Novel benzenesulfonamide-based compound

Abstract

The present invention addresses the problem of providing a novel benzenesulfonamide derivative that is useful as a medical drug.　The present invention is a benzenesulfonamide derivative represented by formula (I) (in the formula, R1 denotes a C1-4 alkyl group, a C1-4 monofluoroalkyl group or a C3-6 cycloalkyl group; R2 denotes a phenylvinyl group, heteroarylvinyl group or heteroaryl group having a substituent group; R3 denotes a hydrogen atom or a methyl group; R4 denotes a hydrogen atom or a fluorine atom; R5 and R6 may be the same as, or different from, each other, and are each selected from among a hydrogen atom, a halogen atom, a C1-3 alkyl group, a C1-3 alkyl group substituted with 1-3 fluorine atoms, a C3-6 cycloalkyl group, or the like, but cannot both be hydrogen atoms), a salt thereof, or solvates of these.

Description

Novel benzenesulfonamide compounds

[0001] This invention relates to novel benzenesulfonamide compounds and their uses.

[0002] PP2A (protein phosphatase 2A) is known to be a tumor suppressor, and decreased PP2A activity has been observed in many cancers. This decrease in PP2A activity is caused by increased expression of PP2A inhibitory proteins such as SET. Therefore, targeting these inhibitors to restore PP2A activity could be a new anti-cancer strategy.

[0003] Non-patent document 1 reports FTY720, which has the following formula, as a SET inhibitor.

[0004]

[0005] However, the SET inhibitory concentration of FTY720 is on the micromolar order, which is not considered sufficiently strong. Furthermore, since FTY720 itself is phosphorylated in vivo and then binds to the S1P receptor, even if used as a SET inhibitor, it can cause undesirable side effects. In other words, there has been a need for the development of new small molecule compounds whose main action is SET inhibition (Non-Patent Literature 2).

[0006] JP-A-6-293730 JP-A-6-72979

[0007] EMBO Mol Med (2013) 5, 105-121. BBA-Reviews on Cancer 1876 (2021) 188578. Biochem. Biophys. Res. Commun. (1991) 181, 968-975.

[0008] The object of the present invention is to provide a low-molecular-weight compound that has excellent SET inhibitory activity and is useful as an active ingredient in pharmaceuticals.

[0009] While diligently searching for low-molecular-weight compounds with SET inhibitory activity, the inventors discovered that a group of compounds having a benzenesulfonamide skeleton exhibits strong SET inhibitory activity, thus completing the present invention.

[0010] The present invention provides the following inventions [1] to [9]: [1] Formula (I)

[0011]

[0012] A benzenesulfonamide compound represented by formula (I), a salt thereof, or a solvate thereof, where R1 represents a C1-4 alkyl group, a C1-4 monofluoroalkyl group, or a C3-6 cycloalkyl group; R2 represents an optionally substituted phenyl vinyl group, an optionally substituted heteroaryl vinyl group, or an optionally substituted heteroaryl group; R3 represents a hydrogen atom or a methyl group; R4 represents a hydrogen atom or a fluorine atom; and R5 and R6 are each the same or different and selected from a hydrogen atom, a halogen atom, a C1-3 alkyl group, a C1-3 alkyl group substituted with 1-3 fluorine atoms, a C3-6 cycloalkyl group, a C3-6 alkynyl group, a C1-6 alkoxy group, a C1-6 alkoxy group substituted with 1-3 fluorine atoms, a C3-6 alkynyloxy group, a C3-6 alkenyloxy group, a C3-6 cycloalkoxy group, an optionally substituted phenyl group, a phenoxy group, and a heteroaryl group, but a hydrogen atom is never selected at the same time. [2] A benzenesulfonamide compound according to [1], a salt thereof, or a solvate thereof, wherein R1 is selected from a methyl group, an ethyl group, a cyclopropyl group, and a 2-fluoroethyl group. [3] A benzenesulfonamide compound according to [1] or [2], a salt thereof, or a solvate thereof, wherein R2 is selected from a 4-chlorophenylvinyl group, a 4-(trifluoromethyl)phenylvinyl group, a 4-cyanophenylvinyl group, a 4-methoxyphenylvinyl group, a 5-chloro-2-pyridylvinyl group, a 5-chloroindolyl group, and a 6-chloroindolyl group.[4] R5 and R6 are the same or different and are selected from a hydrogen atom, a fluorine atom, a bromine atom, a methyl group, an isopropyl group, a cyclopropyl group, a trifluoromethyl group, an ethynyl group, a methoxy group, an ethoxy group, an n-propoxy group, an n-butoxy group, an n-pentyloxy group, an isopropoxy group, a tert-butoxy group, a 2,2-dimethylpropoxy group, a cyclopropylmethoxy group, a cyclobutylmethoxy group, a benzyloxy group, a difluoromethoxy group, a trifluoromethoxy group, a 2,2,2-trifluoroethoxy group, a propargyloxy group, a prenilyloxy group, a cyclopropoxy group, a cyclobutyloxy group, a cyclopentyloxy group, a 2-methoxyphenyl group, a 3-methoxyphenyl group, a phenyl group, a p-tolyl group, a phenoxy group, a 5-triazolyl group, a 1-pyrazolyl group, a 2-benzofuryl group, and a 3-benzofuryl group, provided that a hydrogen atom is not simultaneously selected. The benzenesulfonamide compound, its salt or their solvate according to any one of [1] to [3]. [5] A pharmaceutical composition containing the benzenesulfonamide compound, its salt or their solvate according to any one of [1] to [4]. [6] The pharmaceutical composition according to [5], which is a prophylactic and therapeutic agent for cancer. [7] The benzenesulfonamide compound, its salt or their solvate according to any one of [1] to [4] above, which is used for the treatment and / or prevention of cancer. [8] Use of the benzenesulfonamide compound, its salt or their solvate according to any one of [1] to [4] above for the manufacture of a therapeutic and / or prophylactic agent for cancer. [9] A method for treating and / or preventing cancer, which comprises administering the benzenesulfonamide compound, its salt or their solvate according to any one of [1] to [4] above.

[0013] The benzenesulfonamide compound of the present invention represented by the above formula (I) has an excellent SET inhibitory action and is useful as an active ingredient of a pharmaceutical for the treatment and / or prevention of cancer.

[0014] As used herein, unless otherwise specified, terms are used in their ordinary meanings as commonly used in the art. In this specification, the term "comprising" includes not only the case of containing only one component but also the case of containing other components in addition to a certain component. In this specification, the names of compounds, substituents, etc. are used in their ordinary meanings as commonly used in the art. The heteroaryl group means an aromatic heterocyclic group, specifically, an aromatic heterocyclic group having one or more heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom. The aromatic heterocyclic group includes monocyclic and fused-ring aromatic heterocyclic groups. More specifically, examples thereof include a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, a pyridyl group, a pyrimidyl group, an indolyl group, a thienyl group, a benzothienyl group, a furyl group, and a benzofuryl group.

[0015] One aspect of the present invention is a benzenesulfonamide compound represented by the above formula (I) (hereinafter, also referred to as the compound (I) of the present invention), a salt thereof, or a solvate thereof. Although benzenesulfonamide compounds have been disclosed in Patent Document 1 and Patent Document 2 prior to this application, it has only been shown that their main actions include a vasodilating action, an antiplatelet aggregation action, an anti-ulcer action, and the like. Further, in Non-Patent Document 3, it has been reported that KN-93 having the following formula, which is one of the benzenesulfonamide compounds included in Patent Document 1, inhibits CaMK2, but no suggestion has been made that it inhibits SET. Further, since the above-mentioned FTY-720 does not have a benzenesulfonamide skeleton, it is completely different from the compound (I) of the present invention.

[0016]

[0017] In formula (I), R1 represents a C1-4 alkyl group, a C1-4 monofluoroalkyl group, or a C3-6 cycloalkyl group. Examples of C1-4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl groups, but methyl, ethyl, and isopropyl groups are preferred. Examples of C1-4 monofluoroalkyl groups include fluoromethyl, 2-fluoroethyl, and 3-fluoropropyl groups, but 2-fluoroethyl groups are preferred. Examples of C3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups, but cyclopropyl groups are preferred. For R1, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, fluoromethyl group, 2-fluoroethyl group, 3-fluoropropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group are preferred, and a selection from methyl group, ethyl group, cyclopropyl group, and 2-fluoroethyl group is more preferred. In formula (I), R2 represents a substituted phenyl vinyl group, heteroaryl vinyl group, or heteroaryl group. Substituents on the phenyl group of the phenyl vinyl group include halogen atoms, fluorine-substituted C1-4 alkyl groups, cyano groups, and C1-4 alkoxy groups, with chlorine atoms, trifluoromethyl groups, cyano groups, and methoxy groups being more preferred. Examples of heteroaryl vinyl groups include pyrrolyl vinyl group, imidazolyl vinyl group, pyridyl vinyl group, pyrimidyl vinyl group, and indolyl vinyl group, with pyridyl vinyl group being more preferred. Examples of heteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidyl, indolyl, thienyl, benzothienyl, furyl, and benzofuryl groups, with pyrrolyl, imidazolyl, pyridyl, pyrimidyl, and indolyl groups being preferred, and indolyl groups being more preferred.For R2, a group selected from pyrrolyl vinyl, imidazolyl vinyl, pyridyl vinyl, pyrimidyl vinyl, indolyl vinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidyl, indolyl, thienyl, benzothienyl, furyl, and benzofuryl groups is preferred, and a group selected from 4-chlorophenyl vinyl, 4-(trifluoromethyl)phenyl vinyl, 4-cyanophenyl vinyl, 4-methoxyphenyl vinyl, 5-chloro-2-pyridyl vinyl, 5-chloroindolyl, and 6-chloroindolyl groups is more preferred. In formula (I), R3 represents a hydrogen atom or a methyl group, but a hydrogen atom is preferred. In formula (I), R4 represents a hydrogen atom or a fluorine atom, but a hydrogen atom is preferred.

[0018] In formula (I), R5 and R6 are the same or different and selected from a hydrogen atom, a halogen atom, a C1-3 alkyl group, a C1-3 alkyl group substituted with 1-3 fluorine atoms, a C3-6 cycloalkyl group, a C3-6 alkynyl group, a C1-6 alkoxy group, a C1-6 alkoxy group substituted with 1-3 fluorine atoms, a C3-6 alkynyloxy group, a C3-6 alkenyloxy group, a C3-6 cycloalkoxy group, an optionally substituted phenyl group, a phenoxy group, and a heteroaryl group, and a hydrogen atom is never selected at the same time. As halogen atoms, fluorine atoms and bromine atoms are preferred. As C1-3 alkyl groups, methyl groups, ethyl groups, and isopropyl groups are preferred. As C1-3 alkyl groups substituted with 1-3 fluorine atoms, trifluoromethyl groups are preferred. As C3-6 cycloalkyl groups, cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, and cyclohexyl groups are preferred, with cyclopropyl groups being more preferred. As the C3-6 alkynyl group, the ethynyl group is preferred. As the C1-6 alkoxy group, the methoxy group, ethoxy group, n-propoxy group, n-butoxy group, n-pentyloxy group, isopropoxy group, tert-butoxy group, 2,2-dimethylpropoxy group, cyclopropylmethoxy group, cyclobutylmethoxy group, and benzyloxy group are preferred. As the C1-6 alkoxy group substituted with 1-3 fluorine atoms, the difluoromethoxy group, trifluoromethoxy group, and 2,2,2-trifluoroethoxy group are preferred. As the C3-6 alkynyloxy group, the propargyloxy group is preferred. As the C3-6 alkenyloxy group, the prenyloxy group is preferred. As the C3-6 cycloalkoxy group, the cyclopropoxy group, cyclobutoxy group, and cyclopentyloxy group are preferred. Preferred phenyl groups that may be substituted include phenyl groups, C1-3 alkyl-substituted phenyl groups, and C1-3 alkoxy-substituted phenyl groups, with 2-methoxyphenyl groups, 3-methoxyphenyl groups, and p-tolyl groups being more preferred.Examples of heteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidyl, indolyl, thienyl, benzothienyl, furyl, and benzofuryl groups, with pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furyl, and benzofuryl groups being preferred, and 5-triazolyl, 1-pyrazolyl, 2-benzofuryl, and 3-benzofuryl groups being more preferred. R5 and R6 are preferably the same or different groups selected from a hydrogen atom, a halogen atom, a C1-3 alkyl group, a C1-3 alkyl group substituted with 1-3 fluorine atoms, a C3-6 cycloalkyl group, a C3-6 alkynyl group, a C1-6 alkoxy group, a C1-6 alkoxy group substituted with 1-3 fluorine atoms, a C3-6 alkynyl group, a C3-6 alkenyloxy group, a C3-6 cycloalkoxy group, an optionally substituted phenyl group, a phenoxy group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, a pyridyl group, a pyrimidyl group, an indolyl group, a thienyl group, a benzothienyl group, a furyl group, and a benzofuryl group; and preferably the same or different groups are a hydrogen atom, a fluorine atom, a bromine atom, a methyl group, an isopropyl group, a cyclopropyl group, The group can be selected from trifluoromethyl, ethynyl, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, isopropoxy, tert-butoxy, 2,2-dimethylpropoxy, cyclopropylmethoxy, cyclobutylmethoxy, benzyloxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, propargyloxy, prenyloxy, cyclopropoxy, cyclobutyloxy, cyclopentyloxy, 2-methoxyphenyl, 3-methoxyphenyl, phenyl, p-tolyl, phenoxy, 5-triazolyl, 1-pyrazolyl, 2-benzofuryl, and 3-benzofuryl groups, but it is more preferable that no hydrogen atoms are selected simultaneously.

[0019] Preferred examples of compounds represented by formula (I) include the following:(E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-isopropylbenzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(ethyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(cyclopropyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(2-fluoroethyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-ethoxy-N-(2-hydroxyethyl)benzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-methoxybenzenesulfonamide (E)-N-(2-hydroxyethyl)-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)amino)methyl)phenyl)-[1,1'-biphenyl]-3-sulfonamide (E)-3-ethoxy-N-(2-hydroxyethyl)-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)amino)methyl)phenyl)benzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-(trifluoromethyl)benzenesulfonamide (E)-3-ethynyl-N-(2-hydroxyethyl)-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)amino)methyl)phenyl)benzenesulfonamide (E)-N-(2-hydroxyethyl)-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)amino)methyl)phenyl)-3-(1H-1,2,3-triazole-5-yl)benzenesulfonamide.

[0020] (E)-3-bromo-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)benzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3,5-dimethoxybenzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-(trifluoromethoxy)benzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-ethynyl-N-(2-hydroxyethyl)benzenesulfonamide (E)-3-(difluoromethoxy)-N-(2-hydroxyethyl)-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)amino)methyl)phenyl)benzenesulfonamide (E)-N-(2-hydroxyethyl)-2,5-Dimethoxy-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)aminomethyl)phenyl)benzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)aminomethyl)phenyl)-N-(2-hydroxyethyl)-3-phenoxybenzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)aminomethyl)phenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (E)-N-(2-hydroxyethyl)-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)aminomethyl)phenyl)-3-(1H-pyrazole-1-yl)benzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-cyclopropoxy-N-(2-hydroxyethyl)benzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)-3-fluorophenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (E)-N-(2-hydroxyethyl)-3-isopropoxy-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)amino)methyl)phenyl)benzenesulfonamide,

[0021] (E)-3-(tert-butoxy)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)benzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-5-isopropoxy-2-methoxybenzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-5-isopropoxy-2-methylbenzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-2-fluoro-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-2-methoxy-5-propoxybenzenesulfonamide (E)-3-(benzyloxy)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)benzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-(cyclopropylmethoxy)-N-(2-hydroxyethyl)benzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-(prop-2-in-1-yloxy)benzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-cyclobutoxy-N-(2-hydroxyethyl)benzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-(cyclopentyloxy)-N-(2-hydroxyethyl)benzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-propoxybenzenesulfonamide

[0022] (E)-3-butoxy-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)benzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-((3-methylbuto-2-en-1-yl)oxy)benzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-(pentyloxy)benzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-(neopentyloxy)benzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-(cyclobutylmethoxy)-N-(2-hydroxyethyl)benzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-2'-methoxy-[1,1'-biphenyl]-3-sulfonamide (E)-N-(2-hydroxyethyl)-3-methoxy-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)amino)methyl)phenyl)benzenesulfonamide (E)-3-cyclopropoxy-N-(2-hydroxyethyl)-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)amino)methyl)phenyl)benzenesulfonamide (E)-3-(benzofuran-3-yl)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)benzenesulfonamide (E)-3-(benzofuran-2-yl)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)benzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3'-methoxy-[1,1'-biphenyl]-3-sulfonamide

[0023] (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-4'-methyl-[1,1'-biphenyl]-3-sulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-(2,22-Trifluoroethoxy)benzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)-4-fluorophenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-2-fluoro-N-(2-hydroxyethyl)-5-isopropoxybenzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)-5-fluorophenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (E)-N-(2-hydroxyethyl)-3-isopropoxy-N-(2-(((3-(4-methoxyphenyl)allyl)(methyl)amino)methyl)phenyl)benzenesulfonamide (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)-6-fluorophenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (E)-N-(2-(((3-(4-cyanophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (E)-N-(2-(((3-(5-chloropyridine-2-yl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide N-(2-((((6-chloro-1H-indole-2-yl)methyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide N-(2-((((5-chloro-1H-indole-2-yl)methyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (E)-N-(2-(((3-(5-chloropyridine-2-yl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-2-methoxy-5-propoxybenzenesulfonamide,

[0024] (E)-N-(2-(((3-(5-chloropyridine-2-yl)allyl)(methyl)amino)methyl)phenyl)-5-(cyclobutylmethoxy)-N-(2-hydroxyethyl)-2-methoxybenzenesulfonamide (E)-N-(2-(1-((3-(4-chlorophenyl)allyl)(methyl)amino)ethyl)phenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (S,E)-N-(2-(1-((3-(4-chlorophenyl)allyl)(methyl)amino)ethyl)phenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (R,E)-N-(2-(1-((3-(4-chlorophenyl)allyl)(methyl)amino)ethyl)phenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide

[0025] The salt of compound (I) of the present invention may be any pharmaceutically acceptable salt, such as an acid addition salt. Examples of inorganic acids for forming such a salt include hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, nitric acid, sulfuric acid, phosphoric acid, subphosphoric acid, metaphosphoric acid, pyrophosphoric acid, and the like. In addition, organic acids include, for example, acetic acid, phenylacetic acid, trifluoroacetic acid, acrylic acid, ascorbic acid, benzoic acid, chlorobenzoic acid, dinitrobenzoic acid, hydroxybenzoic acid, methoxybenzoic acid, methylbenzoic acid, o-acetoxybenzoic acid, naphthalene-2-carboxylic acid, isobutyric acid, phenylbutyric acid, α-hydroxybutyric acid, butane-1,4-dicarboxylic acid, hexane-1,6-dicarboxylic acid, capric acid, caproic acid, cinnamic acid, citric acid, formic acid, fumaric acid, glycolic acid, heptanoic acid, hippuric acid, lactic acid, malic acid, maleic acid, hydroxymaleic acid, malonic acid, mandelic acid, mesylic acid, Examples include nicotinic acid, isonicotinic acid, phthalic acid, terephthalic acid, propiolic acid, propionic acid, phenylpropionic acid, salicylic acid, sebacic acid, succinic acid, suberic acid, benzenesulfonic acid, bromobenzenesulfonic acid, chlorobenzenesulfonic acid, ethylsulfonic acid, 2-hydroxyethylsulfonic acid, methylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, p-toluenesulfonic acid, xylenesulfonic acid, tartaric acid, lactic acid, citric acid, camphorsulfonic acid, and the like.

[0026] Furthermore, compound (I) of the present invention may exist in the form of a solvate, such as a hydrate, and this solvate is also included in the present invention. Moreover, compound (I) of the present invention may have optical isomers, and these isomers are also included in the present invention. It is usually obtained as a racemic mixture. These racemic mixtures are pharmacologically active as they are, but can be separated into their respective isomers as desired. For example, isomer mixtures can be separated by known optical resolution methods, such as generating salts with optically active carboxylic acids (e.g., (+)- or (-)-tartaric acid, (+)- or (-)-malic acid) or optically active sulfonic acids (e.g., (+)-camphor sulfonic acid) and performing fractional crystallization, or by using an optically active column. Optical isomers can also be obtained by using optically active starting compounds (S configuration or R configuration).

[0027] Compound (I) of the present invention can be produced by various methods, as described in, but not limited to, the following schemes and examples.

[0028]

[0029] (R1 to R6 are as described above. X represents a leaving group, and Y represents a protecting group for a hydroxyl group.)

[0030] As shown in Scheme 1, in step 1, compound A is subjected to a nucleophilic substitution reaction to obtain compound B. For example, compound A and an alkylamine compound are reacted in amounts of 5 to 10 equivalents in a solvent such as methanol, acetonitrile, or tetrahydrofuran. In the following step 2, compound B is N-alkylated to obtain compound C. For example, compound B and an aldehyde compound are reacted in amounts of 1 to 3 equivalents using sodium cyanoborohydride or sodium triacetoxyborohydride in a solvent such as methanol, acetonitrile, or tetrahydrofuran. In the following step 3, the nitro group of compound C is reduced to obtain compound D. For example, compound C and a metal such as zinc, iron, or tin are reacted in amounts of 2 to 5 equivalents in a mixed solvent of a solvent such as ethanol or methanol and hydrochloric acid or acetic acid. In the following step 4, compound D is sulfonylated to obtain compound E. For example, compound D and a sulfonyl chloride compound are reacted in amounts of 1 to 1.5 equivalents in pyridine. In the following step 5, compound E is N-alkylated to obtain compound F. For example, compound E and an alkyl halide compound are reacted in amounts of 1 to 1.5 equivalents in a solvent such as tetrahydrofuran, acetonitrile, or N,N-dimethylformamide, in the presence of potassium carbonate, cesium carbonate, or sodium hydride. Alternatively, compound E and an alkyl alcohol compound are reacted in amounts of 1 to 1.5 equivalents in the presence of triphenylphosphine and diisopropyl azodicarboxylic acid. Finally, in step 6, the hydroxyl group of compound F is deprotected to obtain the compound of formula (I) of the present invention. For example, in a solvent such as tetrahydrofuran, methanol, or ethanol, silyl protecting groups are reacted under fluorine anionic or acidic conditions, while ester protecting groups are reacted under alkaline hydrolysis conditions. The reactions in steps 1 to 6 above may be carried out at a temperature of room temperature to 100°C for 1 to 24 hours.

[0031]

[0032] (R1 to R6 are as described above. X represents a leaving group, and Y represents a protecting group for a hydroxyl group.)

[0033] As shown in Scheme 2, in step 1, compound G is N-sulfonylated to obtain compound H. For example, a sulfonyl chloride compound is reacted with compound G in a solvent such as pyridine in an amount of 1 to 1.5 equivalents. In the following step 2, compound H is N-alkylated to obtain compound I. For example, a solvent such as tetrahydrofuran, acetonitrile, or N,N-dimethylformamide is reacted with an alkyl halide compound in an amount of 1 to 1.5 equivalents in the presence of potassium carbonate, cesium carbonate, or sodium hydride. In the following step 3, the hydroxyl group of compound I is converted to a leaving group to obtain compound J. For example, a solvent such as dichloromethane or tetrahydrofuran is reacted with a methanesulfonyl chloride or p-toluenesulfonyl chloride in an amount of 1 to 1.5 equivalents. In the following step 4, compound J is subjected to a nucleophilic substitution reaction to obtain compound K. For example, a solvent such as methanol, acetonitrile, or tetrahydrofuran is reacted with an alkylamine compound in an amount of 5 to 10 equivalents. In the following step 5, compound K is N-alkylated to obtain compound F. For example, compound K and the aldehyde compound are reacted in 1 to 3 equivalents using sodium cyanoborohydride or sodium triacetoxyborohydride in a solvent such as methanol, acetonitrile, or tetrahydrofuran. In the final step 6, the compound of formula (I) of the present invention is obtained using the same method as in scheme 1. The reactions in steps 1 to 6 above can be carried out at a temperature of room temperature to 100°C for 1 to 24 hours.

[0034] Compound (I) of the present invention can be made to form the aforementioned salts by known methods. For example, the hydrochloride salt of Compound (I) of the present invention can be obtained by dissolving it in an alcoholic solution of hydrogen chloride or an ethyl ether solution. Solvates (including hydrates) may be obtained by recrystallizing Compound (I) or its salt from a suitable solvent (including water). These solvates are also included in the present invention. For example, the hydrate of Compound (I) of the present invention may be obtained by recrystallizing it from an aqueous alcohol. Compound (I) of the present invention may take on crystalline polymorphisms. These crystalline polymorphisms are also included in the present invention. Compound (I) of the present invention thus produced can be isolated and purified in the form of a free base or an acid addition salt by means known to the present invention, for example, by concentration, liquid-to-liquid conversion, transsolution, solvent extraction, crystallization, fractional distillation, and chromatography.

[0035] Compound (I) of the present invention has excellent SET inhibitory activity, as shown in the examples described below. Therefore, Compound (I) of the present invention is useful as a therapeutic and / or prophylactic agent for cancer. Compound (I) of the present invention shows only low to moderate inhibition of CaMK2, which is mainly inhibited by KN-93 described in Patent Document 1, at concentrations of 10 μM or higher, but strongly inhibits SET at concentrations of 0.1 to 1 μM. That is, because Compound (I) of the present invention has a strong inhibitory activity on SET and good selectivity, administering Compound (I) of the present invention to cancer patients as a SET inhibitor restores the activity of PP2A, a tumor suppressor, and as a result, can exhibit a cancer suppression effect. Therefore, another aspect of the present invention is a pharmaceutical composition containing a benzenesulfonamide compound represented by formula (I), a salt thereof, or a solvate thereof. Another aspect of the present invention is a benzenesulfonamide compound represented by formula (I), a salt thereof, or a solvate thereof, used for the treatment and / or prevention of cancer. Another aspect of the present invention is the use of a benzenesulfonamide compound represented by formula (I), a salt thereof, or a solvate thereof for the manufacture of a drug for the treatment and / or prevention of cancer. Another aspect of the present invention is a method for treating and / or preventing cancer, characterized by administering a benzenesulfonamide compound represented by formula (I), a salt thereof, or a solvate thereof.

[0036] The tumors that can be treated with the pharmacotherapy of the present invention are not particularly limited, but include carcinomas, sarcomas, brain tumors, hematopoietic tumors, etc. Carcinomas are not particularly limited, but include head and neck cancers (oral cancer, pharyngeal cancer, laryngeal cancer, nasal cavity cancer, paranasal sinus cancer, salivary gland cancer, thyroid cancer, etc.), digestive system cancers (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancers (gallbladder and bile duct cancers, etc.), pancreatic cancer, colorectal cancers (colon cancer, rectal cancer, etc.)), lung cancers (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), breast cancer, reproductive system cancers (ovarian cancer, uterine cancers (cervical cancer, endometrial cancer, etc.)), urinary system cancers (kidney cancer, bladder cancer, prostate cancer, testicular tumors, etc.), skin cancer, etc. Sarcomas are not particularly limited, but include bone tumors and soft tissue tumors, etc. Hematopoietic tumors are not particularly limited, but include leukemia, malignant lymphoma, multiple myeloma, etc. Leukemia is not particularly limited, but includes acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, adult T-cell leukemia, myelodysplastic syndrome, and hairy cell leukemia. Malignant lymphoma is not particularly limited, but includes Hodgkin lymphoma and non-Hodgkin lymphoma, with non-Hodgkin lymphomas including B-cell lymphoma, T / NK-cell lymphoma, and lymphoblastic lymphoma. Brain tumors are not particularly limited, but examples include metastatic brain tumors (e.g., brain metastases from lung cancer, breast cancer, gastric cancer, colorectal cancer, bladder cancer, biliary tract cancer, uterine cancer, etc.), pilocytic astrocytoma, diffuse astrocytoma, oligodendroglioma / oligoastrocytoma, anaplastic astrocytoma / anaplastic oligodendroglioma, anaplastic oligoastrocytoma, glioblastoma, ependymoma, anaplastic ependymoma, ganglioglioma, central neurocytoma, medulloblastoma, germinoma, central nervous system lymphoma, meningioma, schwannoma, GH-producing pituitary adenoma, PRL-producing pituitary adenoma, ACTH-producing pituitary adenoma, non-functional pituitary adenoma, craniopharyngioma, chordoma, hemangioblastoma, epithelioidoma, etc. Breast cancer, pancreatic cancer, colorectal cancer, and leukemia are more preferred as cancers to be treated in this invention.

[0037] Compound (I) of the present invention can be administered alone or in the form of a pharmaceutical composition. The composition is a combination of Compound (I) of the present invention and a pharmaceutically acceptable carrier, the ratio and properties of which are determined by the chemical properties and solubility of the selected compounds, the route of administration, and standard pharmaceutical practice. That is, another aspect of the present invention is a pharmaceutical composition containing Compound (I) of the present invention and a pharmaceutically acceptable carrier. Compound (I) of the present invention can be administered by various routes. In order to effectively treat patients with the diseases described herein, Compound (I) of the present invention can be administered in any form or by any method that allows the body to utilize an effective amount thereof, including oral and parenteral administration. For example, Compound (I) of the present invention can be administered orally, by inhalation, or subcutaneously, intramuscularly, intravenously, transdermally, transnasally, rectally, transdermally, topically, sublingually, orally, or otherwise. More specific dosage forms include tablets, capsules, granules, powders, aerosols, inhalants, suppositories, solutions, suspensions, topical applications, etc. Oral preparations such as tablets, capsules, granules, and powders can be prepared by combining the compound of the present invention with, as necessary, excipients such as lactose, mannitol, starch, crystalline cellulose, light anhydrous silicic acid, calcium carbonate, and calcium hydrogen phosphate; lubricants such as stearic acid, magnesium stearate, and talc; binders such as starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone; disintegrants such as carboxymethylcellulose, low-substituted hydroxypropyl methylcellulose, and calcium citrate; coating agents such as hydroxypropyl methylcellulose, macrogol, and silicone resin; stabilizers such as ethyl parahydroxybenzoate and benzyl alcohol; and flavoring and odor-modifying agents such as sweeteners, acidulants, and fragrances.Furthermore, in the case of liquid formulations such as injectable drugs, for example, isotonic agents such as glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, and mannitol; buffering agents such as phosphoric acid, phosphates, citric acid, glacial acetic acid, ε-aminocaproic acid, and trometamol; pH adjusters such as hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate; and soluble compounds such as polysorbate 80, polyoxyethylene hydrogenated castor oil 60, macrogol 4000, refined soy lecithin, and polyoxyethylene (160) polyoxypropylene (30) glycol. The present invention compound can be prepared by combining, as needed, a flaking agent or dispersant, cellulosic polymers such as hydroxypropyl methylcellulose and hydroxypropylcellulose, thickeners such as polyvinyl alcohol and polyvinylpyrrolidone, stabilizers such as edetic acid and sodium edetate, preservatives or antiseptics such as general-purpose sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate, and chlorobutanol, and analgesics such as chlorobutanol, benzyl alcohol, and lidocaine. In the case of an injectable preparation, it is desirable to set the pH to 4.0 to 8.0 and the osmotic pressure ratio to around 1.0.

[0038] The dosage of compound (I) of the present invention can be appropriately selected and used depending on the symptoms, age, dosage form, etc. For example, if administered orally, it can usually be administered at a dose of 0.01 to 1000 mg per day, preferably 1 to 100 mg, in one or several divided doses. If administered by injection, it can usually be administered at a concentration of 0.0001% to 10% (w / v), preferably 0.01% to 5% (w / v), in one or several divided doses. For intravenous administration, the range is 0.1 to 100 mg / person per day, preferably 1 to 30 mg / person. For oral administration, the range is 1 to 1,000 mg / person per day, preferably 10 to 30 mg / person. In some cases, a lower dose may suffice, or conversely, a higher dose may be required. It can also be administered in two to three divided doses per day.

[0039] The present invention will now be described in more detail with reference to examples, but the present invention is not limited in any way to these examples.

[0040] <Reference Example 1> Synthesis of (E)-2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)aniline (3a) and (E)-2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)amino)methyl)aniline (3b)

[0041]

[0042] As shown in Scheme 3, methyl[(2-nitrophenyl)methyl]amine (compound 1) (10.0 g) was dissolved in THF (200 mL), (E)-3-(4-chlorophenyl)acrylaldehyde (10.0 g) and sodium triacetoxyborate (25.5 g) were added, and the mixture was stirred at room temperature for 28 hours. Ice water and saturated sodium bicarbonate aqueous solution were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 9 / 1 to 5 / 1) to obtain compound 2a (yield 342 mg, yield 93%, TLC Rf value 0.51 at n-hexane / ethyl acetate = 4 / 1). Next, compound 2a (8.00 g) was dissolved in a mixed solvent of THF (50 mL), ethanol (10 mL), and water (10 mL). Under ice cooling, ammonium chloride (6.75 g) and zinc (8.26 g) were added, and the mixture was stirred at room temperature for 3 hours. Celite filtration was performed, and the mixture was concentrated under reduced pressure. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration was performed, and the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4 / 1 to 3 / 1) to obtain the title compound 3a (yield 6.00 g, yield 75%, TLC Rf value 0.22 at n-hexane / ethyl acetate = 9 / 1).

[0043] As shown in Scheme 3, compound 3b was obtained from compound 1 in the same manner as the method used to obtain compound 3a from compound 1, but by using (E)-3-(4-(trifluoromethyl)phenyl)acrylaldehyde instead of (E)-3-(4-chlorophenyl)acrylaldehyde (yield 1.80 g, 2-step yield 36%, TLC Rf value 0.11 at n-hexane / ethyl acetate = 9 / 1).

[0044] <Reference Example 2> Synthesis of (E)-2-(((3-(4-chlorophenyl)allyl)(ethyl)amino)methyl)aniline (7a), (E)-2-(((3-(4-chlorophenyl)allyl)(cyclopropyl)amino)methyl)aniline (7b), (E)-2-(((3-(4-chlorophenyl)allyl)(2-fluoroethyl)amino)methyl)aniline (7c), and (E)-2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)-3-fluoroaniline (7d)

[0045]

[0046] As shown in Scheme 4, 2-nitrobenzyl chloride (compound 4a) (1.00 g) was dissolved in methanol (10 mL), 33% aqueous ethylamine solution (8 mL) was added, and the mixture was stirred at room temperature for 72 hours. The mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1 to 40 / 1) to obtain compound 5a (yield 956 mg, yield 91%, TLC Rf value 0.11 at n-hexane / ethyl acetate = 4 / 1). Subsequently, compound 5a (200 mg) was dissolved in THF (10 mL), (E)-3-(4-chlorophenyl)acrylaldehyde (200 mg) and sodium triacetoxyborate (275 mg) were added, and the mixture was stirred at room temperature for 18 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4 / 1) to obtain compound 6a (yield 342 mg, yield 93%, TLC Rf value 0.62 at n-hexane / ethyl acetate = 4 / 1). Subsequently, compound 6a (342 mg) was dissolved in a mixed solvent of 6N hydrochloric acid (3 mL) and acetic acid (3 mL), cooled on ice, tin (400 mg) was added, and the mixture was stirred at room temperature for 18 hours. Water and sodium bicarbonate were added to neutralize the mixture, and it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4 / 1) to obtain the title compound 7a (yield 304 mg, yield 98%, TLC Rf value 0.45 at n-hexane / ethyl acetate = 4 / 1).

[0047] As shown in Scheme 4, compound 7b was obtained from compound 4a by using cyclopropylamine instead of ethylamine in the same manner as in which compound 7a was obtained from compound 4a (yield 531 mg, 3-step yield 72%, TLC Rf value 0.48 at n-hexane / ethyl acetate = 4 / 1). As shown in Scheme 4, compound 7c was obtained from compound 4a by using 2-fluoroethylamine hydrochloride instead of ethylamine in the same manner as in which compound 7a was obtained from compound 4a (yield 1.38 g, 3-step yield 73%, TLC Rf value 0.48 at n-hexane / ethyl acetate = 4 / 1). As shown in Scheme 4, compound 7d was obtained in the same manner as the method used to obtain compound 7a from compound 4a above, but by using 2-fluoro-6-nitrobenzyl bromide 4d instead of 2-nitrobenzyl chloride and a 40% aqueous methylamine solution instead of ethylamine (yield 635 mg, 3-step yield 50%, TLC Rf value 0.42 at n-hexane / ethyl acetate = 4 / 1).

[0048] <Reference Example 3> Synthesis of 3-isopropoxybenzenesulfonyl chloride (11)

[0049]

[0050] As shown in Scheme 5, 3-bromophenol (compound 8) (2.00 g) was dissolved in DMF (20 mL), potassium carbonate (4.60 g), isopropyl iodide (2.55 g), and a catalytic amount of sodium iodide were added, and the mixture was stirred at 70°C for 18 hours. After returning to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4 / 1) to obtain compound 9 (yield 2.00 g, yield 80%, TLC Rf value 0.85 at n-hexane / ethyl acetate = 4 / 1). Next, under a nitrogen atmosphere, compound 9 (2.00 g) was dissolved in anhydrous 1,4-dioxane (30 mL), and Pd2(dba)3 (412 mg), xanthophos (537 mg), DIEA (3 mL), and benzyl mercaptan (1.6 mL) were added, and the mixture was stirred at 100°C for 18 hours. After returning to room temperature, the mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4 / 1) to obtain compound 10 (yield 2.49 g, TLC Rf value 0.51 at n-hexane / ethyl acetate = 18 / 1). Next, compound 10 (2.00 g) was dissolved in a mixed solvent of acetonitrile (150 mL), acetic acid (2.5 mL), and water (2 mL), and cooled on ice. 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) (2.95 g) was added, and the mixture was stirred for 3 hours. The compound was concentrated under reduced pressure, dissolved in dichloromethane, and washed with a 5% aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10 / 1) to obtain compound 11 (yield 1.50 g, 2-step yield 68%, TLC Rf value 0.54 at n-hexane / ethyl acetate = 18 / 1).

[0051] <Reference Example 4> Synthesis of 3-((tert-butyldimethylsilyl)oxy)benzenesulfonyl chloride (14)

[0052]

[0053] As shown in Scheme 6, under a nitrogen atmosphere, compound 12 (2.87 g) was dissolved in anhydrous 1,4-dioxane (30 mL), and Pd2(dba)3 (457 mg), xanthophos (579 mg), DIEA (3 mL), and benzyl mercaptan (1.7 mL) were added, and the mixture was stirred at 100°C for 18 hours. After returning to room temperature, the mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 20 / 1) to obtain compound 13 (yield 3.55 g, TLC Rf value 0.62 at n-hexane / ethyl acetate = 4 / 1). Subsequently, compound 13 (3.55 g) was dissolved in a mixed solvent of acetonitrile (200 mL), acetic acid (3.5 mL), and water (3 mL), and cooled on ice. 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) (4.00 g) was added, and the mixture was stirred for 3 hours. The compound was concentrated under reduced pressure, dissolved in dichloromethane, and washed with a 5% aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 20 / 1) to obtain compound 14 (yield 3.27 g, TLC Rf value 0.48 at n-hexane / ethyl acetate = 18 / 1).

[0054] <Reference Example 5> Synthesis of 3-ethoxybenzenesulfonyl chloride (16)

[0055]

[0056] As shown in Scheme 7, 3-ethoxyaniline (compound 15) (2.50 g) was dissolved in concentrated hydrochloric acid (20 mL) and cooled on ice. A solution of sodium nitrite (1.89 g) dissolved in water (5 mL) was slowly added and stirred for 20 minutes (reaction solution A). Separately, acetic acid (2.5 mL) was dissolved in water (25 mL) and cooled on ice. SO2 gas was blown into this solution and stirred for 20 minutes. Copper(I) chloride (451 mg) was then added, and SO2 gas was blown in again and stirred for 20 minutes (reaction solution B). Reaction solution A was added to reaction solution B and stirred at room temperature for 2 hours, then diethyl ether was added and extracted. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4 / 1 to 3 / 1) to obtain compound 16 as indicated in the title (yield 1.50 g, yield 37%, TLC Rf value 0.44 at n-hexane / ethyl acetate = 3 / 1).

[0057] <Reference Example 6> Synthesis of (E)-3-(5-chloropyridine-2-yl)acrylaldehyde (18)

[0058]

[0059] As shown in Scheme 8, 5-chloropyridine-2-carbaldehyde (compound 17) (711 mg) was dissolved in THF (20 mL), (formylmethylene)triphenylphosphorane (2.00 g) was added, and the mixture was stirred at 70°C for 3 hours. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 3 / 1) to obtain compound 18 (yield 440 mg, yield 52%, TLC Rf value 0.34 at n-hexane / ethyl acetate = 4 / 1).

[0060] <Example 1> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-isopropylbenzenesulfonamide (204)

[0061]

[0062] As shown in Scheme 9, compound 3a (287 mg) obtained in Reference Example 1 was dissolved in pyridine (5 mL), and under ice cooling, commercially available 3-isopropylbenzenesulfonyl chloride (224 mg) was added and the mixture was stirred at room temperature for 3 hours. Toluene was added and the mixture was concentrated under reduced pressure. Water was added and extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 3 / 1) to obtain compound 19 (yield 431 mg, yield 91%, TLC Rf value 0.44 at n-hexane / ethyl acetate = 4 / 1). Subsequently, compound 19 (209 mg) was dissolved in anhydrous THF (10 mL), and under ice cooling, 2-hydroxyethyl benzoate (82 mg), triphenylphosphine (234 mg), and diisopropyl azodicarboxylate (DIAD) (0.12 mL) were added and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 3 / 1) to obtain compound 20 (yield 236 mg, yield 85%, TLC Rf value 0.50 in n-hexane / ethyl acetate = 3 / 1). Subsequently, compound 20 (236 mg) was dissolved in a mixed solvent of methanol (4 mL) and THF (3 mL), and under ice cooling, 2 M aqueous sodium hydroxide solution (0.58 mL) was added and the mixture was stirred at room temperature for 3 hours. Saturated saline solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 2 to ethyl acetate) to obtain the title compound 204 (yield 189 mg, yield 96%, TLC Rf value 0.55 in ethyl acetate). 1HNMR (500MHz, CDCl3) δ1.19 (d, J = 6.5Hz, 3H), 1.20 (d, J = 6.5Hz, 3H), 2.20 (s, 3H), 2.81-2.96 (m, 2H), 3.04 (dd, J = 13.0, 2.5 Hz, 1H), 3.20-3.27 (m, 2H), 3.41 (dd, J=14.0, 6.5Hz, 1H), 3.64-3.68 (m, 1H), 4.06-4.11 (m, 1H), 4.99 (d, J=12.5Hz, 1H), 6.3 4 (d, J=8.0Hz, 1H), 6.34 (dt, J=15.5, 7.0Hz, 1H), 6.69 (d, J=15.5Hz, 1H), 7.13 (td, J=7.5, 1.0Hz, 1H), 7.24-7.27 (m, 3H), 7. 31 (d, J=6.0Hz, 1H), 7.35 (brs, 1H), 7.38-7.39 (m, 2H), 7.41 (d, J=7.5Hz, 1H), 7.45 (d, J=7.5Hz, 1H), 7.48 (d, J=7.5Hz, 1H).

[0063] <Example 2> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(ethyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (205)

[0064]

[0065] (E)-2-((N-(2-(((3-(4-chlorophenyl)allyl)(ethyl)amino)methyl)phenyl)-3-isopropoxyphenyl)sulfonamide)ethylbenzoate was obtained by using compound 7a obtained in Reference Example 2 and 3-isopropoxybenzenesulfonyl chloride (compound 11) obtained in Reference Example 3 in the same manner as in Example 1. Finally, the title compound 205 was obtained by hydrolysis (yield 142 mg, yield 65%, TLC Rf value 0.25 in n-hexane / ethyl acetate = 1 / 1). 1HNMR (500MHz, CDCl3) δ1.19 (t, J = 7.0Hz, 3H), 1.26 (d, J = 6.0Hz, 3H), 1.29 (d, J = 6.0Hz, 3H), 2.33-2.37 (m, 1H), 2.7 9-2.84 (m, 1H), 2.98-3.13 (m, 3H), 3.27 (dd, J = 12.0, 8.0Hz, 1H), 3.52 (dd, J = 13.5, 4.5Hz, 1H), 3.68 (d, J = 13.0Hz, 1H), 4.07-4.11 (m, 1H), 4.42-4.48 (m, 1H), 4.98 (d, J = 12.5Hz, 1H), 6.33-6.38 (m, 1H), 6.42 (d, J = 8.0Hz, 1H), 6.49 (d, J=15.5Hz, 1H), 7.03 (brs, 1H), 7.09 (d, J=8.5Hz, 1H), 7.12-7.16 (m, 2H), 7.22-7.26 (m, 2H), 7.31-7.38 (m, 5H).

[0066] <Example 3> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(cyclopropyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (207)

[0067]

[0068] In the same manner as in Example 1, compound 7b obtained in Reference Example 2 and 3-isopropoxybenzenesulfonyl chloride (compound 11) obtained in Reference Example 3 were used to obtain (E)-2-((N-(2-(((3-(4-chlorophenyl)allyl)(ethyl)amino)methyl)phenyl)-3-isopropoxyphenyl)sulfonamide)ethylbenzoate. Finally, hydrolysis was performed to obtain the title compound 207 (yield 101 mg, 2-step yield 41%, TLC Rf value 0.28 in n-hexane / ethyl acetate = 3 / 1). 1HNMR (500MHz, CDCl3) δ0.19 (brs, 1H), 0.38-0.42 (m, 1H), 0.51-0.55 (m, 1H), 0.74 (brs, 1H), 1.26 (d, J = 6.0Hz, 3H), 1.2 9 (d, J = 6.0Hz, 3H), 1.85-1.87 (m, 1H), 3.04-3.07 (m, 1H), 3.17-3.28 (m, 3H), 3.54-3.61 (m, 2H), 4.02-4.07 (m, 1H), 4.42 -4.49 (m, 1H), 5.05 (d, J = 12.5Hz, 1H), 6.39-6.46 (m, 2H), 6.51 (d, J = 16.0Hz, 1H), 7.03 (brs, 1H), 7.09 (dd, J = 9.0, 2.0H z, 1H), 7.12 (dd, J = 8.0, 2.0Hz, 1H), 7.15 (d, J = 7.5Hz, 1H), 7.22-7.27 (m, 3H), 7.36-7.37 (m, 3H), 7.39 (d, J = 7.5Hz, 1H).

[0069] <Example 4> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(2-fluoroethyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (228)

[0070]

[0071] In the same manner as in Example 1, compound 7c obtained in Reference Example 2 and 3-isopropoxybenzenesulfonyl chloride (compound 11) obtained in Reference Example 3 were used to obtain (E)-2-((N-(2-(((3-(4-chlorophenyl)allyl)(2-fluoroethyl)amino)methyl)phenyl)-3-isopropoxyphenyl)sulfonamide)ethylbenzoate. Finally, hydrolysis was performed to obtain the title compound 228 (yield 27 mg, yield 13%, TLC Rf value 0.12 at n-hexane / ethyl acetate = 4 / 7). 1HNMR (500MHz, CDCl3) δ1.26 (d, J = 6.0Hz, 3H), 1.31 (d, J = 6.0Hz, 3H), 2.72-2.80 (m, 1H), 2.97-3.08 (m, 1H), 3.13 (dd, J = 1 2.5, 2.5Hz, 1H), 3.16-3.23 (m, 2H), 3.26-3.30 (m, 1H), 3.61 (dd, J=13.5, 5.0Hz, 1H), 3.68 (dt, J=13.0, 4.0Hz, 1H), 4.07 -4.13 (m, 1H), 4.41-4.49 (m, 1H), 4.59-4.79 (m, 2H), 5.02 (d, J = 12.5Hz, 1H), 6.32-6.39 (m, 1H, 6.44 (d, J = 7.5Hz, 1H), 6. 52 (d, J=16.0Hz, 1H), 7.03 (m, 1H), 7.09 (dd, J=9.0, 2.5Hz, 1H), 7.13-7.17 (m, 2H), 7.24-7.27 (m, 3H), 7.33-7.38 (m, 4H).

[0072] <Example 5> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-ethoxy-N-(2-hydroxyethyl)benzenesulfonamide (174)

[0073]

[0074] As shown in Scheme 10, compound 21 was obtained by reacting compound 3a obtained in Reference Example 1 with 3-ethoxybenzenesulfonyl chloride (compound 16) obtained in Reference Example 5 in the same manner as in Example 1 (yield 480 mg, yield 72%, Rf value 0.20 at n-hexane / ethyl acetate = 7 / 3). Subsequently, compound 21 (480 mg) was dissolved in DMF (6 mL), potassium carbonate (423 mg) and 2-iodoethyl benzoate (281 mg) were added, and the mixture was stirred at 80°C for 16 hours. After returning to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4 / 1 to 3 / 1) to obtain compound 22 (yield 550 mg, yield 81%, Rf value 0.18 at n-hexane / ethyl acetate = 3 / 1). Next, compound 22 (550 mg) was dissolved in a mixed solvent of THF (8 mL), methanol (2 mL), and water (2 mL), lithium hydroxide (54 mg) was added, and the mixture was stirred at room temperature for 16 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 2 / 3 to 2 / 5) to obtain compound 174 (yield 133 mg, yield 29%, TLC Rf value 0.28 at n-hexane / ethyl acetate = 3 / 7). 1 HNMR (400MHz, DMSO-d6) δ1.31 (t, J = 7.0Hz, 3H), 2.12 (s, 3H), 3.11-3.28 (m, 5H), 3.37-3.40 (m, 1H), 3.84-3.89 (m, 1H), 3.95-4.08 (m, 2H), 4.27 (d, J = 12.8Hz, 1H), 6.00 (brs, 1H), 6.39 (dt, J = 1 6.0, 6.0Hz, 1H), 6.57 (d, J = 8.0Hz, 1H), 6.61 (d, J = 16.0Hz, 1H), 6.99 (brs, 1H), 7.14 (d, J = 8.4Hz , 1H), 7.21 (t, J=8.4Hz, 1H), 7.27 (dd, J=8.2, 2.2Hz, 1H), 7.32-7.38 (m, 3H), 7.48-7.53 (m, 4H).

[0075] <Example 6> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-methoxybenzenesulfonamide (130)

[0076]

[0077] (E)-2-((N-(2-(((3-(4-chlorophenyl)allyl)(methyl)aminomethyl)phenyl)-3-methoxyphenyl)sulfonamide)ethylbenzoate was obtained by using commercially available 3-methoxybenzenesulfonyl chloride in the same manner as in Example 5. Finally, the title compound 130 was obtained by hydrolysis (yield 70 mg, yield 40%, TLC Rf value 0.14 at n-hexane / ethyl acetate = 3 / 7). 1 HNMR (400MHz, DMSO-d6) δ2.12 (s, 3H), 3.11-3.28 (m, 5H), 3.35-3.41 (m, 1H), 3.77 (s, 3H), 3.84-3.90 (m, 1H), 4.28 (d, J = 16.5Hz, 1H), 6.00-6.03 (m, 1H), 6.40 (td, J = 16.8, 6.4Hz, 1H), 6.58 (d, J = 8.4Hz, 1H), 6.61 (d, J=16.8Hz, 1H), 7.00 (t, J=2.0Hz, 1H), 7.16 (d, J=8.0Hz, 1H), 7.22 (td, J=7.8, 1.6Hz, 1H), 7.29 (dd, J =8.0, 2.0Hz, 1H), 7.34 (d, J = 7.6Hz, 1H), 7.38 (d, J = 8.4Hz, 2H), 7.49 (d, J = 8.4Hz, 2H), 7.52-7.55 (m, 2H).

[0078] <Example 7> Synthesis of (E)-N-(2-hydroxyethyl)-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)aminomethyl)phenyl)-[1,1'-biphenyl]-3-sulfonamide (178)

[0079]

[0080] (E)-2-(N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)aminomethyl)phenyl)-[1,1'-biphenyl]-3-sulfonamide)ethylbenzoate was obtained by using 3b obtained in Reference Example 1 and [1,1'-biphenyl]-3-sulfonamide] in the same manner as in Example 5. Finally, the title compound 178 was obtained by hydrolysis (yield 75 mg, yield 25%, TLC Rf value 0.15 in n-hexane / ethyl acetate = 2 / 3). 1 HNMR (400MHz, DMSO-d6) δ2.11 (s, 3H), 3.12-3.31 (m, 5H), 3.40-3.43 (m, 1H), 3.88-3.93 (m, 1H), 4.37 (d, J = 12.8Hz, 1H), 6.49-6.58 (m, 2H), 6.69 (d, J = 15. 6Hz, 1H), 7.21 (t, J=7.2Hz, 1H), 7.34-7.42 (m, 2H), 7.46-7.50 (m, 2H), 7.53 ( d, J=9.6Hz, 1H), 7.57-7.59 (m, 3H), 7.64-7.73 (m, 6H), 7.99 (d, J=7.6Hz, 1H).

[0081] <Example 8> Synthesis of (E)-3-ethoxy-N-(2-hydroxyethyl)-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)amino)methyl)phenyl)benzenesulfonamide (182)

[0082]

[0083] (E)-2-((3-ethoxy-N-(2-(((methyl(3-(4-(trifluoromethyl)phenyl)allyl)amino)methyl)phenyl)phenylsulfonamide)ethylbenzoate was obtained using 3b obtained in Reference Example 1, in the same manner as in Example 5. Finally, hydrolysis was performed to obtain compound 182 of the title (yield 26 mg, yield 81%, TLC Rf value 0.10 in n-hexane / ethyl acetate = 1 / 1). 11H NMR (400 MHz, DMSO-d6) δ 1.31 (t, J = 6.8 Hz, 3H), 2.14 (s, 3H), 3.15 - 3.28 (m, 5H), 3.35 - 3.41 (m, 1H), 3.87 - 3.90 (m, 1H), 3.95 - 4.10 (m, 2H), 4.27 (d, J = 13.2 Hz, 1H), 5.95 (brs, 1H), 6.55 (dt, J = 16.0, 6.4 Hz, 1H), 6.58 (d, J = 7.2 Hz, 1H), 6.72 (d, J = 16.0 Hz, 1H), 6.99 (brs, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.27 (dd, J = 8.2, 2.0 Hz, 1H), 7.35 (t, J = 7.0 Hz, 1H), 7.49 - 7.56 (m, 2H), 7.68 (brs, 4H).

[0084] <Example 9> Synthesis of (E)-N-(2-((((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-(trifluoromethyl)benzenesulfonamide (191)

[0085]

[0086] In the same manner as in Example 5, by using commercially available 3-(trifluoromethyl)benzenesulfonyl chloride, (E)-2-((N-(2-((((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-(trifluoromethyl)phenyl)sulfonamido)ethyl benzoate was obtained. Finally, by hydrolysis, the title compound 191 was obtained (yield 229 mg, yield 45%, Rf value of TLC in n-hexane / ethyl acetate = 3 / 7: 0.20). 1HNMR (400MHz, DMSO-d6) δ2.09 (s, 3H), 3.09-3.17 (m, 3H), 3.23-3.25 (m, 2H), 3.37-3.42 (m, 1H), 3.85-3.91 (m, 1H), 4.32 (d, J = 12.8Hz, 1H), 6.36 (dt, J = 16.0, 6.8Hz, 1H), 6.50 (d, J = 9.5Hz, 1H), 6.59 (d, J=16.0Hz, 1H), 7.19 (t, J=7.8Hz, 1H), 7.35-7.38 (m, 3H), 7.47-7.49 (m, 2H), 7.53 (d, J= 7.6Hz, 1H), 7.65 (brs, 1H), 7.87 (t, J=7.8Hz, 1H), 7.94 (d, J=8.4Hz, 1H), 8.10 (d, J=7.6Hz, 1H).

[0087] <Example 10> Synthesis of (E)-3-ethynyl-N-(2-hydroxyethyl)-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)amino)methyl)phenyl)benzenesulfonamide (193)

[0088]

[0089] (E)-2-((3-ethynyl-N-(2-(((methyl(3-(4-(trifluoromethyl)phenyl)allyl)aminomethyl)phenyl)phenyl)sulfonamide)ethylbenzoate was obtained by using compound 3b obtained in Reference Example 1 and 3-ethynylbenzenesulfonyl chloride obtained in the same manner as in Reference Example 5. Finally, hydrolysis was performed to obtain compound 193 of the title (yield 560 mg, yield 95%, TLC Rf value 0.15 in n-hexane / ethyl acetate = 3 / 7). 1HNMR (400MHz, DMSO-d6) δ2.15 (s, 3H), 3.18-3.28 (m, 5H), 3.38-3.40 (m, 1H), 3.84 -3.90 (m, 1H), 4.25 (d, J = 13.2Hz, 1H), 4.42 (s, 1H), 5.94 (brs, 1H), 6.55 (dt, J = 16 .. 0, 6.4Hz, 1H), 6.59 (d, J = 8.4Hz, 1H), 6.73 (d, J = 16.0Hz, 1H), 7.22 (t, J = 6.8Hz, 1 H), 7.37 (t, J=7.2Hz, 1H), 7.57-7.65 (m, 4H), 7.68 (s, 4H), 7.82 (d, J=6.8Hz, 1H).

[0090] <Example 11> Synthesis of (E)-N-(2-hydroxyethyl)-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)aminomethyl)phenyl)-3-(1H-1,2,3-triazole-5-yl)benzenesulfonamide (185)

[0091]

[0092] As shown in Scheme 11, compound 193 (400 mg) obtained in Example 10 was dissolved in a mixed solvent of DMF (6 mL) and methanol (1.25 mL), trimethylsilyl azide (218 mg) was added, and the mixture was stirred at 100°C for 16 hours. Water was added, and the mixture was extracted with dichloromethane-methanol (95 / 5). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, pentane was added, and the mixture was stirred at room temperature for 5 hours. The precipitate was filtered and purified by preparative HPLC to obtain compound 185 (yield 15 mg, yield 3%, TLC Rf value 0.13 at n-hexane / ethyl acetate = 1 / 4). 1HNMR (400MHz, DMSO-d6) δ2.15 (s, 3H), 3.14-3.28 (m, 5H), 3.38-3.43 (m, 1H), 3.89-3.94 (m, 1H), 4 .30 (d, J=12.8Hz, 1H), 5.97 (brs, 1H), 6.57 (dt, J=16.0, 6.4Hz, 1H), 6.59 (d, J=8.4Hz, 1H), 6.72 (d , J=16.0Hz, 1H), 7.18 (t, J=7.6Hz, 1H), 7.35 (t, J=7.2Hz, 1H), 7.53 (d, J=8.0Hz, 1H), 7.57 (d, J=8. 0Hz, 1H), 7.68-7.71 (m, 5H), 8.07 (brs, 1H), 8.20 (d, J=8.0Hz, 1H), 8.41 (brs, 1H), 15.2 (brs, 1H).

[0093] <Example 12> Synthesis of (E)-3-bromo-N-(2-(((3-(4-chlorophenyl)allyl)(methylamino)methyl)phenyl)-N-(2-hydroxyethyl)benzenesulfonamide (157)

[0094]

[0095] As shown in Scheme 12, compound 23 was obtained by reacting compound 3a obtained in Reference Example 1 with commercially available 3-bromobenzenesulfonyl chloride in the same manner as in Example 1 (yield 800 mg, yield 85%, Rf value 0.22 at n-hexane / ethyl acetate = 7 / 3). Subsequently, compound 23 (800 mg) was dissolved in DMF (5 mL), potassium carbonate (656 mg) and (2-bromoethoxy)(tert-butyl)dimethylsilane (454 mg) were added, and the mixture was stirred at 80°C for 8 hours. After returning to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4 / 1 to 3 / 1) to obtain compound 24 (yield 900 mg, yield 85%, TLC Rf value 0.42 at n-hexane / ethyl acetate = 7 / 3). Next, compound 24 (200 mg) was dissolved in 1,4-dioxane (1 mL), 4 M hydrochloric acid / 1,4-dioxane (0.2 mL) was added, and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure, neutralized with saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the crude product was purified by preparative HPLC to obtain compound 157 (yield 48 mg, yield 28%, TLC Rf value 0.18 at dichloromethane / methanol = 95 / 5). 1 HNMR (400MHz, DMSO-d6) δ2.14 (s, 3H), 3.17-3.28 (m, 5H), 3.38-3.41 (m, 1H), 3.83- 3.90 (m, 1H), 4.26 (d, J = 12.8Hz, 1H), 6.00 (brs, 1H), 6.40 (dt, J = 16.0, 6.4Hz, 1H), 6.61 (d, J=7.2Hz, 1H), 6.62 (d, J=16.0Hz, 1H), 7.24 (t, J=7.0Hz, 1H), 7.36-7.39 (m , 3H), 7.50 (d, J=8.4Hz, 2H), 7.55-7.60 (m, 3H), 7.66 (brs, 1H), 7.93-7.96 (m, 1H).

[0096] <Example 13> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3,5-dimethoxybenzenesulfonamide (158)

[0097]

[0098] (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3,5-dimethoxybenzenesulfonamide was obtained by using commercially available 3,5-dimethoxybenzenesulfonyl chloride in the same manner as in Example 12. Finally, the TBS group was removed to obtain compound 158 of the title (yield 58 mg, yield 31%, TLC Rf value 0.18 at dichloromethane / methanol = 95 / 5). 1 HNMR (400MHz, DMSO-d6) δ2.12 (s, 3H), 3.11-3.27 (m, 5H), 3.35-3.41 (m, 1H), 3.75 (s, 6 H), 3.83-3.89 (m, 1H), 4.29 (d, J = 13.2Hz, 1H), 6.02 (t, J = 6.2Hz, 1H), 6.39 (dt, J = 15.6 , 6.8Hz, 1H), 6.59-6.66 (m, 4H), 6.83 (t, J=2.4Hz, 1H), 7.24 (td, J=7.6, 1.2Hz, 1H), 7. 34 (d, J=7.2Hz, 1H), 7.37-7.39 (m, 2H), 7.48-7.59 (m, 2H), 7.54 (dd, J=7.6, 1.2Hz, 1H).

[0099] <Example 14> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-(trifluoromethoxy)benzenesulfonamide (166)

[0100]

[0101] (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-(trifluoromethoxy)benzenesulfonamide was obtained by using commercially available 3-(trifluoromethoxy)benzenesulfonyl chloride in the same manner as in Example 12. Finally, the TBS group was removed to obtain compound 166 of the title (yield 20 mg, yield 8%, TLC Rf value 0.25 in n-hexane / ethyl acetate = 1 / 1). 1 HNMR (400MHz, DMSO-d6) δ2.08 (s, 3H), 3.08-3.13 (m, 3H), 3.18-3.28 (m, 2H), 3.3 6-3.41 (m, 1H), 3.84-3.91 (m, 1H), 4.34 (d, J = 12.8Hz, 1H), 6.35 (dt, J = 16.0, 6.4H z, 1H), 6.48 (d, J = 7.6Hz, 1H), 6.59 (d, J = 16.0Hz, 1H), 7.18 (td, J = 7.6, 1.2Hz, 1H) , 7.30-7.37 (m, 4H), 7.46-7.51 (m, 3H), 7.68 (d, J=7.2Hz, 1H), 7.72-7.79 (m, 2H).

[0102] <Example 15> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-ethynyl-N-(2-hydroxyethyl)benzenesulfonamide (167)

[0103]

[0104] Using 3-ethynylbenzenesulfonyl chloride obtained in the same manner as in Example 12 and in the same manner as in Reference Example 5, (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-ethynylbenzenesulfonamide). Finally, by removing the TBS group, the title compound 167 was obtained (yield 86 mg, yield 52%, TLC Rf value 0.16 in n-hexane / ethyl acetate = 2 / 3). 1HNMR (400MHz, DMSO-d6) δ2.12 (s, 3H), 3.13-3.29 (m, 5H), 3.36-3.41 (m, 1H), 3.83-3. 89 (m, 1H), 4.24 (d, J = 13.2Hz, 1H), 4.41 (s, 1H), 5.95 (brs, 1H), 6.40 (dt, J = 6.4Hz, 16. 0Hz, 1H), 6.58 (d, J = 7.6Hz, 1H), 6.61 (d, J = 16.0Hz, 1H), 7.22 (td, J = 7.6, 1.2Hz, 1H), 7.34-7.39 (m, 3H), 7.48-7.50 (m, 2H), 7.55-7.65 (m, 4H), 7.81 (dt, J=6.8, 1.6Hz, 1H).

[0105] <Example 16> Synthesis of (E)-3-(difluoromethoxy)-N-(2-hydroxyethyl)-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)amino)methyl)phenyl)benzenesulfonamide (183)

[0106]

[0107] (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(difluoromethoxy)-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)amino)methyl)phenyl)benzenesulfonamide was obtained by using commercially available 3-(difluoromethoxy)benzenesulfonyl chloride in the same manner as in Example 12. Finally, the TBS group was removed to obtain compound 183 of the title (yield 64 mg, yield 27%, TLC Rf value 0.16 in n-hexane / ethyl acetate = 2 / 3). 1HNMR (400MHz, DMSO-d6) δ2.10 (s, 3H), 3.10-3.22 (m, 4H), 3.30 (dd, J=14.4, 5.6Hz, 1H), 3.37-3.41 (m, 1H), 3.84-3.90 (m, 1H), 4.32 (d, J = 12.8Hz, 1H), 6.48-6.55 (m, 2 H), 6.70 (d, J = 16.0Hz, 1H), 7.01 (s, 1H), 7.18-7.22 (m, 3H), 7.34 (d, J = 7.6Hz, 1H), 7.37 (d, J=3.6Hz, 1H), 7.47 (d, J=8.0Hz, 1H), 7.51-7.54 (m, 2H), 7.63-7.69 (m, 3H).

[0108] <Example 17> Synthesis of (E)-N-(2-hydroxyethyl)-2,5-dimethoxy-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)amino)methyl)phenyl)benzenesulfonamide (190)

[0109]

[0110] (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2,5-dimethoxy-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)amino)methyl)phenyl)benzenesulfonamide was obtained by using commercially available 2,5-dimethoxybenzenesulfonyl chloride in the same manner as in Example 12. Finally, the TBS group was removed to obtain compound 190 of the title (yield 125 mg, yield 39%, TLC Rf value 0.26 at dichloromethane / methanol = 95 / 5). 1HNMR (400MHz, DMSO-d6) δ2.06 (s, 3H), 3.06-3.12 (m, 2H), 3.16-3.23 (m, 2H), 3.37-3.4 2 (m, 1H), 3.45-3.51 (m, 1H), 3.56 (s, 3H), 3.92-3.97 (m, 1H), 4.15 (d, J=13.6Hz, 1H), 6. 47 (dt, J=16.0, 6.4Hz, 1H), 6.65 (d, J=16.0Hz, 1H), 6.79 (d, J=7.6Hz, 1H), 6.85 (d, J=2. 8Hz, 1H), 7.15-7.22 (m, 3H), 7.29 (t, J=7.0Hz, 1H), 7.48 (d, J=6.4Hz, 1H), 7.65 (s, 4H).

[0111] <Example 18> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-phenoxybenzenesulfonamide (192)

[0112]

[0113] Using 3-phenoxybenzenesulfonyl chloride obtained in the same manner as in Example 12 and in the same manner as in Reference Example 5, (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-phenoxybenzenesulfonamide. Finally, by removing the TBS group, the title compound 192 was obtained (yield 110 mg, yield 44%, TLC Rf value 0.15 in n-hexane / ethyl acetate = 2 / 3). 1HNMR (400MHz, DMSO-d6) δ2.11 (s, 3H), 3.10-3.26 (m, 5H), 3.35-3.38 (m, 1H), 3.78-3.85 (m, 1H), 4.23 (d, J = 13.6Hz, 1H), 5.98 (t, J = 6.0Hz, 1H), 6.38 (dt, J = 16.0, 6.4Hz, 1H), 6.58-6.6 2 (m, 2H), 6.88-6.89 (m, 1H), 7.05-7.07 (m, 2H), 7.20 (t, J = 7.6Hz, 1H), 7.25 (td, J = 7.6, 1.4 Hz, 1H), 7.33-7.43 (m, 7H), 7.47-7.49 (m, 2H), 7.51 (d, J = 6.4Hz, 1H), 7.65 (t, J = 8.0Hz, 1H).

[0114] <Example 19> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (195)

[0115]

[0116] In the same manner as in Example 12, (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-isopropoxybenzenesulfonamide was obtained using 3-isopropoxybenzenesulfonyl chloride (compound 11) obtained in Reference Example 3. Finally, the TBS group was removed to obtain compound 195 of the title (yield 94 mg, yield 34%, TLC Rf value 0.19 at n-hexane / ethyl acetate = 2 / 3). 1HNMR (400MHz, DMSO-d6) δ1.18 (d, J = 7.5Hz, 3H), 1.21 (d, J = 7.5Hz, 3H), 2.08 (s, 3H), 3.05-3.26 (m, 4H), 3 .25 (dd, J=14.0, 6.0Hz, 1H), 3.36-3.39 (m, 1H), 3.83-3.89 (m, 1H), 4.33 (d, J=12.8Hz, 1H), 4.48-4.56 (m, 1H), 6.36 (dt, J = 16.0, 6.4Hz, 1H), 6.51 (d, J = 7.6Hz, 1H), 6.58 (d, J = 16.0Hz, 1H), 6.89 (brs, 1H), 7.14 (d , J=8.0Hz, 1H), 7.19 (t, J=8.0Hz, 1H), 7.23 (dd, J=8.4, 2.4Hz, 1H), 7.31-7.36 (m, 3H), 7.46-7.52 (m, 4H).

[0117] <Example 20> Synthesis of (E)-N-(2-hydroxyethyl)-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)amino)methyl)phenyl)-3-(1H-pyrazole-1-yl)benzenesulfonamide (202)

[0118]

[0119] Using 3-(1H-pyrazole-1-yl)benzenesulfonyl chloride obtained in the same manner as in Example 12 and in the same manner as in Reference Example 5, (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)amino)methyl)phenyl)-3-(1H-pyrazole-1-yl)benzenesulfonamide). Finally, by removing the TBS group, the title compound 202 was obtained (yield 165 mg, yield 61%, TLC Rf value 0.18 in n-hexane / ethyl acetate = 2 / 3). 1HNMR (400MHz, DMSO-d6) δ2.11 (s, 3H), 3.13-3.18 (m, 3H), 3.25-3.32 (m, 2H), 3.38-3.42 (m, 1H) , 3.88-3.94 (m, 1H), 4.34 (d, J = 13.2Hz, 1H), 6.49-6.61 (m, 3H), 6.69 (d, J = 16.0Hz, 1H), 7.18 (t, J = 7.6Hz, 1H), 7.34 (t, J = 7.2Hz, 1H), 7.46 (d, J = 8.0Hz, 1H), 7.53 (d, J = 7.2Hz, 1H), 7.66 (s, 4H) , 7.72 (t, J=8.0Hz, 1H), 7.77 (s, 1H), 8.00 (s, 1H), 8.14 (d, J=8.0Hz, 1H), 8.53 (d, J=2.4Hz, 1H).

[0120] <Example 21> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-cyclopropoxy-N-(2-hydroxyethyl)benzenesulfonamide (235)

[0121]

[0122] As shown in Scheme 13, compound 25 was obtained by reacting compound 3a obtained in Reference Example 1 with 3-cyclopropoxybenzenesulfonyl chloride obtained in the same manner as in Reference Example 3, in the same manner as in Example 1 (yield 186 mg, yield 89%, TLC Rf value 0.34 at n-hexane / ethyl acetate = 2 / 1). Subsequently, compound 26 was obtained as a crude product by reacting compound 25 with (2-bromoethoxy)(tert-butyl)dimethylsilane in the same manner as in Example 12 (yield 260 mg, TLC Rf value 0.35 at n-hexane / ethyl acetate = 2 / 1). Subsequently, compound 26 (260 mg) was dissolved in THF (5 mL), 1 M TBAF / THF solution (0.43 mL) was added, and the mixture was stirred at room temperature for 16 hours. Water was added, the mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 2 / 1 to 1 / 2) to obtain compound 235 (yield 115 mg, 2-step yield 56%, TLC Rf value 0.34 at n-hexane / ethyl acetate = 1 / 2). 1 HNMR (500MHz, CDCl3) δ0.69-0.78 (m, 4H), 2.23 (s, 3H), 2.87 (d, J = 12.5Hz, 1H), 3.11 (d, J = 13.5Hz, 1H), 3.18-3.28 (m, 2H), 3.41 (dd, J = 13.5, 6.0Hz, 1H), 3.65 (b rs, 2H), 4.11 (t, J=10.0Hz, 1H), 4.98 (d, J=12.5Hz, 1H), 6.39-6.45 (m, 2H), 6.5 2 (d, J=16.0H, 1H), 7.16 (t, J=7.0Hz, 1H), 7.20-7.31 (m, 7H), 7.38-7.39 (m, 3H).

[0123] <Example 22> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)-3-fluorophenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (229)

[0124]

[0125] In the same manner as in Example 21, compound 7d obtained in Reference Example 2 and 3-isopropoxybenzenesulfonyl chloride (compound 11) obtained in Reference Example 3 were used to obtain (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)-3-fluorophenyl)-3-isopropoxybenzenesulfonamide. Finally, the TBS group was removed to obtain the title compound 229 (yield 49 mg, yield 73%, TLC Rf value 0.29 at n-hexane / ethyl acetate = 4 / 1). 1 HNMR (500MHz, CDCl3) δ1.28 (d, J = 5.3Hz, 3H), 1.30 (d, J = 5.3Hz, 3H), 2.25 (s, 3H), 3.0 9 (d, J = 11.0z, 1H), 3.25-3.42 (m, 4H), 3.68 (d, J = 8.5Hz, 1H), 4.10 (brs, 1H), 4.48 (br s, 1H), 4.61 (d, J = 11.5Hz, 1H), 6.28-6.39 (m, 2H), 6.54 (d, J = 14.5Hz, 1H), 7.01-7.08 (m, 2H), 7.10-7.15 (m, 1H), 7.18-7.20 (m, 1H), 7.23-7.30 (m, 3H), 7.35-7.41 (m, 3H).

[0126] <Example 23> Synthesis of (E)-N-(2-hydroxyethyl)-3-isopropoxy-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)amino)methyl)phenyl)benzenesulfonamide (230)

[0127]

[0128] In the same manner as in Example 21, compound 3b obtained in Reference Example 1 and 3-isopropoxybenzenesulfonyl chloride (compound 11) obtained in Reference Example 3 were used to obtain (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-isopropoxy-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)amino)methyl)phenyl)benzenesulfonamide). Finally, the TBS group was removed to obtain the title compound 230 (yield 104 mg, yield 54%, TLC Rf value 0.29 at n-hexane / ethyl acetate = 1 / 1). 1 HNMR (500MHz, CDCl3) δ1.26 (d, J = 6.0Hz, 3H), 1.29 (d, J = 6.0Hz, 3H), 2.21 (s, 3H), 2.87 (d, J = 12.0Hz, 1H), 3.11 (dd, J = 13.5, 4.0Hz, 1H), 3.20-3.28 (m, 2H), 3.46 (dd, J = 14.0, 6.0Hz, 1H), 3.66 (d, J = 12.5Hz, 1H), 4.09-4.14 (m, 1H), 4.43-4.49 (m, 1H), 5 .. 00 (d, J=12.0Hz, 1H), 6.43 (d, J=7.0Hz, 1H), 6.52-6.57 (m, 1H), 6.62 (d, J=15.5Hz, 1H), 7.04-7.05 (m, 1H), 7.09 (dd, J=7.0, 2.2Hz, 1H), 7.13-7.17 (m, 2H), 7.26 (d, J = 7.5Hz, 1H), 7.30 (dd, J = 7.0, 1.7Hz, 1H), 7.31 (t, J = 8.0Hz, 1H), 7.53-7.57 (m, 4H).

[0129] <Example 24> Synthesis of (E)-3-(tert-butoxy)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)benzenesulfonamide (231)

[0130]

[0131] Using 3-(tert-butoxy)benzenesulfonyl chloride obtained in the same manner as in Reference Example 3, in the same manner as in Example 21, (E)-3-(tert-butoxy)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)benzenesulfonamide). Finally, by removing the TBS group, the title compound 231 was obtained (yield 21 mg, yield 50%, TLC Rf value 0.28 at n-hexane / ethyl acetate = 1 / 2). 1 HNMR (500MHz, CDCl3) δ1,32 (s, 9H), 2.20 (s, 3H), 2.86 (d, J = 12.0Hz, 1H), 3.10 ( d, J = 13.0Hz, 1H), 3.18-3.27 (m, 2H), 3.41 (dd, J = 13.0, 5.0Hz, 1H), 3.65 (d, J = 1 3.0Hz, 1H), 4.10-4.13 (m, 1H), 4.98 (d, J=12.0Hz, 1H), 6.39-6.43 (m, 2H), 6.52 (d, J=15.5Hz, 1H), 7.13 (t, J=8.0Hz, 1H), 7.20-7.32 (m, 7H), 7.36-7.41 (m, 3H).

[0132] <Example 25> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-5-isopropoxy-2-methoxybenzenesulfonamide (232)

[0133]

[0134] Using 5-isopropoxy-2-methoxybenzenesulfonyl chloride obtained in the same manner as in Reference Example 3, in the same manner as in Example 21, (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-5-isopropoxy-2-methoxybenzenesulfonamide was obtained. Finally, the TBS group was removed to obtain the title compound 232 (yield 32 mg, yield 56%, TLC Rf value 0.19 at n-hexane / ethyl acetate = 1 / 3). 1HNMR (500MHz, CDCl3) δ1.12 (d, J = 6.0Hz, 3H), 1.20 (d, J = 6.0Hz, 3H), 2.20 (s, 3H), 2.86 (d, J = 12.5Hz, 1H), 3.21 (dd, J = 13 .5, 7.5Hz, 1H), 3.29-3.33 (m, 2H), 3.39 (dd, J = 13.5, 6.0Hz, 1H), 3.71 (d, J = 11.0Hz, 1H), 3.80 (s, 3H), 4.25-4.30 (m, 1H), 4.37-4.41 (m, 1H), 5.02 (d, J = 12.0Hz, 1H), 6.35-6.41 (m, 2H), 6.52 (d, J = 16.0Hz, 1H), 6.65 (d, J = 7.5Hz, 1H), 6.94 (d, J = 9.5Hz, 1H), 7.02 (dd, J = 8.5, 3.0Hz, 1H), 7.07-7.12 (m, 2H), 7.19 (t, J = 6.5Hz, 1H), 7.24-7.26 (m, 2H), 7.36-7.38 (m, 2H).

[0135] <Example 26> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-5-isopropoxy-2-methylbenzenesulfonamide (233)

[0136]

[0137] Using 5-isopropoxy-2-methylbenzenesulfonyl chloride obtained in the same manner as in Reference Example 3, in the same manner as in Example 21, (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-5-isopropoxy-2-methylbenzenesulfonamide was obtained. Finally, the TBS group was removed to obtain the title compound 233 (yield 37 mg, 2-step yield 52%, TLC Rf value 0.32 at n-hexane / ethyl acetate = 1 / 2). 1HNMR (500MHz, CDCl3) δ1.30 (d, J = 6.0Hz, 6H), 1.93 (s, 3H), 2.19 (s, 3H), 2.84 (d, J = 13.0Hz, 1 H), 3.15-3.28 (m, 3H), 3.40 (d, J=14.0Hz, 1H), 3.65 (d, J=12.5Hz, 1H), 4.18-4.21 (m, 1H), 4. 48-4.50 (m, 1H), 4.99 (d, J = 12.0Hz, 1H), 6.38-6.44 (m, 1H), 6.49-6.54 (m, 2H), 6.97 (d, J = 8. 0Hz, 1H), 7.08 (d, J = 8.0Hz, 1H), 7.14 (t, J = 7.0Hz, 1H), 7.25-7.30 (m, 5H), 7.36-7.38 (m, 2H).

[0138] <Example 27> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-2-fluoro-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (234)

[0139]

[0140] Using 2-fluoro-3-isopropoxy-2-methoxybenzenesulfonyl chloride obtained in the same manner as in Reference Example 3, in the same manner as in Example 21, (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-isopropoxybenzenesulfonamide was obtained. Finally, the TBS group was removed to obtain compound 234 of the title (yield 40 mg, yield 92%, TLC Rf value 0.34 at n-hexane / acetone = 2 / 1). 1HNMR (500MHz, CDCl3) δ1.35 (d, J = 6.0Hz, 3H), 1.37 (d, J = 6.0Hz, 3H), 2.20 (s, 3H), 2.87 (d, J = 12.0Hz, 1H), 3,21 (dd, J = 13.0, 7.0Hz, 1H), 3.26-3.30 (m, 2H), 3.41 (dd, J = 13.5, 6.0Hz, 1H), 3.67 (d, J = 12.0Hz, 1H), 4.27-4.31 (m, 1H), 4.5 2-4.57 (m, 1H), 4.97 (d, J = 12.0Hz, 1H), 6.39 (dt, J = 16.0, 6.5Hz, 1H), 6.52 (d, J = 16.0Hz, 1H), 6.59 (d, J = 8.0Hz, 1H) , 7.02-7.07 (m, 2H), 7.14 (td, J=8.0, 2.0Hz, 1H), 7.19 (td, J=8.0, 2.5Hz, 1H), 7.23-7.30 (m, 4H), 7.31-7.38 (m, 2H).

[0141] <Example 28> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-2-methoxy-5-propoxybenzenesulfonamide (246)

[0142]

[0143] Using 2-methoxy-5-isopropoxy-2-methoxybenzenesulfonyl chloride obtained in the same manner as in Reference Example 3, in the same manner as in Example 21, (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-2-methoxy-5-propoxybenzenesulfonamide was obtained. Finally, the TBS group was removed to obtain compound 246 of the title (yield 74 mg, yield 80%, TLC Rf value in ethyl acetate 0.33). 1HNMR (500MHz, CDCl3) δ0.95 (t, J = 7.0Hz, 3H), 1.66-1.71 (m, 2H), 2.21 (s, 3H), 2.88 (d , J=11.5Hz, 1H), 3.24-3.40 (m, 4H), 3.70-3.76 (m, 3H), 3.80 (s, 3H), 4.38-4.42 (m, 1H) , 5.03 (d, J = 12.0Hz, 1H), 6.38-6.42 (m, 1H), 6.52 (d, J = 15.5Hz, 1H), 6.68 (d, J = 8.5Hz , 1H), 6.95 (d, J=8.5Hz, 1H), 7.04-7.13 (m, 3H), 7.21-7.32 (m, 4H), 7.37-7.38 (m, 2H).

[0144] <Example 29> Synthesis of (E)-3-(benzyloxy)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)benzenesulfonamide (208)

[0145]

[0146] As shown in Scheme 14, compound 27 was obtained by reacting compound 3a obtained in Reference Example 1 with 3-(tert-butyldimethylsilyl)oxy)benzenesulfonyl chloride (compound 14) obtained in Reference Example 4 in the same manner as in Example 1 (yield 983 mg, yield 50%, TLC Rf value 0.37 at n-hexane / ethyl acetate = 4 / 1). Subsequently, compound 28 was obtained by reacting compound 27 with 2-hydroxyethyl benzoate in the same manner as in Example 1 (yield 1.02 g, yield 82%, TLC Rf value 0.31 at n-hexane / ethyl acetate = 4 / 1). Subsequently, compound 28 (500 mg) was dissolved in THF (10 mL), 1 M TBAF / THF solution (0.78 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. Water was added, the mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 2 / 1) to obtain compound 29 (yield 387 mg, yield 83%, TLC Rf value 0.48 at n-hexane / ethyl acetate = 1 / 1). Subsequently, compound 29 (102 mg) was dissolved in THF (10 m), potassium carbonate (36 mg) and benzyl bromide (0.025 mL) were added, and the mixture was stirred at 75°C for 5 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 30 (yield 59 mg, yield 50%, TLC Rf value 0.28 at n-hexane / ethyl acetate = 1 / 1). Finally, compound 30 (59 mg) was hydrolyzed in the same manner as in Example 1 to obtain the title compound 208 (yield 33 mg, yield 65%, TLC Rf value 0.22 in n-hexane / ethyl acetate = 1 / 1). 1HNMR (500MHz, CDCl3) δ2.20 (s, 3H), 2.86 (d, J = 12.0Hz, 1H), 2.96 ( d, J = 12.0Hz, 1H), 3.19-3.21 (m, 2H), 3.39-3.41 (m, 1H), 3.61 (d, J = 12.5Hz, 1H), 3.98-4.02 (m, 1H), 4.97 (d, J = 12.5Hz, 1H), 5.03 (s, 2H), 6.34-6.42 (m, 2H), 6.52 (d, J=16Hz, 1H), 7.11-7.45 (m, 16H).

[0147] <Example 30> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-(cyclopropylmethoxy)-N-(2-hydroxyethyl)benzenesulfonamide (209)

[0148]

[0149] Compound 29 was reacted with cyclopropylmethyl bromide in the same manner as in Example 29 to obtain (E)-2-((N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-(cyclopropylmethoxy)phenyl)sulfonamide)ethylbenzoate. Finally, hydrolysis was performed to obtain the title compound 209 (yield 39 mg, yield 62%, TLC Rf value 0.37 in n-hexane / ethyl acetate = 1 / 1). 1HNMR (500MHz, CDCl3) δ0.36-0.33 (m, 2H), 0.61-0.65 (m, 2H), 1.20-1.28 (m, 1H), 2.21 (s, 3H), 2.87 (d, J = 12.0Hz , 1H), 3.10 (dd, J = 13.5, 4.0Hz, 1H), 3.19-3.27 (m, 2H), 3.41 (dd, J = 13.5, 6.0Hz, 1H), 3.65-3.75 (m, 3H), 4.07-4 .. 11 (m, 1H), 4.98 (d, J = 12.0Hz, 1H), 6.37-6.44 (m, 2H), 6.52 (d, J = 16.0Hz, 1H), 7.04 (brs, 1H), 7.12-7.16 (m, 3H) , 7.18 (d, J=8.0Hz, 1H), 7.24-7.27 (m, 2H), 7.30 (d, J=7.5Hz, 1H), 7.36 (d, J=9.0Hz, 1H), 7.38 (d, J=8.5Hz, 2H).

[0150] <Example 31> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-(prop-2-in-1-yloxy)benzenesulfonamide (210)

[0151]

[0152] Compound 29 was reacted with propargyl bromide in the same manner as in Example 29 to obtain (E)-2-((N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-(prop-2-in-1-yloxy)phenyl)sulfonamide)ethylbenzoate. Finally, hydrolysis was performed to obtain the title compound 210 (yield 61 mg, yield 79%, Rf value 0.33 at n-hexane / ethyl acetate = 1 / 1). 1HNMR (500MHz, CDCl3) δ2.21 (s, 3H), 2.50 (s, 1H), 2.87 (d, J = 12.0Hz, 1H), 3.11 (dd, J =12.0, 2.5Hz, 1H), 3.19-3.29 (m, 2H), 3.41 (m, 1H), 3.65-3.67 (m, 1H), 4.09-4.13 (m, 1H), 4.66 (s, 2H), 4.97 (d, J = 12.0Hz, 1H), 6.37-6.44 (m, 2H), 6.52 (d, J = 15.5Hz, 1H) , 7.16 (t, J=7.0Hz, 1H), 7.20-7.28 (m, 6H), 7.30 (d, J=7.0Hz, 1H), 7.37-7.42 (m, 3H).

[0153] <Example 32> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-cyclobutoxy-N-(2-hydroxyethyl)benzenesulfonamide (218)

[0154]

[0155] Compound 29 was reacted with cyclobutyl bromide in the same manner as in Example 29 to obtain (E)-2-((N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-cyclobutoxyphenyl)sulfonamide)ethylbenzoate. Finally, hydrolysis was performed to obtain the title compound 218 (yield 64 mg, 2-step yield 67%, Rf value 0.23 at n-hexane / acetone = 3 / 1). 1HNMR (500MHz, CDCl3) δ1.80-1.87 (m, 1H), 2.05-2.16 (m, 3H), 2.20 (s, 3H), 2.27-2.30 (m, 1H), 2.35-2.45 (m, 1H), 2 .87 (d, J=12.5Hz, 1H), 3.09 (dd, J=12.5, 2.0Hz, 1H), 3.18-3.26 (m, 2H), 3.41 (dd, J=13.5, 6.0Hz, 1H), 3.65 (dt, J= 12.5, 3.5Hz, 1H), 4.07-4.11 (m, 1H), 4.52-4.57 (m, 1H), 4.97 (d, J = 12.5Hz, 1H), 6.37-6.43 (m, 2H), 6.52 (d, J = 16. 0Hz, 1H), 6.94 (brs, 1H), 7.04 (dd, J = 8.0, 2.0Hz, 1H), 7.24-7.27 (m, 5H), 7.30 (d, J = 6.0Hz, 1H), 7.34-7.39 (m, 3H).

[0156] <Example 33> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-(cyclopentyloxy)-N-(2-hydroxyethyl)benzenesulfonamide (219)

[0157]

[0158] Compound 29 was reacted with iodocyclopentane in the same manner as in Example 29 to obtain (E)-2-((N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-(cyclopentyloxy)siphenyl)sulfonamide)ethylbenzoate. Finally, hydrolysis was performed to obtain the title compound 219 (yield 63 mg, 2-step yield 68%, TLC Rf value 0.32 at n-hexane / acetone = 3 / 1). 1HNMR (500MHz, CDCl3) δ1.59-1.85 (m, 8H), 2.21 (s, 3H), 2.87 (d, J = 13.0Hz, 1H), 3.10 (d, J = 11.0Hz, 1H), 3. 19-3.27 (m, 2H), 3.40 (dd, J = 13.0, 5.5Hz, 1H), 3.66 (d, J = 13.0Hz, 1H), 4.10 (t, J = 10.5Hz, 1H), 4.67 (brs, 1 H), 4.98 (d, J = 12.0Hz, 1H), 6.37-6.45 (m, 2H), 6.52 (d, J = 16.0Hz, 1H), 7.04 (brs, 1H), 7.08 (d, J = 8.0Hz, 1 H), 7.15-7.16 (m, 2H), 7.25-7.26 (m, 3H), 7.30 (d, J = 7.5Hz, 1H), 7.34 (d, J = 5.0Hz, 1H), 7.38-7.39 (m, 2H).

[0159] <Example 34> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-propoxybenzenesulfonamide (220)

[0160]

[0161] Compound 29 was reacted with propyl bromide in the same manner as in Example 29 to obtain (E)-2-((N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-propoxysiphenyl)sulfonamide)ethylbenzoate. Finally, hydrolysis was performed to obtain the title compound 220 (yield 60 mg, yield 72%, TLC Rf value 0.29 in n-hexane / ethyl acetate = 1 / 1). 1HNMR (500MHz, CDCl3) δ1.09 (t, J = 7.5Hz, 3H), 1.74-1.81 (m, 2H), 2.21 (s, 3H), 2.87 (d, J = 12.5Hz, 1H), 3.10 (dd, J = 13. 0, 3.0Hz, 1H), 3.19-3.28 (m, 2H), 3.41 (dd, J = 13.0, 6.0Hz, 1H), 3.65 (dt, J = 14.0, 2.5Hz, 1H), 3.79-3.89 (m, 2H), 4.07- 4.12 (m, 1H), 4.98 (d, J = 12.0Hz, 1H), 6.37-6.45 (m, 2H), 6.52 (d, J = 16.0Hz, 1H), 7.05 (brs, 1H), 7.11 (dd, J = 8.0, 2.5Hz , 1H), 7.15 (td, J = 7.5, 1.5Hz, 1H), 7.18 (d, J = 8.5Hz, 1H), 7.24-7.27 (m, 3H), 7.30 (d, J = 7.0Hz, 1H), 7.35-7.39 (m, 3H).

[0162] <Example 35> Synthesis of (E)-3-butoxy-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)benzenesulfonamide (221)

[0163]

[0164] Compound 29 was reacted with butyl bromide in the same manner as in Example 29 to obtain (E)-2-((3-butoxy-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)aminomethyl)phenyl)phenyl)sulfonamide)ethylbenzoate. Finally, hydrolysis was performed to obtain the title compound 221 (yield 62 mg, yield 68%, TLC Rf value 0.14 in n-hexane / ethyl acetate = 1 / 1). 1HNMR (500MHz, CDCl3) δ0.95 (t, J = 7.5Hz, 3H), 1.42-1.49 (m, 2H), 1.70-1.77 (m, 2H), 2.20 (s, 3H), 2.87 (d, J = 12.0Hz, 1H), 3 .10 (dd, J=13.5, 3.0Hz, 1H), 3.18-3.27 (m, 2H), 3.41 (dd, J=13.5, 6.0Hz, 1H), 3.65 (dt, J=12.5, 3.5Hz, 1H), 3.83-3.93 (m, 2 H), 4.07-4.12 (m, 1H), 4.98 (d, J = 12.0Hz, 1H), 6.37-6.44 (m, 2H), 6.52 (d, J = 16.0Hz, 1H), 7.04 (brs, 1H), 7.11 (dd, J = 8.0, 2 0Hz, 1H), 7.15 (td, J=7.5, 1.5Hz, 1H), 7.18 (d, J=8.5Hz, 1H), 7.24-7.27 (m, 3H), 7.30 (d, J=7.5Hz, 1H), 7.35-7.39 (m, 3H).

[0165] <Example 36> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-((3-methylbuto-2-en-1-yl)oxy)benzenesulfonamide (222)

[0166]

[0167] Compound 29 was reacted with 3-methyl-2-butenyl bromide in the same manner as in Example 29 to obtain (E)-2-((N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-((3-methylbuto-2-en-1-yl)oxy)phenyl)sulfonamide)ethylbenzoate. Finally, hydrolysis was performed to obtain the title compound 222 (yield 47 mg, yield 67%, TLC Rf value 0.36 at n-hexane / acetone = 2 / 1). 1HNMR (500MHz, CDCl3) δ1.69 (s, 3H), 1.77 (s, 3H), 2.20 (s, 3H), 2.87 (d, J = 12.0Hz, 1H), 3.09 (dd, J = 13.0, 3.5Hz, 1H), 3.18-3.27 (m, 2H), 3.41 (dd, J = 13.5, 6.0Hz, 1H), 3.65 (dt, J = 13.5, 4.0Hz, 1H), 4.06-4.11 (m, 1H), 4.38-4.4 7 (m, 2H), 4.98 (d, J = 13.0Hz, 1H), 5.41 (t, J = 6.0Hz, 1H), 6.37-6.44 (m, 2H), 6.51 (d, J = 16.0Hz, 1H), 7.06 (brs, 1 H), 7.12 (dd, J = 9.0, 2.0 Hz, 1H), 7.16-7.19 (m, 2H), 7.24-7.26 (m, 3H), 7.30 (d, J = 7.5Hz, 1H), 7.35-7.39 (m, 3H).

[0168] <Example 37> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-(pentyloxy)benzenesulfonamide (224)

[0169]

[0170] Compound 29 was reacted with pentyl bromide in the same manner as in Example 29 to obtain (E)-2-((N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-(pentyloxy)phenyl)sulfonamide)ethylbenzoate. Finally, hydrolysis was performed to obtain the title compound 224 (yield 82 mg, yield 87%, TLC Rf value 0.30 in n-hexane / ethyl acetate = 1 / 1). 1HNMR (500MHz, CDCl3) δ0.92 (t, J = 7.0Hz, 3H), 1.33-1.43 (m, 4H), 1.72-1.77 (m, 2H), 2.21 (s, 3H), 2.87 (d, J = 12. 5Hz, 1H), 3.10 (d, J = 11.0Hz, 1H), 3.19-3.28 (m, 2H), 3.41 (dd, J = 14.0, 6.5Hz, 1H), 3.67 (d, J = 13.0Hz, 1H), 3.82 -3.92 (m, 2H), 4.09 (t, J = 10.5Hz, 1H), 4.98 (d, J = 12.5Hz, 1H), 6.37-6.45 (m, 2H), 6.52 (d, J = 16.0Hz, 1H), 7.05 ( brs, 1H), 7.11 (d, J = 8.0Hz, 1H), 7.14-7.19 (m, 2H), 7.24-7.27 (m, 3H), 7.30 (d, J = 8.0Hz, 1H), 7.35-7.39 (m, 3H).

[0171] <Example 38> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-(neopentyloxy)benzenesulfonamide (225)

[0172]

[0173] Compound 29 was reacted with neopentyl bromide in the same manner as in Example 29 to obtain (E)-2-((N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-(neopentyloxy)phenyl)sulfonamide)ethylbenzoate. Finally, hydrolysis was performed to obtain the title compound 225 (yield 87 mg, yield 78%, TLC Rf value 0.18 in n-hexane / ethyl acetate = 1 / 1). 1HNMR (500MHz, CDCl3) δ1.01 (s, 9H), 2.21 (s, 3H), 2.88 (d, J = 11.0Hz, 1H), 3.10 (d, J = 11.5Hz, 1H), 3.22-3.27 (m, 2H), 3.41-3.53 (m, 3H), 3.67 (d, J = 11.0Hz, 1H), 4.09 ( brs, 1H), 4.99 (d, J = 11.5Hz, 1H), 6.37-6.46 (m, 2H), 6.53 (d, J = 15.5Hz, 1H), 7.05 ( brs, 1H), 7.14-7.17 (m, 3H), 7.25-7.27 (m, 3H), 7.30 (brs, 1H), 7.35-7.39 (m, 3H).

[0174] <Example 39> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-(cyclobutylmethoxy)-N-(2-hydroxyethyl)benzenesulfonamide (226)

[0175]

[0176] Compound 29 was reacted with cyclobutylmethyl bromide in the same manner as in Example 29 to obtain (E)-2-((N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-3-(cyclobutylmethoxy)phenyl)sulfonamide)ethylbenzoate. Finally, hydrolysis was performed to obtain the title compound 226 (yield 79 mg, 2-step yield 83%, TLC Rf value 0.33 in n-hexane / ethyl acetate = 1 / 1). 1HNMR (500MHz, CDCl3) δ1.78-1.95 (m, 4H), 2.08-2.16 (m, 2H), 2.21 (s, 3H), 2.69-2.73 (m, 1H), 2 .88 (d, J=12.0Hz, 1H), 3.11 (d, J=11.0Hz, 1H), 3.19-3.30 (m, 2H), 3.39-3.41 (m, 1H), 3.67 (d, J = 11.5Hz, 1H), 3.83-3.87 (m, 2H), 4.10 (brs, 1H), 4.98 (d, J = 11.5Hz, 1H), 6.40-6.46 (m, 2H), 6. 53 (d, J=15.0Hz, 1H), 7.06 (brs, 1H), 7.13-7.17 (m, 4H), 7.25-7.30 (m, 4H), 7.35-7.39 (m, 2H).

[0177] <Example 40> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-2'-methoxy-[1,1'-biphenyl]-3-sulfonamide (212)

[0178]

[0179] As shown in Scheme 15, compound 31 (4.00 g) and commercially available 3-bromobenzenesulfonyl chloride (4.76 g) were dissolved in dichloromethane, and under ice cooling, pyridine (7 mL) was added and the mixture was stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain compound 32 (yield 7.50 g, yield 97%, TLC Rf value 0.21 at n-hexane / ethyl acetate = 7 / 3). Subsequently, compound 33 was obtained by reacting compound 32 (7.50 g) with 2-iodoethyl benzoate in the same manner as in Example 5 (yield 9.00 g, yield 90%, TLC Rf value 0.41 at n-hexane / ethyl acetate = 3 / 2). Next, compound 33 (9.00 g) was dissolved in 1,4-dioxane (90 mL), and under ice cooling, 19 mL of 4 M hydrochloric acid / 1,4-dioxane solution was added and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, water and sodium bicarbonate were added, and the mixture was extracted with a dichloromethane / methanol (9 / 1) mixed solvent. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain compound 34 (yield 7.40 g, yield 98%, TLC Rf value 0.19 at dichloromethane / methanol = 95 / 5). Subsequently, compound 34 (418 mg) was reacted with (E)-3-(4-chlorophenyl)acrylaldehyde in the same manner as in Reference Example 2 to obtain compound 35 (yield 366 mg, yield 67%, TLC Rf value 0.51 at n-hexane / ethyl acetate = 2 / 1). Next, compound 36 was obtained as a crude product by hydrolyzing compound 35 (366 mg) in the same manner as in Example 1 (yield 320 mg, TLC Rf value 0.20 at n-hexane / ethyl acetate = 2 / 1). Subsequently, compound 36 (159 mg) was dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (5 mL), and 2-bromoanisole (50 mg), tetrakis(triphenylphosphine)palladium (41 mg) and sodium carbonate (190 mg) were added, and the mixture was stirred at 90°C for 1.5 hours. After returning to room temperature, water was added, and the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate.The mixture was filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane / acetone = 3 / 1) to obtain compound 212 (yield 107 mg, 2-step yield 63%, TLC Rf value 0.34 at n-hexane / acetone = 3 / 1). 1 HNMR (500MHz, CDCl3) δ2.21 (s, 3H), 2.88 (d, J = 12.0Hz, 1H), 3.15 (dd, J = 3.0, 12.5Hz, 1H), 3.19-3.29 (m , 2H), 3.41 (dd, J = 13.0, 5.5Hz, 1H), 3.67 (d, J = 13.5Hz, 1H), 3.79 (s, 3H), 4.10-4.17 (m, 1H), 4.99 (d, J = 12.0Hz, 1H), 6.41 (dt, J=16.0, 7.0Hz, 1H), 6.48 (d, J=7.5Hz, 1H), 6.52 (d, J=16.0Hz, 1H), 6.98 (d, J=8. 0Hz, 1H), 7.02 (t, J=8.0Hz, 1H), 7.24-7.39 (m, 9H), 7.49-7.50 (m, 2H), 7.76-7.78 (m, 1H), 7.84 (s, 1H).

[0180] <Example 1> Synthesis of (E)-N-(2-hydroxyethyl)-3-methoxy-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)amino)methyl)phenyl)benzenesulfonamide (181)

[0181]

[0182] (E)-2-((3-methoxy-N-(2-(((methyl(3-(4-(trifluoromethyl)phenyl)aryl)amino)methyl)phenyl)benzenesulfonamide)ethylbenzoate was obtained by using commercially available 3-methoxybenzenesulfonyl chloride and commercially available (E)-3-(4-(trifluoromethyl)phenyl)allyl)aminomethyl)phenyl)benzenesulfonamide)ethylbenzoate in the same manner as in Example 40. Finally, the title compound 181 was obtained by hydrolysis (yield 25 mg, yield 7%, TLC Rf value 0.14 in n-hexane / ethyl acetate = 1 / 1). 1HNMR (400MHz, DMSO-d6) δ2.14 (s, 3H), 3.15-3.28 (m, 5H), 3.37-3.41 (m, 1H), 3.77 (s, 3H), 3.85-3.90 (m, 1H) ), 4.28 (d, J = 13.6Hz, 1H), 5.93-5.96 (m, 1H), 6.55 (dt, J = 15.8, 6.4Hz, 1H), 6.58 (d, J = 8.8Hz, 1H), 6.72 (d, J=15.8Hz, 1H), 7.01 (t, J=2.2Hz, 1H), 7.17 (d, J=8.0Hz, 1H), 7.22 (td, J=6.8, 1.6Hz, 1H), 7.28 (dd, J=2.8, 8.0Hz, 1H), 7.35 (td, J=7.6, 1.2Hz, 1H), 7.51 (d, J=8.0Hz, 1H), 7.56 (dd, J=8.0, 1.8Hz, 1H), 7.68 (brs, 4H).

[0183] <Example 42> Synthesis of (E)-3-cyclopropoxy-N-(2-hydroxyethyl)-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)aminomethyl)phenyl)benzenesulfonamide (197)

[0184]

[0185] As shown in Scheme 16, (E)-2-((3-bromo-N-(2-((methyl(3-(4-(trifluoromethyl)phenyl)allyl)aminomethyl)phenyl)benzenesulfonamide)ethylbenzoate (compound 37) was obtained by using commercially available (E)-3-(4-(trifluoromethyl)phenyl)acrylaldehyde in the same manner as in Example 40. Next, compound 37 (500 mg) was dissolved in a mixed solvent of 1,4-dioxane (12.5 mL) and water (2.5 mL), and cyclopropylboronic acid (250 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (119 mg) and potassium phosphate (292 mg) were added. The mixture was reacted under microwave at 100°C for 1 hour, and then stirred for a further 16 hours. After returning to room temperature, ethyl acetate was added, and the mixture was filtered. The mixture was concentrated under reduced pressure to obtain compound 38 (yield 500 mg, yield 47%, TLC Rf value 0.46 at n-hexane / ethyl acetate = 4 / 1). Finally, compound 38 (1.00 g) was hydrolyzed in the same manner as in Example 5 to obtain the title compound 197 (yield 69 mg, yield 18%, TLC Rf value 0.27 at n-heptane / ethyl acetate = 2 / 3). 1 HNMR (400MHz, DMSO-d6) δ0.60-0.69 (m, 2H), 0.99 (d, J = 5.0Hz, 1H), 1.99-2.06 (m, 1H), 2.13 (s, 3H) ), 3.15-3.26 (m, 5H), 3.36-3.41 (m, 1H), 3.81-3.87 (m, 1H), 4.27 (d, J = 13.2Hz, 1H), 5.94-5.97 (m , 1H), 6.51 (d, J = 8.0Hz, 1H), 6.54 (dt, J = 16.0, 6.4Hz, 1H), 6.72 (d, J = 16.0Hz, 1H), 7.16 (brs, 1H) , 7.21 (t, J=6.8Hz, 1H), 7.33-7.37 (m, 2H), 7.42-7.48 (m, 2H), 7.55 (d, J=6.8Hz, 1H), 7.68 (s, 4H).

[0186] <Example 43> Synthesis of (E)-3-(benzofuran-3-yl)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)benzenesulfonamide (211)

[0187]

[0188] Compound 211 was obtained by reacting compound 36 with commercially available benzofuran-3-boronic acid in the same manner as in Example 40 (yield 24 mg, yield 29%, TLC Rf value 0.35 at n-hexane / acetone = 1 / 1). 1 HNMR (500MHz, CDCl3) δ2.23 (s, 3H), 2.91 (d, J = 12.0Hz, 1H), 3.16 (dd, J = 12.5, 3.0Hz, 1H), 3.20-3.31 (m, 2H), 3.44 (dd, J = 13.0, 6.0Hz, 1H), 3.68-3.70 (m, 1H), 4.14-4.19 (m, 1H), 5.02 (d, J = 13.0Hz, 1H), 6.42 (dt, J = 16.0, 6.0Hz, 1H), 6.48 (d, J = 8.0Hz, 1H), 6.54 (d, J = 16.0Hz, 1H), 7.17 (td, J = 7.0, 1.5Hz, 1H), 7.26-7.30 (m, 4H), 7. 34-7.39 (m, 4H), 7.55 (d, J = 8.0Hz, 1H), 7.59-7.66 (m, 3H), 7.78 (s, 1H), 7.83 (brs, 1H), 7.89 (d, J = 7.0Hz, 1H).

[0189] <Example 44> Synthesis of (E)-3-(bensofran-2-yl)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)benzenesulfonamide (213)

[0190]

[0191] Compound 213, as described in the title, was obtained by reacting compound 36 with commercially available benzofuran-2-boronic acid in the same manner as in Example 40 (yield 130 mg, yield 70%, TLC Rf value 0.44 at n-hexane / acetone = 3 / 1). 1HNMR (500MHz, CDCl3) δ2.22 (s, 3H), 2.91 (d, J = 12.0Hz, 1H), 3.14 (dd, J = 11.5, 2.5Hz, 1H), 3.20-3.30 ( m, 2H), 3.43 (dd, J = 13.0, 5.5Hz, 1H), 3.68 (dt, J = 13.0, 4.0Hz, 1H), 4.13-4.18 (m, 1H), 5.01 (d, J = 12.5H) z, 1H), 6.42 (dt, J = 16.0, 6.5Hz, 1H), 6.46 (d, J = 8.0Hz, 1H), 6.54 (d, J = 16.0Hz, 1H), 7.05 (s, 1H), 7.15 ( td, J = 8.0, 2.0 Hz, 1H), 7.23-7.35 (m, 6H), 7.38-7.40 (m, 2H), 7.52 (d, J = 8.5Hz, 1H), 7.55-7.60 (m, 3H). 8.05 (s, 1H), 8.08 (dt, J=7.0, 1.5Hz, 1H).

[0192] <Example 45> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3'-methoxy-[1,1'-biphenyl]-3-sulfonamide (217)

[0193]

[0194] Compound 217 was obtained by reacting compound 36 with commercially available 3-methoxyphenylboronic acid in the same manner as in Example 40 (yield 55 mg, yield 69%, TLC Rf value 0.37 at n-hexane / acetone = 3 / 1). 1HNMR (500MHz, CDCl3) δ2.21 (s, 3H), 2.89 (d, J = 12.5Hz, 1H), 3.11 (d, J = 12.5Hz, 1H), 3.17-3.29 (m, 2H), 3 .38-3.43 (m, 1H), 3.67 (d, J = 14.0Hz, 1H), 3.84 (s, 3H), 4.11-4.15 (m, 1H), 4.99 (d, J = 12.0Hz, 1H), 6.39-6 .. 44 (m, 2H), 6.53 (d, J = 15.5Hz, 1H), 6.92 (d, J = 8.5Hz, 1H), 7.01 (s, 1H), 7.09 (d, J = 7.5Hz, 1H), 7.16 (t, J = 7.5Hz, 1H), 7.24-7.29 (m, 3H), 7.32-7.39 (m, 4H), 7.53-7.61 (m, 2H), 7.76 (s, 1H), 7.81 (d, J = 7.5Hz, 1H).

[0195] <Example 46> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-4'-methyl-[1,1'-biphenyl]-3-sulfonamide (223)

[0196]

[0197] Compound 223, as described in the title, was obtained by reacting compound 36 with commercially available 4-methylphenylboronic acid in the same manner as in Example 40 (yield 40 mg, yield 52%, TLC Rf value 0.27 at n-hexane / acetone = 2 / 1). 1HNMR (500MHz, CDCl3) δ2.21 (s, 3H), 2.39 (s, 3H), 2.90 (d, J = 12.5Hz, 1H), 3.11 (dd, J = 13.0, 3.5Hz, 1H ), 3.20-3.29 (m, 2H), 3.42 (dd, J = 13.0, 5.5Hz, 1H), 3.66-3.69 (m, 1H), 4.10-4.15 (m, 1H), 5.01 (d, J = 1 2.0Hz, 1H), 6.38-6.45 (m, 2H), 6.53 (d, J = 16.0Hz, 1H), 7.15 (t, J = 8.0Hz, 1H), 7.24-7.29 (m, 5H), 7.3 3 (d, J=6.5Hz, 1H), 7.38-7.42 (m, 4H), 7.52-7.56 (m, 2H), 7.77 (brs, 1H), 7.80 (dt, J=7.0, 2.5Hz, 1H).

[0198] <Example 47> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-(2,2,2-trifluoroethoxy)benzenesulfonamide (236)

[0199]

[0200] As shown in Scheme 17, compound 40 was obtained as a crude product by reacting commercially available 2-aminobenzyl alcohol (compound 39) with 3-(trifluoroethoxy)benzenesulfonyl chloride obtained in the same manner as in Reference Example 3 (yield 80 mg, TLC Rf value 0.51 at n-hexane / ethyl acetate = 1 / 1). Subsequently, compound 41 was obtained by reacting compound 40 (80 mg) with (2-bromoethoxy)(tert-butyl)dimethylsilane in the same manner as in Example 12 (yield 98 mg, 2-step yield 93%, TLC Rf value 0.54 at n-hexane / ethyl acetate = 3 / 1). Subsequently, compound 41 (98 mg) was dissolved in dichloromethane (5 mL), and under ice cooling, triethylamine (0.03 mL) and methanesulfonyl chloride (0.015 mL) were added and the mixture was stirred at room temperature for 4 hours. Water was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane / acetone = 2 / 1) to obtain compound 42 (yield 92 mg, yield 81%, TLC Rf value 0.41 at n-hexane / acetone = 3 / 1). Subsequently, compound 42 (92 mg) was dissolved in acetonitrile (5 mL), 12 M aqueous methylamine solution (0.2 mL) was added, and the mixture was stirred at room temperature for 48 hours. Water was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane / acetone = 2 / 1 to dichloromethane / methanol = 6 / 1) to obtain compound 43 (yield 68 mg, yield 83%, TLC Rf value 0.30 at dichloromethane / methanol = 9 / 1). Next, compound 44 was obtained by reacting compound 43 (68 mg) with (E)-3-(4-chlorophenyl)acrylaldehyde in the same manner as in Reference Example 2 (yield 74 mg, yield 85%, TLC Rf value 0.62 at n-hexane / ethyl acetate = 2 / 1). Finally, compound 236 of the title was obtained by removing the TBS group from compound 44 (74 mg) in the same manner as in Example 20 (yield 42 mg, yield 68%, TLC Rf value 0.44 at n-hexane / acetone = 2 / 1).1 HNMR (500MHz, CDCl3) δ2.20 (s, 3H), 2.87 (d, J = 12.0Hz, 1H), 3.10 (dd, J = 13.0, 3.0Hz, 1H), 3.18-3.28 (m, 2H), 3.41 (dd, J = 13.0, 5.0Hz, 1H), 3.65-3.68 (m, 1H), 4.07-4.12 (m, 1H), 4.22-4.34 (m, 2H), 4.97 (d, J = 12 .. 5Hz, 1H), 6.37-6.43 (m, 2H), 6.52 (d, J = 16.0Hz, 1H), 7.07-7.08 (m, 1H), 7.16 (td, J = 7.5, 2.0Hz, 1H), 7.2 0 (dd, J = 7.5, 2.0 Hz, 1H), 7.24-7.29 (m, 3H), 7.32-7.34 (m, 2H), 7.37-7.39 (m, 2H), 7.46 (t, J = 8.0Hz, 1H).

[0201] <Example 48> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)-4-fluorophenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (237)

[0202]

[0203] In the same manner as in Example 47, (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)-4-fluorophenyl)-3-isopropoxybenzenesulfonamide was obtained using commercially available (2-amino-5-fluorophenyl) methanol and 3-isopropoxybenzenesulfonyl chloride (compound 11) obtained in Reference Example 3. Finally, the TBS group was removed to obtain compound 237 of the title (yield 73 mg, yield 65%, TLC Rf value 0.35 at n-hexane / ethyl acetate = 1 / 2). 1HNMR (500MHz, CDCl3) δ1.28 (d, J = 5.3Hz, 3H), 1.30 (d, J = 5.3Hz, 3H), 2.22 (s, 3H), 2.83 (d, J = 12.0Hz, 1H) , 3.06 (d, J = 12.5 Hz, 1H), 3.19-3.28 (m, 2H), 3.41-3.43 (m, 1H), 3.67 (d, J = 12.0Hz, 1H), 4.08-4.10 (m, 1H) , 4.47-4.49 (m, 1H), 4.94 (d, J = 12.0Hz, 1H), 6.33-6.41 (m, 2H), 6.54 (d, J = 15.5Hz, 1H), 6.79-6.85 (m, 1H) ), 6.99-7.05 (m, 2H), 7.11 (d, J = 7.0Hz, 1H), 7.15 (d, J = 7.5Hz, 1H), 7.25-7.27 (m, 2H), 7.38-7.42 (m, 3H).

[0204] <Example 49> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-2-fluoro-N-(2-hydroxyethyl)-5-isopropoxybenzenesulfonamide (238)

[0205]

[0206] Using 2-fluoro-5-isopropoxybenzenesulfonyl chloride obtained in the same manner as in Example 47 and in the same manner as in Reference Example 3, (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)phenyl)-2-fluoro-5-3-isopropoxybenzenesulfonamide. Finally, by removing the TBS group, the title compound 238 was obtained (yield 27 mg, yield 73%, TLC Rf value 0.27 at n-hexane / ethyl acetate = 1 / 2). 1HNMR (500MHz, CDCl3) δ1.16 (d, J = 6.0Hz, 3H), 1.24 (d, J = 6.0Hz, 3H), 2.21 (s, 3H), 2.87 (d, J = 12.0Hz, 1H ), 3.19-3.22 (m, 1H), 3.27-3.31 (m, 2H), 3.41 (dd, J=14.0, 6.0Hz, 1H), 3.68 (d, J=12.5Hz, 1H), 4.26-4. 34 (m, 2H), 4.97 (d, J = 12.5Hz, 1H), 6.37-6.42 (m, 2H), 6.52 (d, J = 16.0Hz, 1H), 6.61 (d, J = 7.5Hz, 1H), 6. 92-6.95 (m, 1H), 7.01-7.05 (m, 1H), 7.14 (dt, J=20.0, 9.0Hz, 1H), 7.23-7.31 (m, 4H), 7.34-7.39 (m, 2H).

[0207] <Example 50> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)-5-fluorophenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (239)

[0208]

[0209] In the same manner as in Example 47, (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)-5-fluorophenyl)-3-isopropoxybenzenesulfonamide was obtained using commercially available (2-amino-4-fluorophenyl) methanol and 3-isopropoxybenzenesulfonyl chloride (compound 11) obtained in Reference Example 3. Finally, the TBS group was removed to obtain compound 239 of the title (yield 30 mg, yield 67%, TLC Rf value 0.22 at n-hexane / ethyl acetate = 1 / 2). 1HNMR (500MHz, CDCl3) δ1.28 (d, J = 6.0Hz, 3H), 1.31 (d, J = 6.0Hz, 3H), 2.20 (s, 3H), 2.86 (d, J = 13.0Hz, 1H), 3.04 (d , J=12.0Hz, 1H), 3.18-3.28 (m, 2H), 3.41-3.43 (m, 1H), 3.67 (d, J=12.0Hz, 1H), 4.08-4.10 (t, J=10.5Hz, 1H), 4.49 (d, J=5.5Hz, 1H), 4.92 (d, J=12.5Hz, 1H), 6.17 (d, J=8.5Hz, 1H), 6.37-6.40 (m, 1H), 6.52 (d, J=15.5Hz, 1H), 6.97 -7.00 (m, 1H), 7.06 (brs, 1H), 7.12 (d, J=8.0Hz, 1H), 7.18 (d, J=7.5Hz, 1H), 7.25-7.27 (m, 2H), 7.37-7.45 (m, 4H).

[0210] <Example 51> Synthesis of (E)-N-(2-hydroxyethyl)-3-isopropoxy-N-(2-(((3-(4-methoxyphenyl)allyl)(methyl)amino)methyl)phenyl)benzenesulfonamide (240)

[0211]

[0212] In the same manner as in Example 47, (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-isopropoxy-N-(2-(((3-(4-methoxyphenyl)allyl)(methyl)amino)methyl)phenyl)benzenesulfonamide was obtained using 3-isopropoxybenzenesulfonyl chloride (compound 11) and (E)-3-(4-methoxyphenyl)acrylaldehyde obtained in Reference Example 3. Finally, the TBS group was removed to obtain compound 240 of the title (yield 40 mg, yield 63%, TLC Rf value 0.54 at dichloromethane / methanol = 6 / 1). 1HNMR (500MHz, CDCl3) δ1.26 (d, J = 6.5Hz, 3H), 1.29 (d, J = 6.5Hz, 3H), 2.21 (s, 3H), 2.91 (d, J = 12.0Hz, 1H), 3.11 (dd, J = 12.5, 3.0, 1H), 3.2 0-3.28 (m, 2H), 3.38 (dd, J = 13.0, 6.5Hz, 1H), 3.66 (dt, J = 14.5, 2.5H z, 1H), 3.78 (s, 3H), 4.07-4.12 (m, 1H), 4.42-4.49 (m, 1H), 4.95 (d, J =12.5Hz, 1H), 6.25 (dt, 16.0, 7.0Hz, 1H), 6.44 (d, J = 7.5Hz, 1H), 6.5 0 (d, J = 16.0Hz, 1H), 6.82-6.85 (m, 2H), 7.05-7.06 (m, 1H), 7.09 (dd, J = 8.0, 3.0Hz, 1H), 7.14 (td, J = 8.0, 1.5Hz, 1H), 7.18 (d, J = 8.0Hz, 1H ), 7.21-7.27 (m, 1H), 7.30 (dd, J=8.0, 1.5Hz, 1H), 7.35-7.39 (m, 3H).

[0213] <Example 52> Synthesis of (E)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)-6-fluorophenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (241)

[0214]

[0215] In the same manner as in Example 47, (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-(((3-(4-chlorophenyl)allyl)(methyl)amino)methyl)-6-fluorophenyl)-3-isopropoxybenzenesulfonamide was obtained using commercially available (2-amino-3-fluorophenyl) methanol and 3-isopropoxybenzenesulfonyl chloride (compound 11) obtained in Reference Example 3. Finally, the TBS group was removed to obtain compound 241 of the title (yield 32 mg, yield 76%, Rf value 0.31 at n-hexane / ethyl acetate = 1 / 2). 1HNMR (500MHz, CDCl3) δ1.28 (d, J = 5.5Hz, 3H), 1.31 (d, J = 5.5Hz, 3H), 2.22 (s, 3H), 2.94 (d, J = 12.0Hz, 1H), 3.21 (d d, J=13.0, 7.0Hz, 1H), 3.30 (dd, J=13.5, 5.0Hz, 1H), 3.36 (dd, J=12.5, 7.5Hz, 1H), 3.42 (d, J=13.5, 6.5Hz, 1H), 3 .. 83 (dd, J=11.8, 5.0Hz, 1H), 4.05 (dd, J=14.0, 7.5Hz, 1H), 4.47-4.50 (m, 1H), 4.99 (d, J=12.5Hz, 1H), 6.37-6.40 (m, 1H), 6.53 (d, J=16.0Hz, 1H), 6.91 (t, J=9.0Hz, 1H), 7.09-7.11 (m, 3H), 7.21-7.27 (m, 2H), 7.35-7.39 (m, 5H).

[0216] <Example 53> Synthesis of (E)-N-(2-(((3-(4-cyanophenyl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (243)

[0217]

[0218] In the same manner as in Example 47, (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-(((3-(4-cyanophenyl)allyl)(methyl)amino)methyl)phenyl)-3-isopropoxybenzenesulfonamide was obtained by using 3-isopropoxybenzenesulfonyl chloride (compound 11) and (E)-4-(3-oxoprop-1-en-1-yl)benzonitrile obtained in Reference Example 3. Finally, the TBS group was removed to obtain compound 243 of the title (yield 41 mg, 2-step yield 58%, TLC Rf value 0.58 at dichloromethane / methanol = 6 / 1). 1HNMR (500MHz, CDCl3) δ1.26 (d, J = 6.0Hz, 3H), 1.29 (d, J = 6.0Hz, 3H), 2.20 (s, 3H), 2.83 (d, J = 12.0Hz, 1H), 3.10 (dd, J = 1 2.5, 2.5, 1H), 3.19-3.26 (m, 2H), 3.48 (dd, J = 12.5, 4.0Hz, 1H), 3.64 (dt, J = 12.5, 2.5Hz, 1H), 4.08-4.13 (m, 1H), 4.44- 4.48 (m, 1H), 5.0 (d, J = 12.0Hz, 1H), 6.42 (d, J = 6.5Hz, 1H), 6.57-6.62 (m, 2H), 7.03-7.04 (m, 1H), 7.09 (dd, J = 7.5, 2.0H) z, 1H), 7.14-7.17 (m, 2H), 7.26 (d, J = 9.0Hz, 1H), 7.30 (d, J = 7.5, 1.5Hz, 1H), 7.37 (t, J = 8.0Hz, 1H), 7.55-7.59 (m, 4H).

[0219] <Example 54> Synthesis of (E)-N-(2-(((3-(5-chloropyridine-2-yl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (245)

[0220]

[0221] In the same manner as in Example 47, (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-(((3-(5-chloropyridine-2-yl)allyl)(methyl)amino)methyl)phenyl)-3-isopropoxybenzenesulfonamide was obtained by using 3-isopropoxybenzenesulfonyl chloride (compound 11) obtained in Reference Example 3 and (E)-3-(5-chloropyridine-2-yl)acryl obtained in Reference Example 6. Finally, the TBS group was removed to obtain compound 245 of the title (yield 53 mg, 2-step yield 66%, TLC Rf value 0.42 at dichloromethane / methanol = 6 / 1). 1HNMR (500MHz, CDCl3) δ1.27 (d, J = 6.0Hz, 3H), 1.30 (d, J = 6.0Hz, 3H), 2.23 (s, 3H), 2.92 (d, J=12.5Hz, 1H), 3.11 (dd, J=12.5, 3.0Hz, 1H), 3. 23-3.28 (m, 2H), 3.48 (dd, J=14.5, 6.0Hz, 1H), 3.63-3.68 (m, 1H), 4. 09-4.14 (m, 1H), 4.44-4.49 (m, 1H), 4.97 (d, J = 12.5Hz, 1H), 6.44 (d, J =8.0Hz, 1H), 6.68 (d, J = 16.0Hz, 1H), 6.79 (dt, J = 14.5, 7.5Hz, 1H), 7 .04-7.06 (m, 1H), 7.09 (dd, J=8.0, 2.0Hz, 1H), 7.14-7.19 (m, 2H), 7.2 5-7.29 (m, 1H), 7.32 (dd, J = 7.5, 2.0Hz, 1H), 7.37 (t, J = 8.0Hz, 1H), 7 .54-7.57 (m, 1H), 7.60 (dd, J=8.5, 2.0Hz, 1H), 8.47 (d, J=2.5Hz, 1H).

[0222] <Example 55> Synthesis of N-(2-((((6-chloro-1H-indole-2-yl)methyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (247)

[0223]

[0224] In the same manner as in Example 47, N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-((((6-chloro-1H-indole-2-yl)methyl)(methyl)amino)methyl)phenyl)-3-isopropoxybenzenesulfonamide was obtained by using 3-isopropoxybenzenesulfonyl chloride (compound 11) obtained in Reference Example 3 and commercially available 6-chloro-1H-indole-2-carbaldehyde. Finally, the TBS group was removed to obtain compound 247 of the title (yield 56 mg, yield 64%, TLC Rf value 0.65 in n-hexane / ethyl acetate = 1 / 2). 1HNMR (500MHz, CDCl3) δ1.27 (d, J = 6.0Hz, 3H), 1.30 (d, J = 6.0Hz, 3H), 2.15 (s, 3H), 2.98 (d, J = 12.5Hz, 1H ), 3.15-3.18 (m, 1H), 3.35-3.39 (m, 1H), 3.71-3.82 (m, 3H), 4.16-4.21 (m, 1H), 4.45-4.50 (m, 1H), 5.02 (d, J=12.0Hz, 1H), 6.34 (brs, 1H), 6.47 (d, J=8.0Hz, 1H), 6.99 (dd, J=8.0, 2.0Hz, 1H), 7.04-7.06 (m, 1H) ), 7.11 (dd, J=8.0, 2.5Hz, 1H), 7.16-7.19 (m, 2H), 7.25-7.29 (m, 1H), 7.34-7.42 (m, 4H), 9.93 (brs, 1H).

[0225] <Example 56> Synthesis of N-(2-((((5-chloro-1H-indole-2-yl)methyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (248)

[0226]

[0227] In the same manner as in Example 47, N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-((((5-chloro-1H-indole-2-yl)methyl)(methyl)amino)methyl)phenyl)-3-isopropoxybenzenesulfonamide was obtained by using 3-isopropoxybenzenesulfonyl chloride (compound 11) obtained in Reference Example 3 and commercially available 5-chloro-1H-indole-2-carbaldehyde. Finally, the TBS group was removed to obtain compound 248 of the title (yield 59 mg, yield 73%, TLC Rf value 0.25 in n-hexane / ethyl acetate = 1 / 1). 1HNMR (500MHz, DMSO-d6) δ1.18 (d, J = 6.0Hz, 3H), 1.20 (d, J = 6.0Hz, 3H), 2.08 (s, 3H), 3.35-3.45 (m, 3H) , 3.62-3.65 (m, 2H), 3.76-3.78 (m, 1H), 3.90 (d, J=14.0Hz, 1H), 4.52-4.57 (m, 1H), 5.22 (brs, 1H), 6.3 4 (brs, 1H), 6.58 (d, J = 8.0Hz, 1H), 6.92 (brs, 1H), 7.00 (dd, J = 8.5, 2.0Hz, 1H), 7.12-7.16 (m, 2H), 7.2 1 (dd, J=8.0, 2.5Hz, 1H), 7.32-7.35 (m, 2H), 7.45-7.48 (m, 2H), 7.75 (d, J=7.0Hz, 1H), 11.1 (brs, 1H).

[0228] <Example 57> Synthesis of (E)-N-(2-(((3-(5-chloropyridine-2-yl)allyl)(methyl)amino)methyl)phenyl)-N-(2-hydroxyethyl)-2-methoxy-5-propoxybenzenesulfonamide (249)

[0229]

[0230] In the same manner as in Example 47, using 2-methoxy-5-propoxybenzenesulfonyl chloride obtained by referring to the method of Reference Example 3 and (E)-3-(5-chloropyridine-2-yl)acrylaldehyde obtained in Reference Example 6, (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-(((3-(5-chloropyridine-2-yl)allyl)(methyl)amino)methyl)phenyl)-2-methoxy-5-propoxybenzenesulfonamide. Finally, by removing the TBS group, the title compound 249 was obtained (yield 93 mg, 2-step yield 51%, TLC Rf value 0.62 at dichloromethane / methanol = 6 / 1). 1HNMR (500MHz, CDCl3) δ0.94 (t, J = 10.0Hz, 3H), 1.65-1.72 (m, 2H), 2.24 (s, 3H), 2.92 (d, J=12.5Hz, 1H), 3.24-3.55 (m, 3H), 3.46 (dd, J = 13.5, 6.0Hz, 1H), 3.67-3.71 (m, 2H), 3.74-3.78 (m, 1H), 3.80 (s, 3H), 4.35-4.40 (m, 1H), 5.02 (d, J = 12.5Hz, 1H), 6.66-6.69 (m, 2H) , 6.78 (dt, J=15.0, 7.5Hz, 1H), 6.95 (d, J=9.0Hz, 1H), 7.05 (dd, J= 8.5, 3.0Hz, 1H), 7.08 (d, J = 2.5Hz, 1H), 7.12 (td, J = 8.0, 1.5Hz, 1H) , 7.21 (td, J = 7.5, 1.0 Hz, 1H), 7.27 (dd, J = 7.5, 2.0 Hz, 1H), 7.52 (d , J=8.5Hz, 1H), 7.59 (dd, J=8.5, 2.0Hz, 1H), 8.47 (d, J=3.0Hz, 1H).

[0231] <Example 58> Synthesis of (E)-N-(2-(((3-(5-chloropyridine-2-yl)allyl)(methyl)amino)methyl)phenyl)-5-(cyclobutylmethoxy)-N-(2-hydroxyethyl)-2-methoxybenzenesulfonamide (252)

[0232]

[0233] In the same manner as in Example 47, using 5-(cyclobutylmethoxy)-2-methoxybenzenesulfonyl chloride obtained by referring to the method of Reference Example 3 and (E)-3-(5-chloropyridine-2-yl)acrylaldehyde obtained in Reference Example 6, (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(2-(((3-(5-chloropyridine-2-yl)allyl)(methyl)amino)methyl)phenyl)-5-(cyclobutylmethoxy)-2-methoxybenzenesulfonamide was obtained. Finally, by removing the TBS group, the title compound 252 was obtained (yield 80 mg, 2-step yield 50%, TLC Rf value 0.34 at dichloromethane / methanol = 9 / 1). 1HNMR (500MHz, CDCl3) δ1.74-1.80 (m, 2H), 1.86-1.95 (m, 2H), 2.03-2 .07 (m, 2H), 2.24 (s, 3H), 2.61-2.64 (m, 1H), 2.92 (d, J=13.0Hz, 1H), 3 .26-3.35 (m, 3H), 3.47 (dd, J=13.0, 5.5Hz, 1H), 3.69-3.72 (m, 2H), 3 76-3.78 (m, 1H), 3.80 (s, 3H), 4.35-4.40 (m, 1H), 5.02 (d, J=12.0Hz, 1H), 6.66-6.69 (m, 2H), 6.78 (dt, J = 16.0, 6.5Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 7.05 (dd, J=9.0, 3.0Hz, 1H), 7.08 (d, J=3.5Hz, 1H), 7.13 (td, J=7.5, 1.0Hz, 1H), 7.22 (t, J=7.5Hz, 1H), 7.28 (d, J=6.0Hz, 1H), 7.53 (d, J=8.5Hz, 1H), 7.60 (dd, J=9.0, 2.0Hz, 1H), 8.46 (d, J=2.0Hz, 1H).

[0234] <Example 59> Synthesis of (E)-N-(2-(1-((3-(4-chlorophenyl)allyl)(methyl)amino)ethyl)phenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (242)

[0235]

[0236] As shown in Scheme 18, compound 45 (1.00 g) was mesylated, and the resulting product (1.55 g) was dissolved in THF (20 mL). 12 M methylamine aqueous solution (5 mL) was added, and the mixture was stirred at 70°C for 16 hours. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 1 to dichloromethane / methanol = 6 / 1) to obtain compound 46 (yield 690 mg, yield 64%, TLC Rf value 0.14 at n-hexane / ethyl acetate = 2 / 1). Subsequently, compound 46 (250 mg) was dissolved in dichloromethane (10 mL), triethylamine (0.192 mL) and di-tert-butyl dicarbonate (372 mg) were added, and the mixture was stirred at room temperature for 16 hours. Water was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10 / 1 to 2 / 1) to obtain compound 47 (yield 357 mg, yield 92%, TLC Rf value 0.28 at n-hexane / ethyl acetate = 9 / 1). Subsequently, compound 47 (357 mg) was dissolved in methanol (10 mL), palladium carbon (100 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The mixture was filtered and concentrated under reduced pressure to obtain compound 47 (yield 293 mg, yield 92%, TLC Rf value 0.60 at n-hexane / ethyl acetate = 2 / 1). Next, compound 49 was obtained by reacting compound 47 (293 mg) with 3-isopropoxybenzenesulfonyl chloride (compound 11) obtained in Reference Example 3, in the same manner as in Example 1 (yield 121 mg, yield 23%, TLC Rf value 0.37 at n-hexane / ethyl acetate = 4 / 1). Next, compound 50 was obtained by reacting compound 49 (70 mg) with (2-bromoethoxy)(tert-butyl)dimethylsilane, in the same manner as in Example 12 (yield 66 mg, yield 41%, TLC Rf value 0.62 at n-hexane / ethyl acetate = 4 / 1). Next, compound 50 (66 mg) was dissolved in methanol (5 mL), concentrated hydrochloric acid (1 mL) was added, and the mixture was stirred at room temperature for 16 hours.Water and sodium bicarbonate were added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to obtain compound 51 as the crude product (yield 48 mg, TLC Rf value 0.42 at dichloromethane / methanol = 9 / 1). Subsequently, compound 51 (48 mg) was reacted with (E)-3-(4-chlorophenyl)acrylaldehyde in the same manner as in Reference Example 2 to obtain the title compound 242 (yield 41 mg, yield 68%, TLC Rf value 0.65 at dichloromethane / methanol = 9 / 1). 1 HNMR (500MHz, CDCl3) δ1.27 (d, J=7.0Hz, 3H), 1.30 (d, J=7.0Hz, 3H), 1.35 (d, J=8.5Hz, 3H), 2.16 (s, 3H), 3. 13 (dd, J=16.5, 6.5Hz, 1H), 3.27-3.40 (m, 3H), 3.70 (d, J=14.0Hz, 1H), 4.10-4.14 (m, 1H), 4.45-4.50 (m, 1H) , 5.28 (brs, 1H), 6.39-6.45 (m, 2H), 6.52 (d, J = 16.5Hz, 1H), 7.04-7.06 (m, 1H), 7.09 (dd, J = 8.5, 1.5Hz, 1H) , 7.13 (t, J=7.5Hz, 1H), 7.16 (d, J=7.5Hz, 1H), 7.24-7.32 (m, 3H), 7.35-7.40 (m, 3H), 7.45 (d, J=7.5Hz, 1H).

[0237] <Example 60> Synthesis of (S,E)-N-(2-(1-((3-(4-chlorophenyl)allyl)(methyl)amino)ethyl)phenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (250)

[0238]

[0239] As shown in Scheme 19, compound 52 (1.01 g) obtained by the method described in Molecules 2011, 16, 8098-8109 was mesylated and methylated in the same manner as in Example 59 to obtain compound 53 (yield 458 mg, yield 43%, TLC Rf value 0.45 at dichloromethane / methanol = 9 / 1). Subsequently, compound 53 (245 mg) was reacted with (E)-3-(4-chlorophenyl)acrylaldehyde in the same manner as in Reference Example 2 to obtain compound 54 as a crude product (yield 469 mg, TLC Rf value 0.85 at n-hexane / ethyl acetate = 1 / 1). Subsequently, the Boc group of compound 54 (469 mg) was removed by TFA to obtain compound 55 (yield 102 mg, 2-step yield 34%, TLC Rf value 0.57 at n-hexane / ethyl acetate = 2 / 1). Next, compound 56 was obtained by reacting compound 55 (102 mg) with 3-isopropoxybenzenesulfonyl chloride (compound 11) obtained in Reference Example 3, in the same manner as in Example 1 (yield 72 mg, yield 42%, TLC Rf value 0.71 at n-hexane / ethyl acetate = 2 / 1). Subsequently, compound 57 was obtained as a crude product by reacting compound 56 (72 mg) with (2-bromoethoxy)(tert-butyl)dimethylsilane, in the same manner as in Example 12 (yield 103 mg, TLC Rf value 0.42 at n-hexane / ethyl acetate = 2 / 1). Finally, compound 250, the title compound, was obtained by removing the TBS group from compound 57 (103 mg), in the same manner as in Example 20 (yield 42 mg, 2-step yield 53%, TLC Rf value 0.57 at dichloromethane / methanol = 9 / 1). 1HNMR (500MHz, CDCl3) δ1.27 (d, J = 6.3Hz, 3H), 1.30 (d, J = 6.3Hz, 3H), 1.35 (d, J = 6.5Hz, 3H), 2.16 (s, 3H), 3.13 (dd, J =13.0, 3.5Hz, 1H), 3.26-3.32 (m, 2H), 3.40 (dd, J = 16.0, 6.5Hz, 1H), 3.70 (d, J = 13.0Hz, 1H), 4.10-4.14 (m, 1H), 4.45 -4.51 (m, 1H), 5.25-5.27 (m, 1H), 6.39-6.45 (m, 2H), 6.52 (d, J = 16.5Hz, 1H), 7.04-7.06 (m, 1H), 7.09 (dd, J = 8.5, 1. 5Hz, 1H), 7.13 (t, J = 7.5Hz, 1H), 7.17 (d, J = 7.5Hz, 1H), 7.24-7.32 (m, 3H), 7.34-7.40 (m, 3H), 7.44 (d, J = 8.5Hz, 1H).

[0240] <Example 61> Synthesis of (R,E)-N-(2-(1-((3-(4-chlorophenyl)allyl)(methyl)amino)ethyl)phenyl)-N-(2-hydroxyethyl)-3-isopropoxybenzenesulfonamide (251)

[0241]

[0242] Using the enantiomer of compound 52 (1.33 g) obtained by the method described in Molecules 2011, 16, 8098-8109, the enantiomer of compound 57 was obtained as a crude product in the same manner as in Example 60 (yield 182 mg, TLC Rf value 0.51 in n-hexane / ethyl acetate = 3 / 1). Finally, the title compound 251 was obtained by removing the TBS group (yield 70 mg, yield 49%, TLC Rf value 0.40 in ethyl acetate). 1HNMR(500MHz,CDCl3)δ1.28(d,J=6.3Hz,3H),1.30(d,J=6.3Hz,3H),1.35(d,J=7.0Hz,3H),2.15(s,3H),3.14(dd,J=13.5,3.5Hz,1H),3.27-3.32(m,2H),3.41(dd,J=13.5,5.0Hz,1H),3.68-3.72(m,1H),4.10-4.15(m,1H),4.46-4.51(m,1H),5.25―5.29(m,1H),6.37-6.46(m,2H),6.52(d,J=15.0Hz,1H),7.04-7.06(m,1H),7.10(dd,J=9.0,3.0Hz,1H),7.13(t,J=8.0Hz,1H),7.17(d,J=7.5Hz,1H),7.24-7.26(m,2H),7.30(t,J=8.5Hz,1H),7.35―7.40(m,3H),7.45(d,J=8.0Hz,1H).

[0243] <Test Example 1> Evaluation of SET inhibitory and CaMK2 inhibitory effects The inhibitory effect on SET was analyzed by its effect of dissociating the SET dimer. For this purpose, cells that stably express Promega's NanoBiT system were established. In the cell-free system analysis, SET fused with LargeBiT or SmallBiT was extracted from these cells, and compounds were applied at various concentrations at room temperature for 2 hours. The inhibition rate (%) was calculated as the ratio of the luminescence intensity with compound addition to the luminescence intensity without compound addition. In the cell system analysis, the above cells cultured on a 96-well plate were applied with the compound for 24 hours, and the inhibition rate (%) was calculated in the same manner as in the cell-free system evaluation. The results are shown in Table 1. The SET inhibitory effect of each compound in a cell-free system was expressed as follows: +++++ if the concentration giving a 50% inhibition rate was 50 nM or less, ++++ if it was in the range of 50 to 500 nM, +++ if it was in the range of 500 to 1000 nM, and ++ if it was in the range of 1000 nM or more. The SET inhibitory effect of each compound in a cell system was expressed as ++++ if the concentration giving a 50% inhibition rate was 100 nM or less, +++ if it was in the range of 100 to 1000 nM, and NT if not evaluated. On the other hand, the evaluation of CaMK2 inhibitory effect (cell-free system) as a counter-assay was performed by measuring the ATP concentration remaining after the substrate phosphorylation reaction by CaMK2 with or without compound addition using Promega's Kinase-Glo Plus, and calculating the inhibition rate (%) of the compound. The results are shown in Table 1. If the concentration that yielded a 50% inhibition rate was in the range of 1 to 10 μM, it was represented as ++, and if it was 10 μM or higher, it was represented as +.

[0244]

[0245] As shown in Table 1, the benzenesulfonamide compounds of the present invention strongly inhibit SET at concentrations of 1 μM or less, but inhibit CaMK2 only to the extent of 1 to 10 μM or higher concentrations. In other words, compound (I) of the present invention has strong SET inhibitory activity and high selectivity. On the other hand, KN-93 requires a concentration of 1 μM or higher to show clear inhibition of both SET and CaMK2, and is therefore clearly inferior to compound (I) of the present invention in terms of SET inhibitory activity and selectivity.

[0246] The benzenesulfonamide compounds represented by formula (I), their salts, or solvates provided by the present invention have excellent SET inhibitory activity. A pharmaceutical product containing a substance selected from the group consisting of benzenesulfonamide compounds represented by formula (I), their salts, or solvates as an active ingredient is useful as a pharmaceutical product for the treatment and / or prevention of cancer.

Claims

1. The following formula (I) A benzenesulfonamide compound represented by formula (I), a salt thereof, or a solvate thereof. (In formula (I), R1 represents a C1-4 alkyl group, a C1-4 monofluoroalkyl group, or a C3-6 cycloalkyl group; R2 represents an optionally substituted phenyl vinyl group, an optionally substituted heteroaryl vinyl group, or an optionally substituted heteroaryl group; R3 represents a hydrogen atom or a methyl group; R4 represents a hydrogen atom or a fluorine atom; and R5 and R6 are each the same or different and selected from a hydrogen atom, a halogen atom, a C1-3 alkyl group, a C1-3 alkyl group substituted with 1-3 fluorine atoms, a C3-6 cycloalkyl group, a C3-6 alkynyl group, a C1-6 alkoxy group, a C1-6 alkoxy group substituted with 1-3 fluorine atoms, a C3-6 alkynyloxy group, a C3-6 alkenyloxy group, a C3-6 cycloalkoxy group, an optionally substituted phenyl group, a phenoxy group, and a heteroaryl group, but a hydrogen atom is never selected at the same time.) 2. The benzenesulfonamide compound according to claim 1, a salt thereof, or a solvate thereof, wherein R1 is selected from a methyl group, an ethyl group, a cyclopropyl group, and a 2-fluoroethyl group.

3. A benzenesulfonamide compound according to claim 1 or 2, a salt thereof, or a solvate thereof, wherein R2 is selected from 4-chlorophenylvinyl group, 4-(trifluoromethyl)phenylvinyl group, 4-cyanophenylvinyl group, 4-methoxyphenylvinyl group, 5-chloro-2-pyridylvinyl group, 5-chloroindolyl group, and 6-chloroindolyl group.

4. R5 and R6 are the same or different, and consist of a hydrogen atom, fluorine atom, bromine atom, methyl group, isopropyl group, cyclopropyl group, trifluoromethyl group, ethynyl group, methoxy group, ethoxy group, n-propoxy group, n-butoxy group, n-pentyloxy group, isopropoxy group, tert-butoxy group, 2,2-dimethylpropoxy group, cyclopropyl methoxy group, cyclobutyl methoxy group, benzyloxy group, difluoromethoxy group, trifluoromethoxy group, 2,2,2- A benzenesulfonamide compound according to claims 1 to 3, a salt thereof, or a solvate thereof, selected from a difluoroethoxy group, propargyloxy group, prenyloxy group, cyclopropoxy group, cyclobutyroxy group, cyclopentyroxy group, 2-methoxyphenyl group, 3-methoxyphenyl group, phenyl group, p-tolyl group, phenoxy group, 5-triazolyl group, 1-pyrazolyl group, 2-benzofuryl group, and 3-benzofuryl group, but without any hydrogen atoms being selected simultaneously.

5. A pharmaceutical composition containing a benzenesulfonamide compound according to any one of claims 1 to 4, a salt thereof, or a solvate thereof.

6. The pharmaceutical composition according to claim 5, which is a preventive or therapeutic agent for cancer.

7. A benzenesulfonamide compound, a salt thereof, or a solvate thereof, as described in any of claims 1 to 4, for use in the treatment and / or prevention of cancer.

8. Use of a benzenesulfonamide compound, a salt thereof, or a solvate thereof according to any one of claims 1 to 4 for the manufacture of a drug for the treatment and / or prevention of cancer.

9. A method for treating and / or preventing cancer, characterized by administering a benzenesulfonamide compound, a salt thereof, or a solvate thereof, as described in any one of claims 1 to 4.

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