atom or a C1-6 alkyl group.]

[0027] (A8) 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 may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), R3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxy group.), R5 is a halogen atom or a C1-6 alkyl group, R6 is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R4 is a halogen atom or a cyclopropyl group, R7 is a hydrogen atom or a methyl group, A stabilizer for the RAF / MEK complex as described in (A7).

[0028] (A9) The compound represented by the general formula (11) is a compound represented by the following general formula (6), a stabilizer for the RAF / MEK complex as described in (A7). [Chemical formula] [In the formula, X1, X2, X3 and X4 are each independently -CR2= or -N=, R2 is a hydrogen atom, a halogen atom or a C1-6 alkyl group, R1 is -S(=O)2-NH-R8 or -S(=O)2-R8, R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group.) or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group.), R3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxy group.), R5 is a halogen atom or a C1-6 alkyl group, R6 is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R4 is a halogen atom or a cyclopropyl group.]

[0029] (A10) R2 is a hydrogen atom or a halogen atom, R8 is a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), R3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxy group), R5 is a halogen atom, R6 is a hydrogen atom, R4 is a halogen atom or a cyclopropyl group, A stabilizer of the RAF / MEK complex according to any one of (A7) to (A9).

[0030] The present disclosure also provides a compound, salt or solvate described in the following (A11) to (A15). The compound, salt or solvate described in (A7) includes the compound, salt or solvate described in the following (A11) to (A15). (A11) N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl amino)pyridin-4-yl]methyl]benzamide (Compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl amino)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-(methylsulfamoyl amino)pyridin-4-yl]methyl]benzamide (Compound A-1), N-cyclopropyl-5-[[2-(ethylsulfamoyl amino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-4), N-Cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-6), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide (Compound A-8), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide (Compound A-13), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-25), 5-[[2-(Cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-30), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-31), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-33), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-34), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide (Compound A-35), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoyl)amino]pyridin-4-yl]methyl]benzamide (Compound A-41), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl)amino]pyridin-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide (Compound B-1), 5-[[3-(Ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound D-4), 5-[[3-(Ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (Compound E-1), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoyl)amino]phenyl]methyl]benzamide (Compound E-7), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide (Compound E-13), 4-Fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl)amino]pyridin-4-yl]methyl]benzamide (Compound I-1), N-Cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl)amino]pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (Compound J-5), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoyl]amino]pyridin-4-yl]methyl]-N-methoxybenzamide (Compound A-15), 3,4-Difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-methylsulfanylanilino)benzamide (Compound A-18), 2-(4-Ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-20), 2-(4-Bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-27), 2-(2-Chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-methoxybenzamide (Compound E-9), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxan-4-ylsulfonylamino)phenyl]methyl]benzamide (Compound E-23), 2-[4-(Difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound H-1), 3,4-Difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound H-3), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]oxybenzamide (Compound H-4), 2-(2-Fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine-3-carboxamide (Compound J-8), 2-(2-Fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide (Compound J-10), 5-[[2-(Ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide (Compound J-14), 5-(2-Fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide (Compound L-1), 5-(2-Fluoro-4-iodoanilino)-8-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]imidazo[1,5-a]pyridine-6-carboxamide (Compound M-1), 5-Fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (Compound N-1), 5-Fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (Compound N-2), 4-(2-Fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (Compound P-1), and 1-[[2-(Ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide (Compound P-2) A compound selected from the above, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the above compound or salt.

[0031] (A12) N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl)pyridin-4-yl]methyl]benzamide (Compound A-2) 2-(2-Fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl)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-(methylsulfamoyl)pyridin-4-yl]methyl]benzamide (Compound A-1) N-Cyclopropyl-5-[[2-(ethylsulfamoyl)amino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-4) N-Cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoyl)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-6) 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl)pyridin-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide (Compound A-8) 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl)pyridin-4-yl]methyl]-N-methoxybenzamide (Compound A-13) 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl)pyridin-4-yl]methyl]benzamide (Compound A-25) 5-[[2-(Cyclopropylsulfamoyl)amino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-30) 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-31), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-33), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-34), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide (Compound A-35), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-41), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide (Compound B-1), 5-[[3-(Ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoaniline)benzamide (Compound D-4), 5-[[3-(Ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (Compound E-1), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide (Compound E-7), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzamide (Compound E-13), 4-Fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound I-1), and N-Cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (Compound J-5) A compound selected from the group consisting of the foregoing compounds, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the foregoing compound or salt.

[0032] (A13) 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) A compound selected from the group consisting of the foregoing compounds, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the foregoing compound or salt.

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

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

[0035] (A1) to (A15) The compounds, salts or solvates described have high RAF / MEK complex stabilization activity and can be used as an active ingredient in a therapeutic or prophylactic agent for cell proliferative diseases, particularly cancer (more specifically, for example, cancer having a RAS mutation). That is, according to the present disclosure, there is also provided a pharmaceutical composition containing, as an active ingredient, a compound, salt or solvate described in any one of (A1) to (A15). Further, there is provided a therapeutic or prophylactic agent for cell proliferative diseases, particularly cancer, containing, as an active ingredient, a compound, salt or solvate described in any one of (A1) to (A15).

[0036] The present disclosure also provides compounds, salts or solvates described in the following (B1) to (B3) and an agent described in the following (B4). (B1) A compound represented by the following general formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

Chemical formula

Chemical formula

[0037] (B2) 2-(4-Cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-1), (+ / -)-3,4-Difluoro-5-[[3-fluoro-2-(2-hydroxypropylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-17), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(oxetan-3-ylmethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-21), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-25), 5-[[2-(Cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-30), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoyl)amino]pyridin-4-yl]methyl]benzamide (Compound A-33), 5-[[2-(Ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-40), 3,4-Difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoyl)amino]pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-42), 5-[[2-(Ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (Compound B-16), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound C-3), 2-(2-Fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide (Compound J-10), 5-(2-Fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide (Compound L-1), 5-Fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (Compound N-1), 1-[[2-(Ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide (Compound P-2), 1-[[2-(Ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-N-methoxy-5-methyl-6-oxopyridine-3-carboxamide (Compound P-5), and N-cyclopropyl-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (Compound P-6) a compound selected from the group consisting of the foregoing compounds or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of the foregoing compound or salt.

[0038] (B3) (+ / -)-3,4-difluoro-5-[[3-fluoro-2-(2-hydroxypropylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-17), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(oxetan-3-ylmethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-21), 5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-40), 3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-42), 5-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (Compound B-16), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound C-3), 1-[[2-(Ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-N-methoxy-5-methyl-6-oxopyridine-3-carboxamide (Compound P-5), and N-Cyclopropyl-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoyl amino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (Compound P-6) A compound selected from the above, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

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

[0040] The compounds, salts or solvates described in (B1) to (B3) have high MEK inhibitory activity and can be used as an active ingredient of a therapeutic or prophylactic agent for cell proliferative diseases, particularly cancer (more specifically, for example, cancer having a RAF mutation). That is, according to the present disclosure, there is also provided a pharmaceutical composition containing, as an active ingredient, the compound, salt or solvate described in any one of (B1) to (B3). Further, there is provided a therapeutic or prophylactic agent for cell proliferative diseases, particularly cancer, containing, as an active ingredient, the compound, salt or solvate described in any one of (B1) to (B3).

Effects of the Invention

[0041] According to the present disclosure, there are provided a novel compound having RAF / MEK complex stabilization activity and / or MEK inhibitory activity and being useful for the treatment or prevention of cell proliferative diseases, particularly cancer, or a novel RAF / MEK complex stabilizer or MEK inhibitor useful for the treatment or prevention of cell proliferative diseases, particularly cancer.

Brief Description of the Drawings

[0042]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

BEST MODE FOR CARRYING OUT THE INVENTION

[0043] Hereinafter, exemplary embodiments of the present disclosure will be described.

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

[0045] In the present disclosure, the C1-6 alkyl group means a linear and branched alkyl group having 1 to 6 carbon atoms. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, 1-methylpropyl group, n-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1,1-dimethylpropyl group, 2,2-dimethylpropyl group, 1,2-dimethylpropyl group, 1-ethylpropyl group, n-hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, and 2-ethylbutyl group.

[0046] In the present disclosure, the C2-7 alkenyl group means a linear or branched alkenyl group having 2 to 7 carbon atoms. For example, vinyl group, allyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, pentenyl group, pentadienyl group, hexenyl group, hexadienyl group, heptenyl group, heptadienyl group and heptatrienyl group can be mentioned.

[0047] In the present disclosure, the C2-7 alkynyl group means a linear or branched alkynyl group having 2 to 7 carbon atoms. For example, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, pentynyl group, pentadiynyl group, hexynyl group, hexadiynyl group, heptynyl group, heptadiynyl group and heptatriynyl group can be mentioned.

[0048] In the present disclosure, the C1-6 alkoxy group means an alkyloxy group having a linear or branched alkyl group with 1 to 6 carbon atoms. For example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, n-pentoxy group and n-hexoxy group can be mentioned.

[0049] In the present disclosure, the C1-6 alkylthio group means an alkylthio group having a linear or branched alkyl group with 1 to 6 carbon atoms. For example, methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, sec-butylthio group, tert-butylthio group, n-pentylthio group and n-hexylthio group can be mentioned.

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

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

[0052] In the present disclosure, the unsaturated hetero 5-membered ring means an unsaturated 5-membered ring containing at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom. For example, furan, thiophene, pyrrole, imidazole and thiazole can be mentioned.

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

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

[0055] A first aspect of the present disclosure provides a compound represented by the following general formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt.

Chemical formula

Chemical formula

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

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

[0058] The compound represented by the general formula (1) is preferably, for example, a compound represented by the following general formula (6).

Chemical formula

[0059] Examples of the compound represented by the general formula (1) include, N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (Compound J-1), 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-1), N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-4), N-Cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoyl)amino]pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-6), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl)amino]pyridin-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide (Compound A-8), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl)amino]pyridin-4-yl]methyl]-N-methoxybenzamide (Compound A-13), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl)amino]pyridin-4-yl]methyl]benzamide (Compound A-25), 5-[[2-(Cyclopropylsulfamoyl)amino]-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-30), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoyl)amino]pyridin-4-yl]methyl]benzamide (Compound A-31), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoyl)amino]pyridin-4-yl]methyl]benzamide (Compound A-33), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoyl)amino]pyridin-4-yl]methyl]benzamide (Compound A-34), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoyl]amino]pyridin-4-yl]methyl]benzamide (Compound A-35), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-41), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide (Compound B-1), 5-[[3-(Ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound D-4), 5-[[3-(Ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (Compound E-1), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide (Compound E-7), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzamide (Compound E-13), 4-Fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound I-1), N-Cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (Compound J-5), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]-N-methoxybenzamide (Compound A-15), 3,4-Difluoro-5-[[3-fluoro-2-(methylsulfamoyl amino)pyridin-4-yl]methyl]-2-(2-fluoro-4-methylsulfanylanilino)benzamide (Compound A-18), 2-(4-Ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoyl amino)pyridin-4-yl]methyl]benzamide (Compound A-20), 2-(4-Bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoyl amino)pyridin-4-yl]methyl]benzamide (Compound A-27), 2-(2-Chloro-4-iodoanilino)-5-[[3-(ethylsulfonyl amino)-2-fluorophenyl]methyl]-3,4-difluoro-N-methoxybenzamide (Compound E-9), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxan-4-ylsulfonyl amino)phenyl]methyl]benzamide (Compound E-23), 2-[4-(Difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoyl amino)pyridin-4-yl]methyl]benzamide (Compound H-1), 3,4-Difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoyl amino)pyridin-4-yl]methyl]benzamide (Compound H-3), 2-(2-Fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl amino)pyridin-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine-3-carboxamide (Compound J-8), 2-(2-Fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl amino)pyridin-4-yl]methyl]-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide (Compound J-10), 5-[[2-(Ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide (Compound J-14), 5-(2-Fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide (Compound L-1), 5-(2-Fluoro-4-iodoanilino)-8-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]imidazo[1,5-a]pyridine-6-carboxamide (Compound M-1), 5-Fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (Compound N-1), 5-Fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (Compound N-2), 4-(2-Fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (Compound P-1), and 1-[[2-(Ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide (Compound P-2) are mentioned.

[0060] Among those compounds, for example, in terms of MEK inhibitory activity, RAF inhibitory activity, cell growth inhibitory activity and / or metabolic stability, for example, N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-2), 2-(2-Fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (Compound J-1), 2-(4-Cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-1), N-Cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-4), N-Cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-6), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide (Compound A-8), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide (Compound A-13), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-25), 5-[[2-(Cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-30), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-31), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-33), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-34), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide (Compound A-35), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-41), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide (Compound B-1), 5-[[3-(Ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound D-4), 5-[[3-(Ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (Compound E-1), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide (Compound E-7), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide (Compound E-13), 4-Fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl amino)pyridin-4-yl]methyl]benzamide (Compound I-1), and N-Cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl amino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (Compound J-5) are preferred, N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl amino)pyridin-4-yl]methyl]benzamide (Compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl amino)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-(methylsulfamoyl amino)pyridin-4-yl]methyl]benzamide (Compound A-1) are more preferred, 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoyl amino)pyridin-4-yl]methyl]benzamide (Compound A-1) is particularly preferred. As the pharmaceutically acceptable salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoyl amino)pyridin-4-yl]methyl]benzamide (Compound A-1), for example, a sodium salt or a potassium salt is preferred.

[0061] The second aspect of the present disclosure provides a stabilizer for RAF / MEK complex containing, as an active ingredient, a compound represented by the following general formula (11), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt. [Chemical formula] [In the formula, (wherein the bonds marked with *, **, and *** are each bonded to -NH-, -CONH-, and -X7-, respectively.) is a group represented by the following general formula (2), (3), (4), or (5): [Chemical formula] 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-, m is 1, 2, or 3, R1 is -S(=O)2-NH-R8 or -S(=O)2-R8, R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, or a C3-6 heterocycloalkyl group), a monocyclic or bicyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group or a C1-6 alkoxy group), or a monocyclic or bicyclic C3-6 heterocycloalkyl group, R3 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group, or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group), or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a halogen atom, a hydroxy group, or a C1-6 alkoxy group), R5 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group, R6 is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R4 is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-7 alkenyl group, a C2-7 alkynyl group, a C3-6 cycloalkyl group or a C1-6 alkylthio group, or R6 and R4 together with the carbon atom to which they are attached form an unsaturated hetero 5-membered ring, R7 is a hydrogen atom or a C1-6 alkyl group, R9 is a hydrogen atom, a halogen atom or a C1-6 alkyl group.]

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

[0063] Ring A is preferably a group represented by general formula (2) or (4), more preferably a group represented by general formula (2). R2 is preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, and even more preferably a fluorine atom. X7 is preferably -CH2-. R1 is preferably -S(=O)2-NH-R8. R8 is preferably a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), more preferably a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom or a C1-6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), still more preferably a C1-4 alkyl group (the C1-4 alkyl group may be substituted with a fluorine atom or a C1-4 alkoxy group) or a cyclopropyl group (the cyclopropyl group may be substituted with a C1-4 alkyl group), and still more preferably a C1-4 alkyl group. R3 is preferably a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxy group), more preferably a hydrogen atom, a C1-4 alkyl group, a cyclopropyl group or a C1-4 alkoxy group (the C1-4 alkoxy group may be substituted with a hydroxy group), and still 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 still 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, 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, for example, the compound represented by the following general formula (6).

Chemical formula

[0065] Examples of the compound represented by the general formula (11) include, N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (Compound J-1), 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-1), N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-4), N-Cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoyl)amino]pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-6), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl)amino]pyridin-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide (Compound A-8), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl)amino]pyridin-4-yl]methyl]-N-methoxybenzamide (Compound A-13), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl)amino]pyridin-4-yl]methyl]benzamide (Compound A-25), 5-[[2-(Cyclopropylsulfamoyl)amino]-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-30), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoyl)amino]pyridin-4-yl]methyl]benzamide (Compound A-31), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoyl)amino]pyridin-4-yl]methyl]benzamide (Compound A-33), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoyl)amino]pyridin-4-yl]methyl]benzamide (Compound A-34), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoyl]amino]pyridin-4-yl]methyl]benzamide (Compound A-35), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoyl)amino]pyridin-4-yl]methyl]benzamide (Compound A-41), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl)amino]pyridin-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide (Compound B-1), 5-[[3-(Ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound D-4), 5-[[3-(Ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (Compound E-1), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoyl)amino]phenyl]methyl]benzamide (Compound E-7), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzamide (Compound E-13), 4-Fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl)amino]pyridin-4-yl]methyl]benzamide (Compound I-1), N-Cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl)amino]pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (Compound J-5), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoyl]amino]pyridin-4-yl]methyl]-N-methoxybenzamide (Compound A-15), 3,4-Difluoro-5-[[3-fluoro-2-(methylsulfamoyl amino)pyridin-4-yl]methyl]-2-(2-fluoro-4-methylsulfanylanilino)benzamide (Compound A-18), 2-(4-Ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoyl amino)pyridin-4-yl]methyl]benzamide (Compound A-20), 2-(4-Bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoyl amino)pyridin-4-yl]methyl]benzamide (Compound A-27), 2-(2-Chloro-4-iodoanilino)-5-[[3-(ethylsulfonyl amino)-2-fluorophenyl]methyl]-3,4-difluoro-N-methoxybenzamide (Compound E-9), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxan-4-ylsulfonyl amino)phenyl]methyl]benzamide (Compound E-23), 2-[4-(Difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoyl amino)pyridin-4-yl]methyl]benzamide (Compound H-1), 3,4-Difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoyl amino)pyridin-4-yl]methyl]benzamide (Compound H-3), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[3-fluoro-2-(methylsulfamoyl amino)pyridin-4-yl]oxybenzamide (Compound H-4), 2-(2-Fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl amino)pyridin-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine-3-carboxamide (Compound J-8), 2-(2-Fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide (Compound J-10), 5-[[2-(Ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide (Compound J-14), 5-(2-Fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide (Compound L-1), 5-(2-Fluoro-4-iodoanilino)-8-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]imidazo[1,5-a]pyridine-6-carboxamide (Compound M-1), 5-Fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (Compound N-1), 5-Fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (Compound N-2), 4-(2-Fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (Compound P-1), and 1-[[2-(Ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide (Compound P-2) may be mentioned.

[0066] Among those compounds, for example, in terms of MEK inhibitory activity, RAF inhibitory activity, cell growth inhibitory activity and / or metabolic stability, for example, N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-2), 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (Compound J-1), 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-1), N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-4), N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-6), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide (Compound A-8), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide (Compound A-13), 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-25), 5-[[2-(Cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-30), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-31), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-33), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-34), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide (Compound A-35), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-41), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide (Compound B-1), 5-[[3-(Ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound D-4), 5-[[3-(Ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (Compound E-1), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide (Compound E-7), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide (Compound E-13), 4-Fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound I-1), and N-Cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (Compound J-5) are preferred, N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-2), 2-(2-Fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide (Compound J-1), and 2-(4-Cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-1) are more preferred, 2-(4-Cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-1) is particularly preferred. Preferred pharmaceutically acceptable salts of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoyl amino)pyridin-4-yl]methyl]benzamide (Compound A-1) include, for example, sodium salts or potassium salts.

[0067] The third aspect of the present disclosure provides a compound represented by the following general formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt. The fourth aspect of the present disclosure provides a MEK inhibitor containing such a compound, salt, or solvate as an active ingredient. [Chemical formula] [In the formula, Ring A is a group represented by the following general formula (2), (3), or (4) (wherein the bonds marked with *, **, and *** are each bonded to -NH-, -CONH-, and -CH2-, respectively). [Chemical formula] X1, X2, X3, X4, and X5 are each independently -CR2= or -N=. R2 is a hydrogen atom, a halogen atom, or a C1-4 alkyl group. R1 is -S(=O)2-NH-R8 or -S(=O)2-R8. R8 is a C1-4 alkyl group (the C1-4 alkyl group may be substituted with a halogen atom, a hydroxy group, a C1-4 alkoxy group, a C3-6 cycloalkyl group, or a C3-6 heterocycloalkyl group) or a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-4 alkyl group). 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, R4 is a halogen atom or a C3-6 cycloalkyl group. R7 is a C1-4 alkyl group, R9 is a hydrogen atom.]

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

[0069] Examples of the compound of the third or fourth aspect include, in terms of MEK inhibitory activity and metabolic stability, for example, 2-(4-Cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-1), (+ / -)-3,4-Difluoro-5-[[3-fluoro-2-(2-hydroxypropylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-17), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(oxetan-3-ylmethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-21), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-25), 5-[[2-(Cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-30), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-33), 5-[[2-(Ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-40), 3,4-Difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoyl)amino]pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-42), 5-[[2-(Ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (Compound B-16), 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound C-3), 2-(2-Fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide (Compound J-10), 5-(2-Fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide (Compound L-1), 5-Fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (Compound N-1), 1-[[2-(Ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide (Compound P-2), 1-[[2-(Ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-N-methoxy-5-methyl-6-oxopyridine-3-carboxamide (Compound P-5), and N-Cyclopropyl-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (Compound P-6) is preferred.

[0070] Examples of the abbreviations used in this specification are listed below together with their meanings. Boc: tert-butoxycarbonyl COMU: (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCC: N,N'-dicyclohexylcarbodiimide DCM: dichloromethane DIPEA: N,N-diisopropylethylamine DMA: N,N-dimethylacetamide DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EDC·HCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EtOH: ethanol HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HOAt: 1-hydroxy-7-azabenzotriazole HOOBt: 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine LDA: lithium diisopropylamide MeOH: methanol NMP: N-methyl-2-pyrrolidone TBS: tert-butyldimethylsilyl TFA: trifluoroacetic acid THF: tetrahydrofuran Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0071] Next, examples of preferred production methods of the compounds of the present disclosure will be described. In the following, the definitions of X1, R1, R2, R3, R4, R5, and R7 are as described above unless otherwise construed in the context. Also, R a represents, for example, a 4-methylphenyl group or a 2-nitrophenyl group, and R b represents, for example, a Boc group or a 2,4-dimethoxybenzyl group.

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

[0073]

Chemical Formula

Chemical Formula

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

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

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

[0077] Step 1-4: Coupling of Hydrazone Derivative 1e and Arylboronic Acid Derivative 1f React hydrazone derivative 1e with arylboronic acid derivative 1f in the presence of a base. Examples of the base include carbonates and amines, with potassium carbonate and DIPEA being preferred. Examples of the solvent include polar solvents such as 1,4-dioxane, DMF, NMP, THF, etc., with 1,4-dioxane being preferred. The reaction temperature is preferably 80 °C or higher.

[0078] Step 1-5: Deprotection of Methyl Benzoate Derivative 1g Place methyl benzoate derivative 1g under acidic conditions to remove the protecting group R b Desorb it. Examples of the acid include sulfuric acid, hydrochloric acid, methanesulfonic acid, and trifluoroacetic acid, with trifluoroacetic acid being preferred. Examples of the solvent include nonpolar solvents such as alcohol and DCM, with DCM being preferred.

[0079] Step 1-6: Hydrolysis of Ester Derivative 1h React ester derivative 1h with a hydroxide. Examples of the hydroxide include lithium hydroxide, potassium hydroxide, and sodium hydroxide, with lithium hydroxide being preferred. Examples of the solvent include polar solvents such as alcohol and THF, water, and their mixed solvents, with an aqueous THF solution being preferred.

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

[0081] Steps 1-8: Sulfamidation or Sulfonamidation of Amine Derivatives 1j, 1ja or 1jb Sulfamidation: In the presence of a base, amine derivatives 1j, 1ja or 1jb are reacted with the corresponding sulfamoyl chloride or 4-nitrophenyl sulfamate. The corresponding sulfamoyl chloride or 4-nitrophenyl sulfamate may have a Boc group. Examples of the base include amines, and pyridine, triethylamine, DIPEA, and imidazole are preferred. Examples of the solvent include polar solvents such as DMF, DMA, NMP, THF, 1,4-dioxane, acetonitrile, and pyridine, non-polar solvents such as dichloromethane and dichloroethane, and mixed solvents thereof, and DMF, DMA, THF, and dichloromethane are preferred.

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

[0083] Step 1-9-1: Deprotection of the sulfamide or sulfonamide derivative 1k1 When R1 or R3 of the sulfamide or sulfonamide derivative 1k1 has a Boc group, the Boc group is eliminated by placing the compound 1k1 under acidic conditions. Examples of the acid include sulfuric acid, hydrochloric acid, methanesulfonic acid and trifluoroacetic acid. Also, in alcohol, for example, an acid may be generated with chlorotrimethylsilane (TMSCl) for deprotection. Examples of the solvent include alcohol and non-polar solvents such as DCM. As the combination of the acid and the solvent, for example, the combination of TMSCl and 2,2,2-trifluoroethanol or the combination of trifluoroacetic acid and DCM is preferred.

[0084] Step 1-9-2: Alkylation, alkenylation, alkynylation or thioetherification of the sulfamide or sulfonamide derivative 1k1 When R4 or R5 of the sulfamide or sulfonamide derivative 1k1 is a halogen, for example, alkylation, alkenylation, alkynylation or thioetherification can be carried out by the following method.

[0085] Method 1 (Alkylation or alkenylation by Suzuki-Miyaura cross-coupling): In the presence of Pd, compound 1k1 is reacted with the corresponding boronic acid, boronic ester or borate. For example, it can be carried out by the methods described in Chem. Rev. 1995, vol. 95, no. 7, p. 2457 or Acc. Chem. Res., vol. 40, p. 275. Examples of the base include inorganic salts such as carbonates and hydroxides, and amines such as triethylamine and DIPEA, and sodium carbonate, potassium carbonate and triethylamine are preferred. Examples of the solvent include polar solvents such as THF, 1,4-dioxane, DMF, DMA, NMP, methanol, ethanol, 2-propanol and water, and mixed solvents thereof, and a mixed solvent of THF and 2-propanol and a mixed solvent of THF and water are preferred. Examples of Pd and the ligand include those described in Chem. Rev. 1995, vol. 95, no. 7, p. 2457, Acc. Chem. Res., vol. 40, p. 275, and Acc. Chem. Res., vol. 41, p. 1461, and PdCl2(PPh3)2, Pd(PPh3)4, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride are preferred. The reaction temperature is preferably 80 °C or higher.

[0086] Method 2 (Alkylation or alkenylation by Negishi cross-coupling): In the presence of Pd or Ni, compound 1k1 is reacted with the corresponding organozinc reagent. For example, it can be carried out by the methods described in Tetrahedron. 1992, vol. 48, no. 44, p. 9577 or Aldrichimica Acta. 2005, vol. 38, p. 71. Examples of the solvent include polar solvents such as THF, 1,4-dioxane, DMF, DMA, NMP, and mixed solvents thereof, and THF is preferred. Examples of Pd and Ni include those described in Tetrahedron. 1992, vol. 48, no. 44, p. 9577 and Aldrichimica Acta. 2005, vol. 38, p. 71, as well as PdCl2(PPh3)2, Pd(PPh3)4, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, and PdCl2(PPh3)2, Pd(PPh3)4, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride are preferred.

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

[0088] Method 4 (thioetherification): In the presence of Pd, compound 1k1 is reacted with the corresponding mercaptan or mercaptan salt. Examples of the base include amines such as triethylamine, DIPEA, DBU, piperidine, and triethylamine and DIPEA are preferred. Examples of the Pd catalyst include zero-valent Pd complexes such as Pd(PPh3)4, and [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate is preferred. Examples of the solvent include polar solvents such as THF, 1,4-dioxane, DMF, DMA, NMP, DMSO, methanol, ethanol, 2-propanol, and mixed solvents thereof, and 1,4-dioxane is preferred.

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

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

[0091] Step 1-12-1: Deprotection of the TBS group of the sulfamide or sulfonamide derivative 1k2 When R3 of the sulfamide or sulfonamide derivative 1k2 has a TBS group, the TBS group is eliminated by reacting the compound 1k2 with tetrabutylammonium fluoride. Examples of the solvent include polar solvents such as THF, 1,4-dioxane, and DMF, and THF is preferred.

[0092] Step 1-12-2: Desilylation of the sulfamide or sulfonamide derivative 1k2 When R4 or R5 of the sulfamide or sulfonamide derivative 1k2 has a silyl group, the silyl group is eliminated by reacting the compound 1k2 with a base. Examples of the base include carbonates, and potassium carbonate is preferred. Examples of the solvent include alcohols such as methanol and ethanol, and methanol is preferred.

[0093] (General preparation method - 2) The general preparation method - 2 is another preferred method for producing the compound 1k1. [Chemical formula]

[0094] Process 2-1: The sulfamidation or sulfonamidation of amine derivative 1h is carried out in the same manner as in Process 1-8. Process 2-2: The hydrolysis of ester derivative 2a is carried out in the same manner as in Process 1-6. Process 2-3: The amidation of benzoic acid derivative 2b is carried out in the same manner as in Process 1-7. Before carrying out the amidation, optionally, the de-Boc, alkylation, alkenylation, alkynylation, thioetherification, bromination or chlorination of benzoic acid derivative 2b may be carried out in the same manner as in Process 1-9-1, 1-9-2 or 1-10.

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

[0096] Process 3-1: The hydrazonization of aldehyde derivative 1c is carried out in the same manner as in Process 1-3. Process 3-2: The amidation of benzoic acid derivative 3a is carried out in the same manner as in Process 1-7. Process 3-3: The coupling of hydrazone derivative 3b and arylboronic acid derivative 1f, the elimination of protecting group R b and the sulfamidation or sulfonamidation of the amine derivative are carried out in the same manner as in Process 1-4, 1-5 and 1-8, respectively, in this order.

[0097] (General Preparation Method - 4) General production method - 4 is a preferred method for constructing the skeleton of a compound represented by the general formula (1), wherein ring A is a group represented by the general formula (4), X1 is -N=, X2 is -CF=, and R6 and R9 are hydrogen atoms.

Chemical formula

[0098] Step 4-1: Alkylation of compound 4a In the presence of a base, compound 4a is reacted with compound 4b. Examples of the base include metal alkoxides such as phosphates and sodium tert-butoxide, and tripotassium phosphate is preferred. Further, for example, potassium iodide or tetrabutylammonium iodide may be added to accelerate the reaction, and tetrabutylammonium iodide is preferred as such an additive. Examples of the solvent include polar solvents such as NMP and 1,3-dimethyl-2-imidazolidinone, and 1,3-dimethyl-2-imidazolidinone is preferred. The reaction temperature is preferably 40°C or higher.

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

[0100] When the compounds of the present disclosure are obtained in the free form, they can be converted into pharmaceutically acceptable salts or solvate forms according to conventional methods. Also, when the compounds of the present disclosure are obtained in the form of pharmaceutically acceptable salts or solvates, they can be converted into the free form according to conventional methods.

[0101] The isolation or purification of the compounds of the present disclosure can be carried out using, for example, distillation, recrystallization, or chromatography. Also, when isomers (e.g., enantiomers, diastereomers, or conformational isomers) are present, their isolation or purification can be carried out using, for example, recrystallization, the diastereomeric salt method, the enzymatic resolution method, or chromatography (e.g., thin-layer chromatography, column chromatography, high-performance liquid chromatography, or gas chromatography).

[0102] In one aspect, the present disclosure provides a pharmaceutical composition containing, as an active ingredient, a compound, salt, or solvate according to any one of Aspects 1 to 4.

[0103] In another aspect, the present disclosure provides a therapeutic or prophylactic agent for cell proliferative diseases, particularly cancer, containing, as an active ingredient, a compound, salt, or solvate according to any one of Aspects 1 to 4.

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

[0105] When the compound, salt, or solvate of the present disclosure is used for the treatment or prevention of cell proliferative diseases, the dosage and dosing interval can be appropriately determined according to the degree of symptoms, the age and weight of the administration subject, the presence or absence of concomitant drugs, the administration method, etc. For example, when the administration subject is a human, usually, an amount of 0.00001 to 5000 mg, preferably 0.01 to 100 mg per kg of body weight is administered once every 1 day to 3 weeks. When administered daily, the above amount may be divided into 2 to 4 administrations.

[0106] Examples of the administration method to the subject include systemic administration such as oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneous administration, intravesical administration, intravaginal administration, intraperitoneal administration, intravesical administration, and inhalation administration, and topical administration with an ointment, a gel, or a cream. Oral administration is preferred.

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

[0108] The above various preparations can be produced by mixing the compounds, salts or solvates of the present disclosure with pharmaceutically acceptable additives by well-known methods. 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 starch (such as 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 compounds similar to the above excipients.

[0112] Examples of disintegrants include crosscarmellose sodium, carboxymethyl starch sodium, crosslinked polyvinylpyrrolidone, etc., chemically modified starches and celluloses, as well as compounds similar to the above excipients.

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

[0114] Examples of flavoring and odor-masking agents include commonly used sweeteners, acidulants, and fragrances.

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

[0116] Examples of dispersants include cellulose derivatives (e.g., gum arabic, tragacanth, and methyl cellulose), polyesters of stearic acid, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbates, and sorbitan fatty acid esters.

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

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

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

[0120] Cell proliferative diseases treated or prevented using the compound, salt, or solvate of the present disclosure include cancer, rheumatism, and inflammation, preferably cancer.

[0121] Examples of cancers include cancers of the blood and lymph, such as leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, etc.), malignant lymphoma (e.g., Hodgkin's disease, non-Hodgkin lymphoma, etc.), multiple myeloma, myelodysplastic syndrome, etc.; cancers of the central nervous system, such as brain tumors, gliomas, etc.; and solid cancers, such as head and neck cancers (e.g., pharyngeal cancer, laryngeal cancer, tongue cancer, etc.), esophageal cancer, gastric cancer, colorectal cancer (e.g., cecal cancer, colon cancer, rectal cancer, etc.), lung cancer (e.g., small cell carcinoma, non-small cell carcinoma, etc.), thyroid cancer, breast cancer, bile duct cancer, pancreatic cancer, liver cancer, prostate cancer, ovarian cancer, uterine cancer (e.g., endometrial cancer, cervical cancer, etc.), testicular cancer, renal cell carcinoma, bladder cancer, renal pelvis / ureter cancer, malignant melanoma, skin cancer (e.g., basal cell carcinoma, squamous cell carcinoma, extramammary Paget's disease, Merkel cell carcinoma, sweat gland cancer (e.g., apocrine adenocarcinoma or eccrine adenocarcinoma), sebaceous adenocarcinoma, hair follicle epithelioma, etc.).

[0122] Cancer may or may not have a gene mutation, or it may be unknown whether it has a gene mutation or not. Examples of genes in which mutations occur include EGFR, FGFR, ALK, ROS1, PI3K, BRAF, HRAS, KRAS, and NRAS.

[0123] When using the compound, salt, or solvate of the first or second aspect, cancers such as cancers having a RAS mutation are preferred, and solid cancers having a KRAS mutation (particularly non-small cell lung cancer) are particularly preferred. Also, in one embodiment, it is also used for cancers having a RAF mutation, particularly cancers having both a RAF mutation and a RAS mutation. When using the compound, salt, or solvate of the third or fourth aspect, cancers such as cancers having a RAF mutation are preferred, and solid cancers having a BRAF mutation (particularly malignant melanoma) are particularly preferred. [Examples]

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

[0125] [Production Example] NMR analysis was performed using a BRUKER AVANCE III HD400 (400 MHz). NMR data was shown in ppm (parts per million) (δ), and the deuterium lock signal from the sample solvent was referenced.

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

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

Table 2-1

Table 2-2

[0128] The microwave reaction was carried out using an Initiator manufactured by Biotage. Also, snap cap reaction vials were used for the microwave reaction.

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

[0130] In this specification, "room temperature" means a temperature of about 20°C to about 25°C.

[0131] In the following production examples, "Production Example of Compound A-1" means Production Example A-1-1, and "Production Example of Compound a9" means Production Example a9-1.

[0132] Compound a1: Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-formylbenzoate

Chem.

[0133] Compound a2: Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzoate

Chem.

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

[0135] Compound a4: [2-[(2,4-Dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid [Chemical formula] A solution of N-(2,4-dimethoxybenzyl)-3-fluoro-4-iodopyridin-2-amine (Compound a3, 2.70 g, 6.96 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (568 mg, 0.696 mmol), potassium acetate (2.05 g, 20.9 mmol), and bis(pinacolato)diboron (2.65 g, 10.4 mmol) in 1,4-dioxane (27 mL) was stirred at 90 °C for 5 h and then at 110 °C for 19 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse-phase column chromatography (0.1% aqueous formic acid / 0.1% formic acid acetonitrile solution) to give the title compound (2.07 g, 97%) as an oily substance. LCMS m / z: 307 [M+H] + HPLC retention time: 0.44 min (Analysis condition 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] Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzoate (Compound a2, 1.30 g, 2.16 mmol), [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (Compound a4, 1.98 g, 6.46 mmol), and potassium carbonate (357 mg, 2.59 mmol) in 1,4-dioxane suspension (59 mL) were stirred at 100 °C for 2.5 h and then at 110 °C for 3 h under a nitrogen atmosphere. Ethyl acetate was added to the reaction mixture, and it was washed with water and 13% brine. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (524 mg, 36%) as a foamy substance. LCMS m / z: 682 [M+H] + HPLC retention time: 1.03 min (Analysis condition D)

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

[0139] Compound a8: 5-((2-Amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide

Chemical formula

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

[0141] Compound r1: 4-Nitrophenyl methylsulfamate

Chemical formula

[0142] Compound A-1: 2-(4-Cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoyl)amino]pyridin-4-yl]methyl]benzamide

Chem.

[0143] Compound a10: 5-((2-Amino-3-fluoropyridin-4-yl)methyl)-N-cyclopropyl-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide

Chem.

[0144] Compound A-2: N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl)amino]pyridin-4-yl]methyl]benzamide

Chemical formula

[0145] Compound r2: 1-Chlorosulfonyloxy-4-nitrobenzene

Chemical formula

[0146] Compound r3: 4-Nitrophenyl N-[(2,4-dimethoxyphenyl)methyl]sulfamate

Chemical formula

[0147] Compound r4: 4-Nitrophenyl sulfamate

Chemical formula

[0148] Compound r5: 4-Nitrophenyl N-ethylsulfamate

Chemical formula

[0149] Compound r6: 4-Nitrophenyl N-cyclopropylsulfamate

Chemical formula

[0150] Compound r7: 4-Nitrophenyl N-(2-fluoroethyl)sulfamate

Chemical formula

[0151] Compound r11: 4-Nitrophenyl N-[2-[tert-butyl(dimethyl)silyl]oxypropyl]sulfamate

Chemical Structure

[0152] Compound r8: 4-Nitrophenyl N-(2-methoxyethyl)sulfamate

Chemical Structure

[0153] Compound r9: 4-Nitrophenyl N-(1-methylcyclobutyl)sulfamate

Chemical Structure

[0154] Compound r10: 4-Nitrophenyl N-[1-(methoxymethyl)cyclopropyl]sulfamate

Chem.

[0155] Compound r12: 4-Nitrophenyl N-propylsulfamate

Chem.

[0156] Compound r13: 4-Nitrophenyl N-(oxetan-3-ylmethyl)sulfamate

Chem.

[0157] Compound r14: 4-Nitrophenyl N-(3-oxabicyclo[3.1.0]hexan-6-yl)sulfamate [Chemical formula] Under the same conditions as in the production example of compound r3, the title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine. LCMS m / z: 301 [M+H] + HPLC retention time: 0.63 minutes (analysis condition C)

[0158] Compound r15: 4-Nitrophenyl N-(1-methylcyclopropyl)sulfamate [Chemical formula] Under the same conditions as in the production example of compound r3, the title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine. LCMS m / z: 273 [M+H] + HPLC retention time: 0.73 minutes (analysis condition C)

[0159] Compound r16: 4-Nitrophenyl N-[[(2R)-oxolan-2-yl]methyl]sulfamate [Chemical formula] Under the same conditions as in the production example of compound r3, the title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine. LCMS m / z: 303 [M+H] + HPLC retention time: 0.67 minutes (analysis condition C)

[0160] Compound r17: 4-Nitrophenyl N-(1-methoxy-2-methylpropan-2-yl)sulfamate [Chemical formula] Under the same conditions as in the production example of Compound r3, the title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (Compound r2) and the corresponding amine. HPLC retention time: 0.76 minutes (Analysis condition C) 1 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

[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

[0163] Compound A-5: N-Cyclopropyl-5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

Chem.

[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

Chem.

[0165] Compound A-7: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methylbenzamide

Chem.

[0166] Compound a12: 5-((2-Amino-3-fluoropyridin-4-yl)methyl)-N-(tert-butoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide

Chem.

[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

Chem.

[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

[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

[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

Chem.

[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

Chem.

[0172] Compound A-13: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide

Chem.

[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 Structure

[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 Structure

[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

Chem.

[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

Chem.

[0177] Compound A-17: (+ / -)-3,4-Difluoro-5-[[3-fluoro-2-(2-hydroxypropylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (racemic)

Chem.

[0178] Compound a16: 5-[(2-Amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-methylsulfanylanilino)benzamide

Chem.

[0179] Compound A-18: 3,4-Difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-methylsulfanylanilino)benzamide

Chem.

[0180] Compound a17: 5-((2-Amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzamide

Chem.

[0181] Compound A-19: 2-(4-Ethenyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide

Chem.

[0182] Compound a18: 5-[(2-Amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-[2-fluoro-4-(2-trimethylsilylethynyl)anilino]benzamide

Chem.

[0183] Compound a19: 5-[(2-Amino-3-fluoropyridin-4-yl)methyl]-2-(4-ethynyl-2-fluoroanilino)-3,4-difluorobenzamide

Chem.

[0184] Compound A-20: 2-(4-Ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide

Chem.

[0185] Compound A-21: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(oxetan-3-ylmethylsulfamoylamino)pyridin-4-yl]methyl]benzamide

Chem.

[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

[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

[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] Under the same conditions as in the production example of Compound A-1, 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding 4-nitrophenyl sulfamate were used to synthesize the title compound. However, imidazole was used instead of pyridine, and anhydrous THF was used instead of anhydrous DMF. LCMS m / z: 682 [M+H] + HPLC retention time: 1.27 minutes (Analysis condition 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] 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8, 10.0 mg, 0.019 mmol) was dissolved in anhydrous DMA (0.1 mL), pyridine (2.3 μL, 0.029 mmol) and methylsulfamoyl chloride (2.5 μL, 0.029 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by reverse-phase column chromatography (0.1% aqueous formic acid / 0.1% formic acid acetonitrile solution) to obtain the title compound (10.2 mg, 86%) as a colorless solid. LCMS m / z: 610 [M+H] + HPLC retention time: 1.15 minutes (Analysis condition A)

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

[0191] Compound s3: N-(Oxan-4-yl)sulfamoyl chloride [Chemical formula] The title compound was synthesized from the corresponding amine under the same conditions as in the production example of compound s2. However, 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] The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8) and the corresponding sulfamoyl chloride under the same conditions as in the production example of compound A-25. LCMS m / z: 662 [M+H] + HPLC retention time: 1.27 minutes (analysis condition 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] Under the same conditions as in the production example of Compound A-25, the title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding sulfamoyl chloride. LCMS m / z: 680[M+H] + HPLC retention time: 1.16 minutes (Analysis condition A)

[0194] Compound A-30: 5-[[2-(Cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

Chemical formula

[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

[0196] Compound A-32: 5-[[2-(Cyclobutylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [Chemical formula] Under the same conditions as in the production example of Compound A-25, the title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding sulfamoyl chloride. LCMS m / z: 650 [M+H] + HPLC retention time: 1.26 minutes (Analysis condition 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] Under the same conditions as in the production example of Compound A-25, the title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding sulfamoyl chloride. LCMS m / z: 654 [M+H] + HPLC retention time: 1.17 minutes (Analysis condition 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] Under the same conditions as in the production example of Compound A-25, the title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding sulfamoyl chloride. LCMS m / z: 652 [M+H] + HPLC retention time: 1.31 minutes (Analysis condition 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

Chem.

[0200] Compound A-36: 5-[[2-(Cyclopropylmethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

Chem.

[0201] Compound A-37: 5-[[2-(tert-Butylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

Chem.

[0202] Compound A-38: 5-[[2-(Ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

Chemical formula

[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

[0204] Compound A-40: 5-[[2-(Ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide [Chemical formula] The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding sulfamoyl chloride under the same conditions as in the production example of Compound A-25. LCMS m / z: 624 [M+H] + HPLC retention time: 1.20 minutes (Analysis condition 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] The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding sulfamoyl chloride under the same conditions as in the production example of Compound A-25. LCMS m / z: 638 [M+H] + HPLC retention time: 1.25 minutes (Analysis condition 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] The title compound was synthesized from 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound a8) and the corresponding sulfamoyl chloride under the same conditions as in the production example of Compound A-25. LCMS m / z: 642 [M+H]+ HPLC retention time: 1.17 minutes (Analysis condition A)

[0207] Compound a20: 3,4-Difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-2-[2-fluoro-4-(2-trimethylsilylethynyl)anilino]benzamide

Chem.

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

Chem.

[0209] Compound a21: 5-[(2-Amino-3-fluoropyridin-4-yl)methyl]-2-(4-bromo-2-fluoroanilino)-3,4-difluorobenzamide

Chemical formula

[0210] Compound A-27: 2-(4-Bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide

Chemical formula

[0211] Compound A-43: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[[methyl-(methylamino)-oxo-λ6-sulfanilidene]amino]pyridin-4-yl]methyl]benzamide

Chemical formula

[0212] Compound a22: 5-[(2-Amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid trifluoroacetate

Chemical formula

[0213] Compound a23: 5-[(2-Amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)benzamide

Chem.

[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

Chem.

[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

Chem.

[0216] Compound A-44: 5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)benzamide

Chem.

[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

Chem.

[0218] Compound A-46: 2-(4-Cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide

Chem.

[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

[0220] Compound a26: 5-Bromo-2,3,4-trifluorobenzoic acid

Chemical formula

[0221] Compound a27: 5-Bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzoic acid

Chemical formula

[0222] Compound a28: 5-Bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide

Chem.

[0223] Compound a30: N-[3-Fluoro-4-(hydroxymethyl)pyridin-2-yl]acetamide methanesulfonate

Chem.

[0224] (2) Synthesis of compound a30 To the reaction vessel were added the toluene solution of the obtained N-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-fluoropyridin-2-yl]acetamide, toluene (175 mL), and methanol (195 mL). The mixture was degassed under reduced pressure and replaced with nitrogen. Methanesulfonic acid (188 g, 1.96 mol) was added dropwise at an external temperature of 10 °C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to an external temperature of 0 °C and stirred for 3 hours. The precipitate was collected by filtration and washed with a mixture of cooled toluene (312 mL) and methanol (78 mL). To the reaction vessel were added the solid collected by filtration and a mixture of toluene (1.1 L) and ethanol (492 mL), and the mixture was stirred at an external temperature of 0 °C for 1 hour. The solid was collected by filtration, washed with a mixture of toluene (281 mL) and ethanol (117 mL), and dried under reduced pressure at an external temperature of 40 °C to obtain compound a30 (149 g, 81%). LCMS m / z: 185 [M+H] + HPLC retention time: 0.30 minutes (Analysis condition E)

[0225] Compound a31: (2-Acetamido-3-fluoropyridin-4-yl)methyl methyl carbonate

Chem.

[0226] Compound a32: 5-[(2-Acetamido-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide

Chem.

[0227] Compound a9: 5-[(2-Amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide

Chem.

[0228] Compound A-1: 2-(4-Cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide

Chem.

[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

[0230] (2) Preparation of Sample A-1b To Compound A-1 (53.6 mg) were added 20% sodium ethoxide ethanol solution (0.054 mL) and methyl isobutyl ketone (0.161 mL), and the mixture was stirred at room temperature for 30 minutes. Then, methyl isobutyl ketone (0.161 mL) was added, and the mixture was stirred at 60 °C for 4 days. Thereafter, DMSO (0.054 mL) was added, and the mixture was stirred at 60 °C for 5 hours to obtain the sodium salt of Compound A-1 (25.6 mg) as powdery crystals (Sample A-1b).

[0231] (3) Preparation of Sample A-1c To Compound A-1 (1.02 g) were added DMSO (4.26 mL) and 2 M aqueous sodium hydroxide solution (1.07 mL). This solution was lyophilized at -20 °C for 4 days and then dried under reduced pressure at room temperature for 3 days. To the obtained solid was added 1-pentanol (10.0 mL), and the mixture was stirred at 80 °C for 10 minutes. Thereafter, the mixture was stirred at room temperature for 6 hours to obtain the sodium salt of Compound A-1 (0.966 g) as powdery crystals (Sample A-1c).

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

[0233] The results of the powder X-ray diffraction measurement are shown in Figures 1 to 3. Figure 1 shows the powder X-ray diffraction pattern of Sample A-1a (Form I). Figure 2 shows the powder X-ray diffraction pattern of Sample A-1b. Figure 3 shows the powder X-ray diffraction pattern of Sample A-1c. In Figures 1 to 3, the horizontal axis (X-axis) represents the diffraction angle 2θ (°), and the vertical axis (Y-axis) represents the diffraction intensity.

[0234] (5) Ion chromatography When the ratio of sodium ions in the crystal of Sample A-1a (Form I) was measured by ion chromatography, the molar ratio of sodium ions to Compound A-1 was 0.99. From this, it was confirmed that Sample A-1a is a monosodium salt. Ion chromatography was performed under the following conditions. Measuring device: Dionex ICS-1600, AS-AP (manufactured by Thermo Fisher Scientific) Column: Dionex IonPac CG16 (5×50 mm) / CS16 (5×250 mm) (manufactured by Thermo Fisher Scientific) Eluent: 30 mmol / L methanesulfonic acid solution Suppressor: Dionex CERS-500 4 mm, 88 mA (manufactured by Thermo Fisher Scientific) Column temperature: 40 °C Eluent flow rate: 1.00 mL / min Sample injection volume: 10 μL Detector: Conductivity detector Sample treatment: Sample A-1a was suspended in a 20 mmol / L methanesulfonic acid solution at a concentration of 0.5 mg / mL, shaken and stirred for 17 hours to extract sodium ions, and the supernatant was measured.

[0235] Compound b1: Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoate

Chemical formula

[0236] Compound b2: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoic acid

Chem.

[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

Chem.

[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

Chem.

[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 (4-isomer mixture)

Chemical formula

[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

[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) [Chemistry] Compound B-5: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoyl amino)pyridin-4-yl]methyl]-N-[(1R,2R)-(+ / -)-2-methylcyclopropyl]benzamide (racemate) [Chemistry] 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-methylcyclopropyl)benzamide (4 isomer mixture, Compound B-3, 57 mg) was purified by preparative HPLC (YMC Triart C18 plus 5μm, 4.6×150mm column, 0.1% aqueous TFA / 0.1% TFA acetonitrile solution) to obtain Compound B-4 (14.7 mg) and Compound B-5 (41 mg) as solids respectively. Compound B-4 LCMS m / z: 664 [M+H] + HPLC retention time: 1.70 minutes (Analysis condition B) Compound B-5 LCMS m / z: 664 [M+H] + HPLC retention time: 1.72 minutes (Analysis condition B)

[0242] Compound B-8: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfonyl amino)pyridin-4-yl]methyl]benzamide [Chemistry] Under the same conditions as in the production examples of Compound A-25, Compound b2 and Compound a8, 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. However, triethylamine and anhydrous DCM were used instead of pyridine and anhydrous DMA used in the production example of Compound A-25 respectively. LCMS m / z: 623 [M+H] + HPLC retention time: 1.63 minutes (Analysis condition B)

[0243] Compound B-9: 3,4-Difluoro-5-[[3-fluoro-2-(2-hydroxyethylsulfamoyl amino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide

Chem.

[0244] Compound b8: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(2-methylpropan-2-yl)oxycarbonylsulfamoyl amino]pyridin-4-yl]methyl]benzoic acid

Chem.

[0245] Compound b9: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(sulfamoyl amino)pyridin-4-yl]methyl]benzoic acid

Chem.

[0246] Compound B-10: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(sulfamoyl amino)pyridin-4-yl]methyl]benzamide

Chemical Structure

[0247] Compound b10: 2-(2-Chloro-4-iodoanilino)-3,4-difluoro-5-formylbenzoic acid

Chemical Structure

[0248] Compound b12: Methyl 2-(2-chloro-4-iodoanilino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzoate

Chemical formula

[0249] Compound b14: Methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate

Chemical formula

[0250] Compound B-11: 2-(2-Chloro-4-iodoanilino)-5-[[2-(cyclopropylsulfamoyl amino)-3-fluoropyridin-4-yl]methyl]-3,4-difluorobenzamide

Chemical Structure

[0251] Compound B-12: 2-(2-Chloro-4-iodoanilino)-N-cyclopropyl-5-[[2-(cyclopropylsulfamoyl amino)-3-fluoropyridin-4-yl]methyl]-3,4-difluorobenzamide

Chemical Structure

[0252] Compound B-13: 2-(2-Chloro-4-iodoanilino)-5-[[2-(cyclopropylsulfamoyl amino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-N-[(2-methylpropan-2-yl)oxy]benzamide

Chemical formula

[0253] Compound B-14: N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methanesulfonamido)pyridin-4-yl]methyl]benzamide

Chemical formula

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

[0256] Compound c1: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzamide

Chem.

[0257] Compound c2: [2-[(2,4-Dimethoxyphenyl)methylamino]pyridin-4-yl]boronic acid

Chem.

[0258] Compound c4: 5-[(2-Aminopyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

Chem.

[0259] Compound C-1: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(sulfamoylamino)pyridin-4-yl]methyl]benzamide

Chemical Structure

[0260] Compound C-2: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide

Chemical Structure

[0261] Compound C-3: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide

Chem.

[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

Chem.

[0263] Compound c5: 5-Ethenyl-3,4-difluoro-2-(4-iodo-2-methylanilino)benzoic acid

Chem.

[0264] Compound c6: 3,4-Difluoro-5-formyl-2-(4-iodo-2-methylanilino)benzoic acid

Chemical formula

[0265] Compound C-5: 3,4-Difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-2-(4-iodo-2-methylanilino)benzamide

Chem.

[0266] Compound C-6: N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-(methylsulfamoylamino)phenyl]methyl]benzamide

Chem.

[0267] Compound d1: Methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate

Chem.

[0268] Compound d2: 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid

Chem.

[0269] Compound D-1: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(2-methoxyethylsulfamoylamino)phenyl]methyl]benzamide

Chem.

[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

Chem.

[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

[0272] Compound D-4: 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

Chemical formula

[0273] Compound D-5: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(2-methoxyethylsulfonylamino)phenyl]methyl]benzamide

Chem.

[0274] Compound D-6: N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide

Chem.

[0275] Compound D-7: N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(sulfamoylamino)phenyl]methyl]benzamide

Chem.

[0276] Compound D-8: N-Cyclopropyl-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

Chemical Structure

[0277] Compound D-9: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclobutyl)sulfamoylamino]phenyl]methyl]benzamide

Chemical Structure

[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

[0279] Compound D-11: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]-N-methoxybenzamide

Chemical formula

[0280] Compound D-12: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(sulfamoylamino)phenyl]methyl]-N-methoxybenzamide

Chemical formula

[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

[0282] Compound D-14: 2-(4-Cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide [Chemical formula] The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) under the same conditions as in the production examples of Compound a9, Compound a7, Compound a8 and Compound A-25. However, an aqueous solution of 1M sodium hydroxide was used instead of lithium hydroxide monohydrate used in the production example of Compound a7. LCMS m / z: 523 [M+H] + HPLC retention time: 1.58 minutes (Analysis condition 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] The title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) under the same conditions as in the production examples of Compound a9, Compound a7, Compound a8 and Compound A-25. However, an aqueous solution of 1M sodium hydroxide was used instead of lithium hydroxide monohydrate used in the production example of Compound a7, and the corresponding amine was used instead of the 7M ammonia MeOH solution used in the production example of Compound a8. LCMS m / z: 563 [M+H] + HPLC retention time: 1.68 minutes (Analysis condition B)

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

[0285] Compound E-1: 5-[[3-(Ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide

Chemical Structure

[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 Structure

[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

[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

[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] Under the same conditions as in the production examples of Compound A-25, Compound b2 and Compound a12, methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfonyl chloride were used to synthesize the title compound. However, pyridine was used as the solvent in the sulfonamidation step. Also, the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the production example of Compound a12. LCMS m / z: 664 [M+H] + HPLC retention time: 1.73 minutes (Analysis condition 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] Under the same conditions as in the production examples of Compound A-25, Compound b2 and Compound a12, methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfonyl chloride were used to synthesize the title compound. However, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 706 [M+H] + HPLC retention time: 1.86 minutes (Analysis condition B)

[0291] Compound E-7: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide [Chemical formula] Under the same conditions as in the production examples of Compound A-25, Compound b2, and Compound a12, the title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1). However, pyridine was used as the solvent in the sulfamidation step. Also, the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the production example of Compound a12. LCMS m / z: 609 [M+H] + HPLC retention time: 1.23 minutes (Analysis condition 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] Under the same conditions as in the production examples of Compound A-25, Compound b2, and Compound a12, the title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound d1) and the corresponding sulfamoyl chloride. However, pyridine was used as the solvent in the sulfamidation step. Also, the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the production example of Compound a12. LCMS m / z: 695 [M+H] + HPLC retention time: 0.74 minutes (Analysis condition D)

[0293] Compound E-8: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(sulfamoylamino)phenyl]methyl]benzamide [Chemical formula] Under the same conditions as in the production example of compound b9, 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). LCMS m / z: 595[M+H] + HPLC retention time: 1.17 minutes (analysis condition A)

[0294] Compound E-9: 2-(2-Chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-methoxybenzamide

Chemical Structure

[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 Structure

[0296] Compound E-11: 2-(2-Chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluorobenzamide

Chemical Structure

[0297] Compound e17: Methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate

Chemical Structure

[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

[0299] Compound e20: Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzoate

Chemical formula

[0300] Compound E-13: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide

Chem.

[0301] Compound E-14: 5-[[3-(Cyclopropylmethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

Chem.

[0302] Compound E-15: 3,4-Difluoro-5-[[2-fluoro-3-(3-fluoropropylsulfonylamino)phenyl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide

Chemical formula

[0303] Compound E-16: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclopropyl)sulfonylamino]phenyl]methyl]benzamide

Chemical formula

[0304] Compound E-17: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(2-methylpropylsulfonylamino)phenyl]methyl]benzamide

Chem.

[0305] Compound E-18: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(propylsulfonylamino)phenyl]methyl]benzamide

Chem.

[0306] Compound E-19: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[[1-(methoxymethyl)cyclopropyl]sulfonylamino]phenyl]methyl]benzamide

Chem.

[0307] Compound E-20: 5-[[3-(Cyclobutylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

Chemical Structure

[0308] Compound E-21: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxetan-3-ylsulfonylamino)phenyl]methyl]benzamide

Chemical Structure

[0309] Compound E-22: 5-[[3-(Cyclopropylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

Chem.

[0310] Compound E-23: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxan-4-ylsulfonylamino)phenyl]methyl]benzamide

Chem.

[0311] Compound E-24: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(propan-2-ylsulfonylamino)phenyl]methyl]benzamide

Chem.

[0312] Compound E-25: N-Cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide

Chemical formula

[0313] Compound E-26: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]-N-methoxybenzamide

Chemical formula

[0314] Compound F-1: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-(methylsulfamoylamino)phenyl]methyl]benzamide

Chem.

[0315] Compound F-2: 5-[[3-(ethylsulfonylamino)phenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

Chem.

[0316] Compound F-3: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-(2-methoxyethylsulfonylamino)phenyl]methyl]benzamide [Chemical formula] Under the same conditions as in the production example of Compound a5 and Compound A-25, 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. However, 3-aminophenylboronic acid 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. Also, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 620 [M+H] + HPLC retention time: 1.65 minutes (Analysis condition B)

[0317] Compound g2: 2-(4-Cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoic acid [Chemical formula] Under the same conditions as in the production example of Compound a9 and Compound A-1, 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). LCMS m / z: 525 [M+H] + HPLC retention time: 0.83 minutes (Analysis condition 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] Under the same conditions as in the production example of compound a10, the title compound was synthesized from 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoyl amino)pyridin-4-yl]methyl]benzoic acid (compound g2). LCMS m / z: 564[M+H] + HPLC retention time: 1.61 minutes (analysis condition 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 Structure

[0320] Compound G-3: 2-(4-Bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide

Chemical Structure

[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

[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

[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 Structure

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

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

[0326] Compound G-9: 2-(4-Cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methanesulfonamido)pyridin-4-yl]methyl]-N-methoxybenzamide

Chem.

[0327] Compound h1: Methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-[3-(2-ethylhexyloxy)-3-oxopropyl]sulfanyl-2-fluoroanilino]-3,4-difluorobenzoate

Chem.

[0328] Compound h2: Methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluorobenzoate

Chemical formula

[0329] Compound h3: 5-[(2-Amino-3-fluoropyridin-4-yl)methyl]-2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluorobenzamide

Chemical formula

[0330] Compound H-1: 2-[4-(Difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide

Chem.

[0331] Compound h4: 2-(1-Benzothiophen-5-ylamino)-3,4-difluoro-5-formylbenzoic acid

Chem.

[0332] Compound h5: 2-(1-Benzothiophen-5-ylamino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzamide

Chemical Structure

[0333] Compound h7: 5-[(2-Amino-3-fluoropyridin-4-yl)methyl]-2-(1-benzothiophen-5-ylamino)-3,4-difluorobenzamide

Chem.

[0334] Compound H-2: 2-(1-Benzothiophen-5-ylamino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide

Chem.

[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

[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

[0337] Compound h9: 1,2,3-Trifluoro-4-[(4-methoxyphenyl)methoxy]benzene

Chemical formula

[0338] Compound h10: 2,3,4-Trifluoro-5-[(4-methoxyphenyl)methoxy]benzoic acid

Chemical formula

[0339] Compound h13: Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-hydroxybenzoate

Chemical formula

[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

[0341] Compound H-4: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]oxybenzamide

Chemical formula

[0342] Compound h17: 5-[[6-[Bis[(4-methoxyphenyl)methyl]amino]pyridin-2-yl]-hydroxymethyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid

Chem.

[0343] Compound h18: 5-[(6-Aminopyridin-2-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid

Chem.

[0344] Compound H-5: 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-5-[[6-(methylsulfamoylamino)pyridin-2-yl]methyl]benzamide

Chem.

[0345] Compound I-1: 4-Fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide

Chem.

[0346] Compound I-2: 5-[[2-(Ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-4-fluoro-2-(2-fluoro-4-iodoanilino)benzamide

Chemical Structure

[0347] Compound I-3: 5-[[2-(Cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-4-fluoro-2-(2-fluoro-4-iodoanilino)benzamide

Chemical Structure

[0348] Compound I-4: 4-Fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide

Chemical Structure

[0349] Compound j1: Methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate

Chemical Structure

[0350] To a solution of methyl 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (7.90 g, 19.7 mmol) and tetrabutylammonium iodide (0.726 g, 1.97 mmol) in 1,3-dimethyl-2-imidazolidinone (39 mL) were added the crude product of 2-amino-4-(chloromethyl)-3-fluoropyridine (3.47 g) and tripotassium phosphate (5.00 g, 23.6 mmol), and the mixture was stirred at 50 °C for 4 hours. Water was added to the reaction mixture, and the obtained solid was collected by filtration and washed with a mixture of acetonitrile / water to obtain the title compound (10.3 g, 60%). LCMS m / z: 527 [M+H] + HPLC retention time: 0.63 minutes (analysis condition 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 Structure

[0352] Compound j3: 5-[(2-Amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide

Chem.

[0353] Compound J-1: 2-(2-Fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide

Chem.

[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

Chem.

[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

[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

[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

Chem.

[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

Chem.

[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

Chem.

[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

[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

[0362] Compound J-13: 5-[[2-(Cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide

Chem.

[0363] Compound J-14: 5-[[2-(Ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide

Chem.

[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

Chem.

[0365] Compound J-3: 2-(4-Cyclopropyl-2-fluoroanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide

Chem.

[0366] Compound J-4: 2-(4-Cyclopropyl-2-fluoroanilino)-5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide

Chem.

[0367] Compound j12: 5-[[2-(Ethylsulfonylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid

Chem.

[0368] Compound J-12: 5-[[2-(Ethylsulfonylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide

Chem.

[0369] Compound k1: Methyl 2-(2-fluoro-4-iodoanilino)-5-formyl-1-methyl-6-oxopyridine-3-carboxylate

Chemical formula

[0370] Compound k4: Methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate

Chemical formula

[0371] Compound K-1: 2-(2-Fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]-1-methyl-6-oxopyridine-3-carboxamide

Chemical Structure

[0372] Compound K-2: 5-[[3-(Ethylsulfamoylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide

Chemical Structure

[0373] Compound K-3: 5-[[3-(Cyclopropylsulfamoylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide

Chemical Structure

[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 Structure

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

[0376] Compound K-13: N-Cyclopropyl-5-[[3-(ethylsulfamoylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide [Chem.] Under the same conditions as in the production examples of Compound b2, Compound a10 and Compound A-1, 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). However, the corresponding 4-nitrophenyl sulfamate was used instead of 4-nitrophenyl methylsulfamate used in the production example of Compound A-1. LCMS m / z: 658 [M+H] + HPLC retention time: 1.52 minutes (Analysis condition 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] Under the same conditions as in the production examples of Compound A-25, Compound b2 and Compound a8, methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (Compound k4) and the corresponding sulfonyl chloride were used to synthesize the title compound. However, pyridine was used as the solvent in the sulfonamidation step. LCMS m / z: 629 [M+H] + HPLC retention time: 1.48 minutes (Analysis condition B)

[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] Under the same conditions as in the production examples of Compound A-25, Compound b2 and Compound a12, methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (Compound k4) and the corresponding sulfonyl chloride were used to synthesize the title compound. However, pyridine was used as the solvent in the sulfonamidation step. Also, the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the production example of Compound a12. LCMS m / z: 659 [M+H] + HPLC retention time: 1.47 minutes (Analysis condition B)

[0379] Compound K-11: N-Cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclopropyl)sulfonylamino]phenyl]methyl]-1-methyl-6-oxopyridine-3-carboxamide [Chemical formula] Under the same conditions as in the production examples of Compound A-25, Compound b2, and Compound a8, the title compound was synthesized from methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate (Compound k4) and the corresponding sulfonyl chloride. However, pyridine was used as the solvent in the sulfonamidation step. Also, the corresponding amine was used instead of the 7M ammonia MeOH solution used in the production example of Compound a8. LCMS m / z: 669[M+H] + HPLC retention time: 1.59 minutes (Analysis condition B)

[0380] Compound K-12: 2-(2-Fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclopropyl)sulfonylamino]phenyl]methyl]-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide

Chemical Structure

[0381] Compound k11: 5-[[3-(Ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid

Chemical Structure

[0382] Compound K-8: N-Cyclopropyl-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide

Chemical formula

[0383] Compound K-9: 5-[[3-(Ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide

Chemical formula

[0384] Compound K-10: 5-[[3-(Ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide

Chem.

[0385] Compound l2: Methyl 2-bromo-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate

Chem.

[0386] Compound l3a: Methyl 5-(2-fluoro-4-trimethylsilylanilino)-2-formylpyridine-4-carboxylate

Chem.

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

[0388] Compound l4: Methyl 5-(2-fluoro-4-trimethylsilylanilino)-2-(hydroxymethyl)pyridine-4-carboxylate

Chemical formula

[0389] Compound l5: Methyl 2-(chloromethyl)-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate

Chemical formula

[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

[0391] Compound l7: Methyl 2-[(2-Amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate

Chemical formula

[0392] Compound l8: Methyl 2-[(2-Amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)pyridine-4-carboxylate

Chemical formula

[0393] Compound L-1: 5-(2-Fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide

Chemical formula

[0394] Compound m1: Methyl 2-amino-6-(aminomethyl)pyridine-3-carboxylate diacetate

Chem.

[0395] Compound m2: Methyl 2-amino-6-(formamidomethyl)pyridine-3-carboxylate

Chem.

[0396] Compound m3: Methyl 2-amino-5-bromo-6-(formamidomethyl)pyridine-3-carboxylate

Chem.

[0397] Compound m4: Methyl 5-amino-8-bromoimidazo[1,5-a]pyridine-6-carboxylate

Chem.

[0398] Compound m5: Methyl 5 - [bis[(2 - methylpropan - 2 - yl)oxycarbonyl]amino]-8 - bromoimidazo[1,5 - a]pyridine - 6 - carboxylate

Chem.

[0399] Compound m6: Methyl 5 - [bis[(2 - methylpropan - 2 - yl)oxycarbonyl]amino]-8 - ethenylimidazo[1,5 - a]pyridine - 6 - carboxylate

Chemical formula

[0400] Compound m8: Methyl 5 - amino - 8 - formylimidazo[1,5 - a]pyridine - 6 - carboxylate trifluoroacetate

Chemical formula

[0401] Compound m9: Methyl 5 - amino - 8 - (5,5 - dimethyl - 1,3 - dioxan - 2 - yl)imidazo[1,5 - a]pyridine - 6 - carboxylate

Chemical formula

[0402] Compound m10: Methyl 5 - chloro - 8 - (5,5 - dimethyl - 1,3 - dioxan - 2 - yl)imidazo[1,5 - a]pyridine - 6 - carboxylate

Chemical formula

[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

Chem.

[0404] Compound m12: Methyl 5 - (2 - fluoro - 4 - iodoanilino)-8 - formylimidazo[1,5 - a]pyridine - 6 - carboxylate

Chem.

[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

[0406] Compound m16: 8 - [(2 - amino - 3 - fluoropyridin - 4 - yl)methyl]-5 - (2 - fluoro - 4 - iodoanilino)imidazo[1,5 - a]pyridine - 6 - carboxylic acid trifluoroacetate

Chemical formula

[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

[0408] Compound M-1: 5 - (2 - fluoro - 4 - iodoanilino)-8 - [[3 - fluoro - 2 - (methylsulfamoyl)amino]pyridin - 4 - yl]methyl]imidazo[1,5 - a]pyridine - 6 - carboxamide [Chemical formula] Under the same conditions as in the production example of Compound A-1, 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). LCMS m / z: 614 [M+H] + HPLC retention time: 1.18 minutes (Analysis condition B)

[0409] Compound n1: 6 - chloro - 5 - fluoro - 4 - (2 - fluoro - 4 - iodoanilino)pyridine - 3 - carboxylic acid [Chemical formula] A solution of 2-fluoro-4-iodoaniline (2.26 g, 9.52 mmol) in anhydrous THF (8 ml) was cooled to -78 °C, 2M LDA THF / heptane / ethylbenzene solution (7.14 mL, 14.3 mmol) was added, and the mixture was stirred for 30 minutes. Then, a solution of 4,6-dichloro-5-fluoropyridine-3-carboxylic acid (1.00 g, 4.76 mmol) in anhydrous THF (8 mL) was added, and the mixture was stirred at -78 °C for 30 minutes. Thereafter, water and 6M hydrochloric acid were added to the reaction mixture to adjust the pH to 1 to 2, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. Recrystallization (DCM) was performed on the obtained residue to obtain the title compound (850 mg, 44%) as a light brown solid. LCMS m / z: 411 [M+H] + HPLC retention time: 0.85 minutes (Analysis condition G)

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

[0411] Compound n3: Methyl 5 - fluoro - 4 - (2 - fluoro - 4 - iodoanilino)-6 - hydroxypyridine - 3 - carboxylate

Chemical formula

[0412] Compound n4: N - [4 - (bromomethyl)-3 - fluoropyridin - 2 - yl]-1,1 - diphenylmethanimine

Chemical formula

[0413] Compound n5: Methyl 1-[[2-(benzhydrylideneamino)-3-fluoropyridin-4-yl]methyl]-5-fluoro-4-(2-fluoro-4-iodoanilino)-6-oxopyridine-3-carboxylate

Chemical Structure

Claims

1. A compound represented by the following general formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt. 【Chemical Formula 1】 [In the formula, Ring A is a group represented by the following general formula (2), (4) or (5) (wherein the bonds marked with *, ** and *** are —NH—, —CONH— and —CH ２ — bonded thereto, respectively). 【Chemical Formula 2】 X １ , X ２ , X ３ , X4 and X ６ are each independently —CR ２ ═ or —N═. R ２ is a hydrogen atom, a halogen atom or a C1-6 alkyl group. R １ is —S(═O) ２ —NH—R ８ or —S(═O) ２ —R ８ . R ８ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group, a C1-6 alkoxy group, a C3-6 cycloalkyl group or a C3-6 heterocycloalkyl group), a monocyclic or bicyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group or a C1-6 alkoxy group) or a monocyclic or bicyclic C3-6 heterocycloalkyl group. R ３ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group) or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group). R ５ is a halogen atom or a C1-6 alkyl group, R ６ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R ４ is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-7 alkenyl group, a C2-7 alkynyl group, a C3-6 cycloalkyl group or a C1-6 alkylthio group, or R ６ and R ４ together with the carbon atom to which they are attached form an unsaturated hetero 5-membered ring, R ７ is a hydrogen atom or a C1-6 alkyl group, R ９ is a hydrogen atom, a halogen atom or a C1-6 alkyl group. However, ring A is a group represented by the general formula (2) or (4), X1, X2, X3 and X4 are each independently -CR2= or -N=, R2 is a hydrogen atom, a halogen atom or a C1-6 alkyl group, R1 is -S(=O)2-NH-R8 or -S(=O)2-R8, R8 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), R3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxy 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, R4 is a halogen atom or a cyclopropyl group, R7 is a hydrogen atom or a methyl group, When R9 is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and the compound represented by the general formula (1) is 3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-methylsulfanylanilino)benzamide, 2-(4-ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxan-4-ylsulfonylamino)phenyl]methyl]benzamide, 3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide, and 5-(2-fluoro-4-iodoanilino)-8-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]imidazo[1,5-a]pyridine-6-carboxamide excluding the case where it is a compound selected from. ]

2. A stabilizer for RAF / MEK complex containing, as an active ingredient, a compound represented by the following general formula (11), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt. [Chemical formula 3] [In the formula, Ring A is a group represented by the following general formula (2), (4) or (5) (wherein the bonds marked with *, ** and *** are -NH-, -CONH- and -X ７ - respectively bonded to. ), [Chemical formula 4] X １ X ２ X ３ X4 and X ６is each independently -CR ２ = or -N=, R ２ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, X ７ is -(CH ２ ) ｍ - or -O-, m is 1, 2 or 3, R １ is -S(=O) ２ -NH-R ８ or -S(=O) ２ -R ８ and R ８ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group, a C1-6 alkoxy group, a C3-6 cycloalkyl group or a C3-6 heterocycloalkyl group), a monocyclic or bicyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group or a C1-6 alkoxy group) or a monocyclic or bicyclic C3-6 heterocycloalkyl group, R ３ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group) or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), R ５ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, R ６ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, R ４ is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-7 alkenyl group, a C2-7 alkynyl group, a C3-6 cycloalkyl group or a C1-6 alkylthio group, or R ６ and R ４ together with the carbon atom to which they are attached form an unsaturated hetero 5-membered ring, R ７ is a hydrogen atom or a C1-6 alkyl group, R ９ is a hydrogen atom, a halogen atom or a C1-6 alkyl group. ]

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

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

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

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