JP2001261649A - Sulfonamide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an aromatic sulfonamide derivative having high cell cycle inhibitory activity, and more useful as an antitumor agent than conventionally known aromatic sulfonamide-based antitumor compounds. SOLUTION: This sulfonamide derivative is shown by the general formula (1), wherein, ring A a (substituted) benzene ring or (substituted) thiophene; X is a group of the formula CH=CH or the like; n is 0 or 1; R1 is H, a 1-6C alkyl or the like; R2 is a 1-6C alkylene; and Y is cyano, a group of the formula CONR3R4 (R3 and R4 are each H, OH, a 1-6C alkyl or the like) or group of the formula SO2NR5R6 (R5 and R6 are each H or a 1-6C alkyl).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel aromatic sulfonamide derivative having excellent cell cycle inhibitory activity and useful as an antitumor agent, and a pharmaceutically acceptable salt thereof.

[0002]

2. Description of the Related Art As aromatic sulfonamide-based antitumor compounds, 4-aminobenzenesulfonamide derivatives described in JP-B-43-3093 and JP-A-62-42 are disclosed.
2-sulfanilamide-quinoxaline derivative described in JP-A-5-39256;
(2-anilino-3-pyridinyl) benzenesulfonamide derivatives, bicyclic heterocycle-containing sulfonamide derivatives described in JP-A-7-165708, JP-A-8-8
1441; a tricyclic heterocycle-containing sulfonamide derivative described in JP-A-8-231505; an indole-containing sulfonamide derivative described in JP-A-8-231505; WO95 / 276
Aminostilbazole derivative described in WO99, WO9
N- (N'-acyl-2-) described in 8/54131
Anilino) benzenesulfonamide derivatives and the like are known.

[0003]

DISCLOSURE OF THE INVENTION The present invention relates to an aromatic sulfonamide-based antitumor compound which has excellent cell cycle inhibitory activity and is more useful as an antitumor agent than a conventionally known aromatic sulfonamide type antitumor compound. Another object is to provide a sulfonamide derivative, and also to provide a pharmaceutical composition containing the aromatic sulfonamide derivative as an active ingredient.

[0004]

Means for Solving the Problems The present inventors have proposed a sulfone amide which has an excellent cell cycle inhibitory activity and is more useful as an antitumor agent than the conventionally known aromatic sulfonamide type antitumor compounds. As a result of intensive studies on the synthesis of the amide derivative and its pharmacological activity, a novel sulfonamide derivative having strong antitumor activity was found, and the present invention was completed.

That is, the present invention provides a compound represented by the general formula (1)

[0006]

Embedded image

(Wherein ring A may have a substituent selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms and a halogeno group, X represents a benzene ring or a thiophene ring;
H ＝ CH—, a formula —CH ₂ CH ₂ —, a formula —CONR ^7a — (wherein R ^7a represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms) or a formula —NR ^7b CO— ( In the formula, R ^7b represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (provided that the right end of the formula is bonded to a pyridine ring);
¹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkylsulfonylamino group having 1 to 6 carbon atoms, a halogeno group, a nitro group, an amino group or a cyano group. shown, R ² represents a 1 to 6 alkylene group having a carbon, Y is a cyano group, a group represented by the formula -CONR ³
R ⁴ (wherein, R ³ and R ⁴ are the same or different and are each a hydrogen atom, a hydroxy group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, 3 to 8 carbon atoms Cycloalkyl group, 3 to 8 cycloalkyloxy groups, C6 to C10 aryl group, C6 to C1
0 aryloxy groups, aryl having 7 to 16 carbon atoms
A cycloalkylalkyl group, an arylalkyloxy group having 7 to 16 carbon atoms, a cycloalkylalkyl group having 4 to 14 carbon atoms, a cycloalkylalkyloxy group having 4 to 14 carbon atoms, or a tetrahydrofuranyloxy group. Or a formula —SO ₂ NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ are the same or different and each represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms). ) And pharmacologically acceptable salts thereof.

In the above formula (1), “C 1” which may be a substituent of “benzene ring or thiophene ring” of “ring A”
Examples of the "to 6 alkyl groups" include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1- Ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl,
2,2-dimethylbutyl, 1,1-dimethylbutyl,
1,2-dimethylbutyl, 1,3-dimethylbutyl,
Examples thereof include a linear or branched alkyl group having 1 to 6 carbon atoms such as 2,3-dimethylbutyl and 2-ethylbutyl, preferably methyl or ethyl, and more preferably methyl. Group.

In the above formula (1), “C 1” which may be a substituent of “benzene ring or thiophene ring” of “ring A”
Examples of the "-6 alkoxy groups" include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-
Butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3, 1 to 6 carbon atoms such as 3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, and 2,3-dimethylbutoxy groups A straight-chain or branched-chain alkoxy group is mentioned, preferably a methoxy or ethoxy group, more preferably a methoxy group.

The "halogeno group" which can be a substituent of the "benzene ring or thiophene ring" of "ring A" in the above formula (1) includes, for example, fluoro, chloro, bromo and iodo groups. , A chloro group.

In the “ring A” of the above formula (1), preferred rings are
Unsubstituted benzene, methylbenzene, ethylbenzene,
Methoxybenzene, ethoxybenzene, unsubstituted thiophene, methylthiophene, ethylthiophene, methoxythiophene or ethoxythiophene, more preferably an unsubstituted benzene ring or an unsubstituted thiophene ring; It is a substituted benzene ring.

In the above formula (1), "X-CONR
^As the “alkyl group having 1 to 6 carbon atoms” for R ^{7a in 7a} −, the same groups as described above can be mentioned, preferably a methyl or ethyl group, and more preferably a methyl group. .

In the above formula (1), "X-formula -NR ^7b C
Examples of the “alkyl group having 1 to 6 carbon atoms” for R ^7b in O— ”include the same as described above, preferably a methyl or ethyl group, and more preferably a methyl group. It is.

In X of the above formula (1), preferred groups are those of the formula -C
H = CH—, a formula —CH ₂ CH ₂ —, a formula —NHCO— or a formula —CONH—, more preferably a formula —CHＣＨCH
— (Trans) or —NHCO—.

In the above formula (1), n is preferably 0.

Examples of the "alkyl group having 1 to 6 carbon atoms" for R ¹ in the above formula (1) include the same as described above, preferably a methyl or ethyl group, more preferably , A methyl group.

Examples of the “alkoxy group having 1 to 6 carbon atoms” for R ¹ in the above formula (1) include, for example, methoxy,
Ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, tert-butoxy,
n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, linear or branched alkoxy groups having 1 to 6 carbon atoms such as 2,3-dimethylbutoxy group, Preferably, it is a methoxy or ethoxy group, more preferably, a methoxy group.

The “alkylsulfonylamino group having 1 to 6 carbon atoms” in R ¹ of the above formula (1) includes, for example, methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, n- Butylsulfonylamino, isobutylsulfonylamino, s-butylsulfonylamino, te
rt-butylsulfonylamino, n-pentylsulfonylamino, isopentylsulfonylamino, 2-methylbutylsulfonylamino, neopentylsulfonylamino, 1-ethylpropylsulfonylamino, n-hexylsulfonylamino, isohexylsulfonylamino,
4-methylpentylsulfonylamino, 3-methylpentylsulfonylamino, 2-methylpentylsulfonylamino, 1-methylpentylsulfonylamino, 3,3
-Dimethylbutylsulfonylamino, 2,2-dimethylbutylsulfonylamino, 1,1-dimethylbutylsulfonylamino, 1,2-dimethylbutylsulfonylamino, 1,3-dimethylbutylsulfonylamino, 2,3
-Dimethylbutylsulfonylamino, a linear or branched alkyl group having 1 to 6 carbon atoms such as a 2-ethylbutylsulfonylamino group, preferably a methylsulfonylamino or ethylsulfonylamino group, More preferably, it is a methylsulfonylamino group.

In R ¹ of the above formula (1), a preferred group is a methyl, ethyl, methoxy or ethoxy group, more preferably a methoxy group.

The “alkylene group having 1 to 6 carbon atoms” in R ² of the above formula (1) includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene,
Hexamethylene is mentioned, preferably a methylene or ethylene group, more preferably a methylene group.

In the above formula (1), the expression “-CONR
³ The R ⁴ R ³ and "alkyl group having 1 to 6 carbon atoms, R ^4" on ", for example, the same groups as those described above,
It is preferably a methyl group or an ethyl group, and more preferably a methyl group.

In the above formula (1), the formula “-CONR” in Y
³ The R ⁴ R ³ and "alkoxy group of 1 to 6 carbon atoms of R ⁴ in"", for example, the same groups as those described above,
Preferably, it is a methoxy or ethoxy group, and more preferably, a methoxy group.

In the above formula (1), the formula "-CONR" in Y
³ R ⁴ R ³ and R ⁴ in "as the" cycloalkyl group having 3 to 8 carbon atoms "include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, include cyclooctyl group, preferably, carbon The number is from 4 to 6, more preferably a cyclopentyl group.

In the above formula (1), the formula "-CONR" in Y
Of ³ R ⁴ R ³ and R ⁴ "as the" 3 to 8 cycloalkyloxy group ", for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyl group And preferably 4 to 6 carbon atoms, and more preferably a cyclopentyloxy group.

In the above formula (1), the formula "-CONR" in Y
³ R ⁴ "of R ³ and ant" having 6 to 10 carbon atoms R ⁴ - The Le group ", for example, phenyl, 1-naphthyl, 2-
Examples include a naphthyl group and the like, and preferably a phenyl group.

In the above formula (1), the formula "-CONR" in Y
³ R ⁴ R ³ and R ⁴ in "as the" aryloxy group having 6 to 10 carbon atoms ", for example, phenyloxy, 1-naphthyloxy, 2-naphthyloxy group and the like, preferably, It is a phenyloxy group.

In the above formula (1), the formula "-CONR" in Y
³ R ⁴ "of R ³ and ant" having 7 to 16 carbon R ⁴ - The Ruarukiru group ", for example, benzyl, 1-naphthylmethyl, 2-naphthylmethyl, 1-phenethyl, 2-
Phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3
-Phenylpropyl, 1-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-
Phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl, 1-
Phenylpentyl, 2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl, 5-phenylpentyl, 1-naphthylpentyl, 2-naphthylpentyl,
3-naphthylpentyl, 4-naphthylpentyl, 5-naphthylpentyl, 1-phenylhexyl, 2-phenylhexyl, 3-phenylhexyl, 4-phenylhexyl, 5-phenylhexyl, 6-phenylhexyl,
-Naphthylhexyl, 2-naphthylhexyl, 3-naphthylhexyl, 4-naphthylhexyl, 5-naphthylhexyl, and 6-naphthylhexyl. A benzyl group is preferable.

In the above formula (1), in Y, “formula —CONR
³ R ⁴ R ³ and R ⁴ "as the" number 7 to 16 arylalkyloxy group having a carbon ", for example, benzyloxy, 1-naphthyl methyloxy, 2-naphthyl methyloxy, 1-phenethyloxy, 2 -Phenethyloxy,
1-naphthylethyloxy, 2-naphthylethyloxy, 1-phenylpropyloxy, 2-phenylpropyloxy, 3-phenylpropyloxy, 1-naphthylpropyloxy, 2-naphthylpropyloxy, 3-naphthylpropyloxy, 1- Phenylbutyloxy, 2
-Phenylbutyloxy, 3-phenylbutyloxy,
4-phenylbutyloxy, 1-naphthylbutyloxy, 2-naphthylbutyloxy, 3-naphthylbutyloxy, 4-naphthylbutyloxy, 1-phenylpentyloxy, 2-phenylpentyloxy, 3-phenylpentyloxy, 4- Phenylpentyloxy, 5-phenylpentyloxy, 1-naphthylpentyloxy,
2-naphthylpentyloxy, 3-naphthylpentyloxy, 4-naphthylpentyloxy, 5-naphthylpentyloxy, 1-phenylhexyloxy, 2-phenylhexyloxy, 3-phenylhexyloxy, 4-
Phenylhexyloxy, 5-phenylhexyloxy, 6-phenylhexyloxy, 1-naphthylhexyloxy, 2-naphthylhexyloxy, 3-naphthylhexyloxy, 4-naphthylhexyloxy, 5-naphthylhexyloxy, 6-naphthylhexyl An oxy group is mentioned, and it is preferably a benzyloxy group.

In the above formula (1), “formula —CONR” in Y
³ R ⁴ as "number 4 to 14 of the cycloalkylalkyl group having a carbon" of R ³ and R ⁴ ", for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
Cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl; cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, cyclooctylethyl; cyclopropylpropyl, cyclobutylpropyl, cyclopentylpropyl, cyclohexylpropyl, cycloheptylpropyl Cyclopropylbutyl, cyclobutylbutyl, cyclopentylbutyl, cyclohexylbutyl, cycloheptylbutyl, cyclooctylbutyl; cyclopropylpentyl, cyclobutylpentyl, cyclopentylpentyl, cyclohexylpentyl, cycloheptylpentyl, cyclooctylpentyl; cyclo Propylhexyl, cyclobutylhexyl, cyclopen Hexyl, cyclohexyl hexyl, cycloheptyl hexyl, include cyclooctyl hexyl group, preferably are those having 4 to 8 carbon atoms, more preferably a cyclopropylmethyl group.

In the above formula (1), the formula "-CONR" in Y
³ R ⁴ R ³ and R ⁴ in "as the" number 4 to 14 of the cycloalkylalkyl group atoms ", for example, cyclopropylmethyloxy, cyclobutylmethyl oxy, cyclopentylmethyl oxy, cyclohexylmethyloxy, cycloheptyl Methyloxy, cyclooctylmethyloxy; cyclopropylethyloxy, cyclobutylethyloxy, cyclopentylethyloxy, cyclohexylethyloxy, cycloheptylethyloxy, cyclooctylethyloxy; cyclopropylpropyloxy, cyclobutylpropyloxy, cyclopentylpropyloxy, Cyclohexylpropyloxy, cycloheptylpropyloxy, cyclooctylpropyloxy; cyclopropylbutyloxy, cyclobutylbutyloxy, cyclope Chill butyloxy, cyclohexyl butyloxy, cycloheptyl butyloxy, cyclooctyl butyloxy; cyclopropyl pentyloxy,
Cyclobutylpentyloxy, cyclopentylpentyloxy, cyclohexylpentyloxy, cycloheptylpentyloxy, cyclooctylpentyloxy; cyclopropylhexyloxy, cyclobutylhexyloxy, cyclopentylhexyloxy, cyclohexylhexyloxy, cycloheptylhexyloxy, cyclooctylhexyloxy And is preferably a group having 4 to 8 carbon atoms, more preferably a cyclopropylmethyloxy group.

In the above formula (1), the expression "-SO ₂ N
The R ⁵ R ⁶ R ⁵ and "having 1 to 6 alkyl groups of carbon atoms of R ⁶ in the"", for example, the same groups as those described above,
Preferably, it is a methyl or ethyl group, and more preferably, a methyl group.

In Y of the above formula (1), preferred groups are those of the formula -C
ONHR ^3a (wherein, R ^3a is a hydrogen atom, a hydroxy group,
Represents an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or a tetrahydrofuranyloxy group)
Or a formula -CONCH ₃ R ^3b (wherein R ^3b represents an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms), and more preferably, a compound of the formula -CONHR ^3c
(Wherein, R ^3c represents a hydrogen atom, a hydroxy group, a methyl group,
A methoxy group or a benzyl group) or a formula -CONCH
₃ R ^3d (wherein, R ^3d represents a methyl group or a methoxy group), and particularly preferably, a group represented by the formula —CONH ₂ or a group represented by the formula —CO
NHCH _3, formula -CONHOH or formula -CONCH ₃ OC
H ₃ .

The preferred compounds of the present invention include the following: 1) When “Ring A” is an unsubstituted benzene, methylbenzene,
A compound which is ethylbenzene, methoxybenzene, ethoxybenzene, unsubstituted thiophene, methylthiophene, ethylthiophene, methoxythiophene or ethoxythiophene; 2) a compound wherein “Ring A” is an unsubstituted benzene ring or an unsubstituted thiophene ring 3) a compound wherein “Ring A” is an unsubstituted benzene ring; 4) X is a compound of the formula —CH ＝ CH—, formula —CH ₂ CH ₂ —, formula —
5) X is a compound of the formula -CH = CH- (trans form) or a compound of the formula -N.
6) a compound wherein n is 0; 7) a compound wherein R ¹ is a methyl, ethyl, methoxy or ethoxy group; 8) a compound wherein R ¹ is a methoxy group; 9) R ² Is a methylene or ethylene group; 10) a compound wherein R ² is a methylene group; 11) Y is a compound of the formula —CONHR ^3a (where R ^3a is a hydrogen atom, a hydroxy group, a carbon number of 1 to 6) Alkyl group, an alkoxy group having 1 to 6 carbon atoms or a tetrahydrofuranyloxy group) or a formula -CONCH ₃ R ^3b (wherein
R ^3b is a compound having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms) 12) Y is a compound of the formula —CONHR ^3c (where R ^3c is a hydrogen atom, hydroxy group, a methyl group, a methoxy group or a benzyl group) or wherein -CONCH ₃ R ^3d (wherein, R ^{3 d} is
Methyl or an methoxy group), Compound, 13) Y has the formula -CONH _2, wherein -CONHCH _3, wherein -
It can be exemplified CONHOH or compound is of formula -CONCH ₃ OCH _3.

Further, 1 is selected from 1) to 3), and 4)
Or select 1 from 5), select 6), 7) or 8)
1 from 9) or 1 from 9) and 1
Compounds obtained by selecting 1 from 1) to 13) and arbitrarily combining 2 to 6 selected are also suitable.

The compound of the present invention may have an asymmetric carbon in the molecule. In this case, there are stereoisomers each of which is in the R-coordination or S-coordination. In any case.

The compounds of the present invention can be made into salts, and the salts are also included in the present invention. Such salts include hydrofluorides, hydrochlorides, hydrobromides, hydrohalides such as hydroiodates, nitrates, perchlorates, sulfates, phosphates and the like. Inorganic acid salts; lower alkanesulfonic acid salts such as methanesulfonic acid salt, trifluoromethanesulfonic acid salt, ethanesulfonic acid salt, benzenesulfonic acid salt,
Aryl sulfonate such as p-toluene sulfonate, organic acid such as acetic acid, malic acid, fumarate, succinate, citrate, tartrate, maleate, etc. and glutamate, aspartate Such amino acid salts can be mentioned.

When the compound of the present invention is left in the air, it may absorb water and may absorb water or form a hydrate, and such salts are also included in the present invention. Is done.

Specific examples of the compounds included in the present invention are shown below, but the present invention is not limited thereto. In Tables 1 to 6, Me represents a methyl group, Et represents an ethyl group, Bn represents a benzyl group, diMeO represents a dimethoxy group, THF represents a tetrahydrofuranyl group, cPr represents a cyclopropyl group, and cPn represents a cyclopentyl group. 4-M
eOPh represents a 4-methoxyphenyl group.

[0039]

Embedded image

[0040]

[Table 1] ---------------------------------------------- ---------------- No. Pyridine n R ¹ R ² R ⁸ Y ------------------------ -------------------------------------- 1-1 4- 1 4-OMe CH ₂ H CONH ₂ 1-2 4--0 4-OMe CH ₂ H CONH ₂ 1-3 4- 1 4-OMe CH ₂ H CONHOH 1-4 4--0 4-OMe CH ₂ H CONHOH 1-5 4- 1 4- OMe CH ₂ H CONHMe 1-6 4--0 4-OMe CH ₂ H CONHMe 1-7 4- 1 4-OMe CH ₂ H CONMe ₂ 1-8 4--0 4-OMe CH ₂ H CONMe ₂ 1-9 4 -1 4-OMe CH ₂ H CONHOMe 1-10 4- 0 4-OMe CH ₂ H CONHOMe 1-11 4- 1 4-OMe CH ₂ H CONHBn 1-12 4--0 4-OMe CH ₂ H CONHBn 1- 13 4- 1 4-OMe CH ₂ H CONHPh 1-14 4--0 4-OMe CH ₂ H CONHPh 1-15 4- 1 4-OMe CH ₂ H CONHOBn 1-16 4--0 4-OMe CH ₂ H CONHOBn 1-17 4- 1 4-OMe CH ₂ H CONHOCH ₂ -4-MeOPh 1-18 4--0 4-OMe CH ₂ H CONHOCH ₂ -4-MeOPh 1-19 4- 1 4-OMe CH ₂ H CONMeOMe 1 -20 4- 0 4-OMe CH ₂ H CONMeOMe 1-21 4- 1 4-OMe CH ₂ H CONHOTHF 1-22 4--0 4-OMe CH ₂ H CONHOTHF 1-23 4- 1 4-OMe CH ₂ H CONHcPn 1-24 4- 0 4-OMe CH 2 H CONHcPn 1-25 4- 1 4-OMe CH 2 H CONHCH 2 cPn 1-26 4- 0 4-OMe CH 2 H CONHC H ₂ cPn 1-27 4- 1 4-OMe CH ₂ H CONHOPh 1-28 4--0 4-OMe CH ₂ H CONHOPh 1-29 4- 1 4-OMe CH ₂ H CONHOcPn 1-30 4--0 4- OMe CH ₂ H CONHOcPn 1-31 4-1 4-OMe CH ₂ H CONHOCH ₂ cPr 1-32 4--0 4-OMe CH ₂ H CONHOCH ₂ cPr 1-33 4- 1 4-OMe CH ₂ H CN 1- 34 4- 0 4-OMe CH ₂ H CN 1-35 4- 1 4-OMe CH ₂ H SO ₂ NH ₂ 1-36 4- 0 4-OMe CH ₂ H SO ₂ NH ₂ 1-37 4- 1 4 -OMe CH ₂ H SO ₂ NHMe 1-38 4- 0 4-OMe CH ₂ H SO ₂ NHMe 1-39 4- 1 4-OMe CHMe H CONHOH 1-40 4--0 4-OMe CHMe H CONHOH 1-41 4- 1 4-OMe CH ₂ 5-Me CONH ₂ 1-42 4-0 4-OMe CH ₂ 5-Me CONH ₂ 1-43 4- 1 4-OMe CH ₂ 5-Me CONHOH 1-44 4- 0 4-OMe CH ₂ 5-Me CONHOH 1-45 4- 1 4-OMe CH ₂ 3-OMe CONH ₂ 1-46 4- 0 4-OMe CH ₂ 3-OMe CONH ₂ 1-47 4- 1 4-OMe CH ₂ 3-OMe CONHOH 1-48 4--0 4-OMe CH ₂ 3-OMe CONHOH 1-49 4- 1 4-NO ₂ CH ₂ H CONHOH 1-50 4--0 4-NO ₂ CH ₂ H CONHOH 1 -51 4- 1 4-Me CH ₂ H CONHOH 1-52 4--0 4-Me CH ₂ H CONHOH 1-53 4- 1 4-Br CH ₂ H CONHOH 1-54 4--0 4-Br CH ₂ H CONHOH 1-55 4- 1 4-Br CH ₂ H CONH ₂ 1-56 4- 0 4-Br CH ₂ H CONH ₂ 1-57 4- 1 3,4-diMeO CH ₂ H CONHOH 1-58 4- 0 3,4-diMeO CH ₂ H CONHOH 1-59 4- 1 2,5-diMeO CH ₂ H CONHOH 1-60 4- 0 2,5-diMeO CH ₂ H CONHOH 1-61 3- 1 4-OMe CH ₂ H CONH ₂ 1-62 3--0 4-OMe CH ₂ H CONH ₂ 1-63 3- 1 4-OMe CH ₂ H CONHOH 1-64 3--0 4-OMe CH ₂ H CONHOH 1-65 2- 1 4 -OMe CH ₂ H CONH ₂ 1-66 2--0 4-OMe CH ₂ H CONH ₂ 1-67 2- 1 4-OMe CH ₂ H CONHOH 1-68 2--0 4-OMe CH ₂ H CONHOH 1-69 _{4- 1 4-CN CH 2 H} CONH 2 1-70 4- 0 4-CN CH 2 H CONH 2 1-71 4- 1 4-CN CH 2 H CONHOH 1-72 4- 0 4-CN CH 2 H _{CONHOH 1-73 4- 1 4-NH 2} CH 2 H CONH 2 1-74 4- 0 4-NH 2 CH 2 H CONH 2 1-75 4- 1 4-NH 2 CH 2 H CONHOH 1-76 4- 0 4-NH ₂ CH ₂ H CONHOH 1-77 4- 1 4-NHSO ₂ Me CH ₂ H CONH ₂ 1-78 4- 0 4-NHSO ₂ Me CH ₂ H CONH ₂ 1-79 4- 1 4-NHSO ₂ Me CH ₂ H CONHOH 1-80 4--0 4-NHSO ₂ Me CH ₂ H CONHOH 1-81 4- 1 4-Cl CH ₂ H CONH ₂ 1-82 4--0 4-Cl CH ₂ H CONH ₂ 1 -83 4- 1 4-Cl CH ₂ H CONHOH 1-84 4--0 4-Cl CH ₂ H CONHOH 1-85 4- 1 H CH ₂ H CONH ₂ 1-86 4- 0 H CH ₂ H CONH ₂ 1 -87 4- 1 H CH ₂ H CONHOH 1-88 4- 0 H CH ₂ H CONHOH 1-89 4- 1 4-Et CH ₂ H CONH ₂ 1-90 4--0 4-Et CH ₂ H CONH ₂ 1 -91 4 -1 4-Et CH ₂ H CONHOH 1-92 4--0 4-Et CH ₂ H CONHOH 1-93 4- 1 4-Et CH ₂ CH ₂ H CONH ₂ 1-94 4--0 4-Et CH ₂ CH ₂ H CONH ₂ 1-95 4- 1 4-Et CH ₂ CH ₂ H CONHOH 1-96 4--0 4-Et CH ₂ CH ₂ H CONHOH 1-97 4- 1 4-OMe CH ₂ 4-OMe CONH ₂ 1-98 4--0 4-OMe CH ₂ 4-OMe CONH ₂ 1-99 4- 1 4-OMe CH ₂ 4-OMe CONHOH 1-100 4--0 4-OMe CH ₂ 4-OMe CONHOH ---- -------------------------------------------------- -------

[0041]

Embedded image

[0042]

[Table 2] ---------------------------------------------- --------------- Number pyridine n R ¹ R ² R ⁸ Y ------------------------- ------------------------------------ 2-1 4- 1 4-OMe CH ₂ H CONH ₂ 2-2 4--0 4-OMe CH ₂ H CONH ₂ 2-3 4- 1 4-OMe CH ₂ H CONHOH 2-4 4--0 4-OMe CH ₂ H CONHOH 2-5 3- 1 4-OMe CH ₂ H CONH ₂ 2-6 3--0 4-OMe CH ₂ H CONH ₂ 2-7 3- 1 4-OMe CH ₂ H CONHOH 2-8 3--0 4-OMe CH ₂ H CONHOH 2-9 2- 1 4-OMe CH ₂ H CONH ₂ 2-10 2--0 4-OMe CH ₂ H CONH ₂ 2-11 2- 1 4-OMe CH ₂ H CONHOH 2-12 2--0 4-OMe CH ₂ H CONHOH- -------------------------------------------------- ---------

[0043]

Embedded image

[0044]

[Table 3] ---------------------------------------------- --------------- Number pyridine n R ¹ R ² R ⁸ Y ------------------------- ------------------------------------ 3-1 4- 1 4-OMe CH ₂ H CONH ₂ 3-2 4--0 4-OMe CH ₂ H CONH ₂ 3-3 4- 1 4-OMe CH ₂ H CONHOH 3-4 4--0 4-OMe CH ₂ H CONHOH 3-5 3- 1 4-OMe CH ₂ H CONH ₂ 3-6 3--0 4-OMe CH ₂ H CONH ₂ 3-7 3- 1 4-OMe CH ₂ H CONHOH 3-8 3--0 4-OMe CH ₂ H CONHOH 3-9 2- 1 4-OMe CH ₂ H CONH ₂ 3-10 2--0 4-OMe CH ₂ H CONH ₂ 3-11 2- 1 4-OMe CH ₂ H CONHOH 3-12 2--0 4-OMe CH ₂ H CONHOH 3- 13 4- 1 4-OMe CH ₂ H CONHMe 3-14 4- 0 4-OMe CH ₂ H CONHMe -------------------------- ----------------------------------

[0045]

Embedded image

[0046]

[Table 4] ---------------------------------------------- ---------------------- No. Pyridine n R ¹ R ² R ^7a R ⁸ Y ---------------- -------------------------------------------------- -4-1 4- 1 4-OMe CH ₂ HH CONH ₂ 4-2 4--0 4-OMe CH ₂ HH CONH ₂ 4-3 4- 1 4-OMe CH ₂ HH CONHOH 4-4 4- 0 4 -OMe CH ₂ HH CONHOH 4-5 3- 1 4-OMe CH ₂ HH CONH ₂ 4-6 3--0 4-OMe CH ₂ HH CONH ₂ 4-7 3- 1 4-OMe CH ₂ HH CONHOH 4-8 3- 0 4-OMe CH ₂ HH CONHOH 4-9 2- 1 4-OMe CH ₂ HH CONH ₂ 4-10 2--0 4-OMe CH ₂ HH CONH ₂ 4-11 2- 1 4-OMe CH ₂ HH CONHOH 4-12 2--0 4-OMe CH ₂ HH CONHOH 4-13 4- 1 4-OMe CH ₂ Me H CONH ₂ 4-14 4--0 4-OMe CH ₂ Me H CONH ₂ ------ -------------------------------------------------- --------------

[0047]

Embedded image

[0048]

[Table 5] ---------------------------------------------- ------------------------ No. Pyridine n R ¹ R ² R ^7b R ⁸ Y -------------- -------------------------------------------------- ------ 5-1 4- 1 4-OMe CH ₂ HH CONH ₂ 5-2 4--0 4-OMe CH ₂ HH CONH ₂ 5-3 4- 1 4-OMe CH ₂ HH CONHOH 5-4 4--0 4-OMe CH ₂ HH CONHOH 5-5 3- 1 4-OMe CH ₂ HH CONH ₂ 5-6 3--0 4-OMe CH ₂ HH CONH ₂ 5-7 3- 1 4-OMe CH ₂ HH CONHOH 5-8 3--0 4-OMe CH ₂ HH CONHOH 5-9 2- 1 4-OMe CH ₂ HH CONH ₂ 5-10 2--0 4-OMe CH ₂ HH CONH ₂ 5-11 2- 1 4- _{OMe CH 2 HH CONHOH 5-12 2- 0} 4-OMe CH 2 HH CONHOH 5-13 4- 1 4-OMe CH 2 Me H CONH 2 5-14 4- 0 4-OMe CH 2 Me H CONH 2 5- 15 4- 1 4-OMe CH ₂ HH CONHMe 5-16 4--0 4-OMe CH ₂ HH CONHMe -------------------------- ----------------------------------------------

[0049]

Embedded image

[0050]

[Table 6] ---------------------------------------------- ------ Number pyridine nR ¹ R ² Y ------------------------------------ ---------------- 6-1 4- 1 4-OMe CH ₂ CONH ₂ 6-2 4- 0 4-OMe CH ₂ CONH ₂ 6-3 4- 1 4- OMe CH ₂ CONHOH 6-4 4--0 4-OMe CH ₂ CONHOH 6-5 3- 1 4-OMe CH ₂ CONH ₂ 6-6 3--0 4-OMe CH ₂ CONH ₂ 6-7 3- 1 4- OMe CH ₂ CONHOH 6-8 3- 0 4-OMe CH ₂ CONHOH 6-9 2- 1 4-OMe CH ₂ CONH ₂ 6-10 2--0 4-OMe CH ₂ CONH ₂ 6-11 2- 1 4- OMe CH ₂ CONHOH 6-12 2--0 4-OMe CH ₂ CONHOH ---------------------------------- --------------------- In the above Tables 1 to 6, the preferred compound is Compound No. 1-
1, 1-2, 1-4, 1-5, 1-6, 1-20, 5-
1, 5-2, 5-4, 5-15 and 5-16, and more preferred compounds are (E) -4- (2- (2- (N-
(Aminocarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (1-2), (E) -4- (2- (2- (N- (hydroxylaminocarbonylmethyl)-) N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (1-4), (E) -4- (2- (2- (N- (methylaminocarbonylmethyl) -N- (4-methoxy) Benzenesulfonyl) amino) phenyl) vinyl) pyridine (1-6), 4- (2- (N- (aminocarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenylaminocarbonyl) pyridine (5-2) ),
4- (2- (N- (hydroxylaminocarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenylaminocarbonyl) pyridine (5-4) and 4- (2- (N- (methylaminocarbonylmethyl) )
—N- (4-methoxybenzenesulfonyl) amino) phenylaminocarbonyl) pyridine (5-16).

[0051]

The method for producing the compound of the present invention will be described below.

The compound (1) of the present invention can be produced according to the following process charts A to C. Further, the starting material or the compound serving as an intermediate can be produced according to the following process charts D to I.

[0053]

Embedded image

[0054]

Embedded image

[0055]

Embedded image

[0056]

Embedded image

[0057]

Embedded image

[0058]

Embedded image

[0059]

Embedded image

[0060]

Embedded image

[0061]

Embedded image

In the above process chart, rings A, X, Y, n, R ¹ ,
R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^7a and R ^7b have the same meanings as described above, and R ⁸ is an alkyl group having 1 to 6 carbon atoms, 1 to 6 carbon atoms. R ⁹ represents a hydroxyl-protecting group, R ¹⁰ , R ¹¹ and R ¹² represent an alkyl group having 1 to 6 carbon atoms, and W represents
Shows a halogeno group.

<Step A> (First Step) Alkylation This step is a step of synthesizing compound (3) from compound (2) and alkyl halide (26). That is, this is a method of reacting compound (2) with alkyl halide (26) in an inert solvent in the presence of a base to obtain compound (3).

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, but is preferably an aliphatic hydrocarbon such as hexane, hebutane, ligroin or petroleum ether. Hydrogens; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA ); Halogenated hydrocarbons such as dichloromethane and chloroform, and particularly preferably, N, N-dimethylformamide,
Amides such as N, N-dimethylacetamide.

As the base used, for example, lithium amides such as lithium diisopropylamide and lithium hexamethyldisilazide; hydrides of alkali metals such as sodium hydride and potassium hydride; potassium carbonate and sodium carbonate And preferred are alkali metal carbonates such as potassium carbonate and sodium carbonate.

The reaction temperature varies depending on the compound, base, solvent and the like, but is usually from -20 ° C to 40 ° C, preferably from 0 ° C to 30 ° C, and the reaction time depends on the compound, the reaction temperature and the like. Varies, but is usually 1 to 24 hours,
Preferably, it is 1 to 5 hours.

After completion of the reaction, for example, the reaction solution is poured into water,
It is obtained by extracting with a water-immiscible solvent, for example, benzene, ether, ethyl acetate, etc., washing the extract with water and saturated brine, drying over anhydrous sodium sulfate, and distilling off the solvent. If desired, it can be isolated and purified by various chromatography or recrystallization methods.

(Second Step) Hydrolysis This step is a step of producing compound (4) from compound (3). That is, in an inert solvent, the compound (3) is
This is a method of obtaining a compound (4) by hydrolysis with an acid or a base. In the case of hydrolysis with an acid, the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably hexane, hebutane, ligroin, or petroleum ether. Aliphatic hydrocarbons; aromatic hydrocarbons such as benzene, toluene, and xylene; and halogenated hydrocarbons such as dichloromethane and chloroform. Particularly preferred are halogenated hydrocarbons such as dichloromethane and chloroform. It is.

Examples of the acid used include carboxylic acids such as trifluoroacetic acid; sulfonic acids such as p-toluenesulfonic acid; and inorganic acids such as hydrochloric acid. Preferably, trifluoroacetic acid is used.

The reaction temperature varies depending on the compound, solvent and the like, but is usually 0 to 40 ° C., preferably 10 to 3 ° C.
0 ° C., and the reaction time varies depending on the compound, the reaction temperature, etc., but is usually 1 to 224 hours, preferably 1 to 224 hours.
From 5 to 5 hours.

After completion of the reaction, for example, it can be obtained by distilling off the solvent and the acid under reduced pressure. If desired, it can be isolated and purified by various chromatography or recrystallization methods. In the case of hydrolysis with a base, the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably alcohols such as methanol and ethanol; tetrahydrofuran And ethers such as dioxane; water and mixed solvents thereof. Particularly preferred is a mixed solvent of alcohols such as methanol and ethanol and water.

Examples of the base used include hydroxides of alkyl metals such as sodium hydroxide and potassium hydroxide;
Alkyl metal carbonates such as sodium carbonate and potassium carbonate can be mentioned, and preferred are alkyl metal hydroxides such as sodium hydroxide and potassium hydroxide.

The reaction temperature varies depending on the compound, the solvent and the like, but is usually from 0 to 40 ° C., preferably from 10 to 3 ° C.
The temperature is 0 ° C., and the reaction time varies depending on the compound, the reaction temperature and the like, but is usually 1 to 24 hours, preferably 1 to 10 hours.

After the completion of the reaction, for example, the reaction solution is poured into water,
After washing with a water-immiscible solvent, for example, benzene, ether, dichloromethane, etc., the aqueous layer is acidified with hydrochloric acid,
Water-immiscible solvents, such as benzene, ethyl acetate,
Extract with dichloromethane or the like, and extract the extract with water,
It is obtained by washing with a saturated saline solution, drying over anhydrous sodium sulfate, and distilling off the solvent. If desired, it can be isolated and purified by various chromatography or recrystallization methods.

(Third Step) Condensation This step is a step of producing compound (1-a) from compound (4). That is, compound (4) in an inert solvent
Is reacted with HNR ³ R ⁴ in the presence of a base and a condensing agent to obtain a compound (1-a).

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, but is preferably an aliphatic solvent such as hexane, hebutane, ligroin or petroleum ether. Hydrocarbons; aromatic hydrocarbons such as benzene, toluene and xylene; and halogenated hydrocarbons such as dichloromethane and chloroform. Particularly preferred are halogenated hydrocarbons such as dichloromethane and chloroform.

The base used includes triethylamine, tributylamine, diisopropylethylamine,
Organic bases such as N-methylmorpholine, pyridine, N, N-dimethylaminopyridine, and 1,8-diazabicyclo [5.4.0] undec-7-ene are preferred.
Triethylamine, N-methylmorpholine.

Examples of the condensing agent to be used include carbodiimides such as dicyclohexylcarbodiimide (DCC) and N-ethyl-N'-dimethylaminopropylcarbodiimide (WSC); carbonyldiimidazole and disuccinimidyl carbonate. Carbonic acid derivatives such as oxalyl chloride and thionyl chloride, and carbodiimides such as dicyclohexylcarbodiimide (DCC) and N-ethyl-N'-dimethylaminopropylcarbodiimide (WSC); It is.

When carbodiimides such as dicyclohexylcarbodiimide (DCC) and N-ethyl-N'-dimethylaminopropylcarbodiimide (WSC) are used as the condensing agent, 1-hydroxybenzotriazole can be used together.

The reaction temperature varies depending on the compound, solvent and the like, but is usually from 0 to 40 ° C., preferably from 10 to 3 ° C.
The reaction temperature is 0 ° C., and the reaction time varies depending on the compound, the reaction temperature and the like, but is usually 1 to 24 hours, preferably 1 to 5 hours.

After the completion of the reaction, for example, the reaction solution is poured into water,
Extracted with a water-immiscible solvent, for example, benzene, ether, ethyl acetate, etc., and the extract is washed with water, then with saturated saline, dried over anhydrous sodium sulfate, and evaporated to remove the solvent. Can be If desired, it can be isolated and purified by various chromatography or recrystallization methods.

(Fourth Step) Condensation This step is a step of producing compound (5) from compound (4). That is, in an inert solvent, the compound (4) is
This is a method for obtaining a compound (5) by reacting HNR ³ OR ⁹ in the presence of a base and a condensing agent, and can be carried out in the same manner as in the third step.

(Fifth Step) Deprotection This step is a step for producing a compound (1-a) from a compound (5). That is, compound (5) in an inert solvent
Is deprotected under general deprotection conditions to give compound (1-a)
Is a way to get

For example, when R ⁹ is a tetrahydrofuranyl group, the compound (5) is treated with an acid in an inert solvent to obtain a compound (1-a).

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. Preferably, the solvent is an aliphatic hydrocarbon such as hexane, hebutane, ligroin, petroleum ether. Hydrogens; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; alcohols such as methanol and ethanol; particularly preferred are alcohols such as methanol and ethanol. Kind. Examples of the acid used include carboxylic acids such as trifluoroacetic acid; p-toluenesulfonic acid.
Monohydrate, sulfonic acid or sulfonic acid salt such as pyridinium p-toluenesulfonate; inorganic acid such as hydrochloric acid;
Monohydrate, a sulfonic acid or a sulfonate such as pyridinium p-toluenesulfonate.

The reaction temperature varies depending on the compound, solvent and the like, but is usually 0 to 100 ° C., preferably 10 to 6 ° C.
The reaction temperature is 0 ° C., and the reaction time varies depending on the compound, the reaction temperature and the like, but is usually 1 to 48 hours, preferably 1 to 20 hours.

After completion of the reaction, for example, the reaction solution is poured into water,
It is obtained by extracting with a water-immiscible solvent, for example, benzene, ether, ethyl acetate, etc., washing the extract with water, then with saturated saline, drying over anhydrous sodium sulfate, and distilling off the solvent. . If desired, it can be isolated and purified by various chromatography or recrystallization methods.

<Step B> (Sixth Step) Oxidation This step is a step of producing compound (6) from compound (3). That is, this is a method of obtaining compound (6) by treating compound (3) with an oxidizing agent in an inert solvent.

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, but is preferably an aliphatic solvent such as hexane, hebutane, ligroin or petroleum ether. Hydrocarbons; aromatic hydrocarbons such as benzene, toluene and xylene; and halogenated hydrocarbons such as dichloromethane and chloroform. Particularly preferred are halogenated hydrocarbons such as dichloromethane and chloroform.

Examples of the oxidizing agent to be used include peracids such as m-chloroperbenzoic acid and peracetic acid; peroxides such as dimethyldioxirane; and hydrogen peroxide. Peracids such as chloroperbenzoic acid and peracetic acid.

The reaction temperature varies depending on the compound, solvent and the like, but is usually 0 to 40 ° C., preferably 10 to 3 ° C.
The reaction temperature is 0 ° C., and the reaction time varies depending on the compound, the reaction temperature and the like, but is usually 1 to 24 hours, and preferably 1 to 5 hours.

After completion of the reaction, for example, the reaction solution is poured into water,
After extraction with a water-immiscible solvent, for example, benzene, ether, ethyl acetate, etc., the extract is washed with a saturated aqueous solution of sodium hydrogencarbonate, water, and then with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent is distilled off. Obtained by leaving. If desired, it can be isolated and purified by various chromatography or recrystallization methods.

(Seventh Step) Hydrolysis This step is a step of producing a compound (7) from a compound (6). That is, a method of treating a compound (6) with an acid or a base in an inert solvent to obtain a compound (7),
It can be performed in the same manner as in the second step.

(Eighth Step) Condensation This step is a step of producing compound (1-b) from compound (7). That is, in an inert solvent, compound (7)
Is reacted with HNR ³ R ⁴ in the presence of a base and a condensing agent,
This is a method for obtaining the compound (1-b), which can be performed in the same manner as in the third step.

(Ninth Step) Condensation This step is a step of producing compound (8) from compound (7). That is, in an inert solvent, the compound (7) is
This is a method for obtaining a compound (8) by reacting HNR ³ OR ⁹ in the presence of a base and a condensing agent, and can be carried out in the same manner as in the third step.

(Tenth Step) Deprotection This step is a step for producing a compound (1-b) from a compound (8). That is, compound (8) in an inert solvent
Is deprotected under general deprotection conditions to give compound (1-b)
And can be performed in the same manner as in the fifth step.

<Step C> (Eleventh Step) Alkylation This step is a step of synthesizing compound (1-c) from compound (2) and alkyl halide (27). That is, this is a method of reacting compound (2) with alkyl halide (27) in an inert solvent in the presence of a base to obtain compound (1-c), which can be carried out in the same manner as in the first step. .

(Twelfth Step) Oxidation This step is a step for producing a compound (1-d) from a compound (1-c). That is, the compound (1-d) is obtained by treating the compound (1-c) with an oxidizing agent in an inert solvent, and can be carried out in the same manner as in the sixth step.

<Step D> (Step 13) Reduction This step is a step of producing compound (3b) from compound (3a). That is, compound (3) in an inert solvent
In this method, compound (3b) is obtained by treating a) with a reducing agent.

Examples of the reducing agent used include metals such as iron and zinc. If desired, a salt such as ammonium chloride can coexist.

The solvent to be used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, but is preferably alcohols such as methanol and ethanol; and carboxylic acids such as acetic acid. Acids; ethers such as dioxane and tetrahydrofuran; water; and more preferably, when the reducing agent is iron, a mixed solvent of alcohols such as methanol and ethanol with water; Is a carboxylic acid such as acetic acid.

The reaction temperature varies depending on the compound, the solvent and the like, but is usually -20 to 100 ° C., preferably 0 to 80 ° C. The reaction time varies depending on the compound, the reaction temperature and the like. Usually 1 to 24 hours, preferably
One to five hours.

After the completion of the reaction, for example, insolubles are removed by filtration, the solvent is distilled off under reduced pressure, and the residue is extracted with a water-immiscible solvent such as benzene, ether, ethyl acetate and the like. It is obtained by washing with a saturated aqueous solution of sodium hydrogencarbonate, water, and subsequently with a saturated saline solution, drying over anhydrous sodium sulfate, and distilling off the solvent. If desired, it can be isolated and purified by various chromatography or recrystallization methods.

(14th step) Sulfonylation This step is a step of producing compound (3c) from compound (3b). That is, the compound (3b) is reacted with sulfonyl chloride in an inert solvent in the presence of a base,
This is a method for obtaining compound (3c).

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, but is preferably an aliphatic solvent such as hexane, hebutane, ligroin or petroleum ether. Hydrocarbons; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane;
3-dimethyl-3,4,5,6-tetrahydro-2 (1
H) -Pyrimidinone (N, N'-dimethyl-N, N'-
Examples include amides such as propylene urea, DMPU) and N, N-dimethylacetamide (DMA), and particularly preferred are halogenated hydrocarbons such as dichloromethane and chloroform.

The base to be used includes triethylamine, tributylamine, diisopropylethylamine,
Organic bases such as N-methylmorpholine, pyridine, N, N-dimethylaminopyridine, and 1,8-diazabicyclo [5.4.0] undec-7-ene are preferred.
Pyridine, triethylamine and N-methylmorpholine.

The reaction temperature varies depending on the compound, base, solvent and the like, but is usually from -20 ° C to 40 ° C, preferably from 0 ° C to 30 ° C, and the reaction time depends on the compound, the reaction temperature and the like. Varies, but is usually 1 to 24 hours,
Preferably, it is 1 to 5 hours.

After the completion of the reaction, for example, the reaction solution is poured into water,
It is obtained by extracting with a water-immiscible solvent, for example, benzene, ether, ethyl acetate, etc., washing the extract with water, then with saturated saline, drying over anhydrous sodium sulfate, and distilling off the solvent. . If desired, it can be isolated and purified by various chromatography or recrystallization methods.

<Step E> (15th step) Heck reaction This step is a step of producing a compound (11) from the compound (9) and the compound (10). That is, this is a method of reacting compound (9) with compound (10) in an inert solvent in the presence of a palladium catalyst and phosphine to obtain compound (11).

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, but is preferably an organic base such as triethylamine or pyridine.

Examples of the palladium catalyst used include palladium acetate, palladium chloride and the like. Palladium acetate is preferred.

Examples of the phosphine to be used include triphenylphosphine, tri-tolylphosphine and the like, preferably tri-o-tolylphosphine.

The reaction temperature varies depending on the compound, catalyst, solvent and the like, but is usually from 20 ° C to 150 ° C, preferably from 80 ° C to 100 ° C.
Although it varies depending on the reaction temperature and the like, it is usually 1 to 24 hours, preferably 1 to 12 hours.

After completion of the reaction, the reaction solution is obtained, for example, by pouring the reaction solution into water and a solvent immiscible with water, for example, benzene, ether, ethyl acetate and the like, and filtering off insolubles. Further, the organic layer is obtained by washing with a saturated saline solution, drying over anhydrous magnesium sulfate, and distilling off the solvent. If desired, it can be isolated and purified by various chromatography or recrystallization methods.

(Step 16) Reduction This step is a step of producing compound (12) from compound (11). That is, in an inert solvent, the compound (1)
This is a method of obtaining compound (12) by treating 1) with a reducing agent, and can be performed in the same manner as in the thirteenth step.

(Step 17) Sulfonylation In this step, compound (12) and sulfonyl chloride (2
This is a step of producing a compound (2a) from 8). That is, the compound (12) is reacted with the sulfonyl chloride (28) in an inert solvent in the presence of a base to give the compound (2a)
Is a way to get

The solvent to be used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, but is preferably an aliphatic hydrocarbon such as hexane, hebutane, ligroin or petroleum ether. Hydrogens; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; DM
Examples include amides such as PU and DMA, and particularly preferred are halogenated hydrocarbons such as dichloromethane and chloroform.

The base to be used includes triethylamine, tributylamine, diisopropylethylamine,
Organic bases such as N-methylmorpholine, pyridine, N, N-dimethylaminopyridine, and 1,8-diazabicyclo [5.4.0] undec-7-ene are preferred, and pyridine, triethylamine, N-methyl are preferred. Morpholine.

The reaction temperature varies depending on the compound, base, solvent and the like, but is usually from -20 ° C to 40 ° C, preferably from 0 ° C to 30 ° C. The reaction time depends on the compound, the reaction temperature and the like. Varies, but is usually 1 to 24 hours,
Preferably, it is 1 to 5 hours.

After the completion of the reaction, for example, the reaction solution is poured into water,
It is obtained by extracting with a water-immiscible solvent, for example, benzene, ether, ethyl acetate, etc., washing the extract with water, then with saturated saline, drying over anhydrous sodium sulfate, and distilling off the solvent. . If desired, it can be isolated and purified by various chromatography or recrystallization methods.

<Step F> (Step 18) Sulfonylation In this step, compound (13) and sulfonyl chloride (2
This is a step of producing a compound (14) from 8). That is, the compound (13) is reacted with the sulfonyl chloride (28) in an inert solvent in the presence of a base to give the compound (14)
And can be performed in the same manner as in the seventeenth step.

(Step 19) Acylation In this step, compound (14) and pyridinecarboxylic acid (2
This is a step of producing a compound (2b) from 9). That is, this is a method of reacting compound (14) with pyridinecarboxylic acid (29) in an inert solvent in the presence of a condensing agent and a base to obtain compound (2b).

The solvent to be used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent, but is preferably an aliphatic hydrocarbon such as hexane, hebutane, ligroin or petroleum ether. Hydrogen; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform, and particularly preferably halogenated hydrocarbons such as dichloromethane and chloroform.

The base to be used includes triethylamine, tributylamine, diisopropylethylamine,
Organic bases such as N-methylmorpholine, pyridine, N, N-dimethylaminopyridine, and 1,8-diazabicyclo [5.4.0] undec-7-ene are preferred.
Triethylamine, N-methylmorpholine.

Examples of the condensing agent used include carbodiimides such as dicyclohexylcarbodiimide (DCC) and N-ethyl-N'-dimethylaminopropylcarbodiimide (WSC); carbonyldiimidazole and disuccinimidyl carbonate. Acid derivatives such as oxalyl chloride and thionyl chloride; preferably, carbodiimides such as dicyclohexylcarbodiimide (DCC) and N-ethyl-N'-dimethylaminopropylcarbodiimide (WSC). It is.

When carbodiimides such as dicyclohexylcarbodiimide (DCC) and N-ethyl-N'-dimethylaminopropylcarbodiimide (WSC) are used as the condensing agent, 1-hydroxybenzotriazole can be used together.

The reaction temperature varies depending on the compound, solvent and the like, but is usually 0 to 40 ° C., preferably 10 to 3 ° C.
The reaction temperature is 0 ° C., and the reaction time varies depending on the compound, the reaction temperature and the like, but is usually 1 to 24 hours, and preferably 1 to 5 hours.

After the completion of the reaction, for example, the reaction solution is poured into water,
It is obtained by extracting with a water-immiscible solvent, for example, benzene, ether, ethyl acetate, etc., washing the extract with water and then with saturated saline, drying over anhydrous sodium sulfate, and distilling off the solvent. If desired, it can be isolated and purified by various chromatography or recrystallization methods.

<Step G> (Step 20) Sulfonylation In this step, compound (15) and sulfonyl chloride (2
This is a step of producing a compound (16) from 8). That is, the compound (15) is reacted with the sulfonyl chloride (28) in an inert solvent in the presence of a base to give the compound (16)
And can be performed in the same manner as in the seventeenth step.

(Step 21) Alkylation In this step, compound (16) and alkyl halide (26)
This is a step of producing a compound (17) from a). That is, the compound (16) is reacted with an alkyl halide (26a) in an inert solvent in the presence of a base to give the compound (16)
And can be performed in the same manner as in the first step.

(Step 22) Hydrolysis This step is a step of producing compound (18) from compound (17). That is, in an inert solvent, the compound (1)
In this method, compound (18) is obtained by hydrolyzing 7) with a base.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Preferably, alcohols such as methanol and ethanol; N, N-dimethyl Formamide, N, N
Amides such as dimethylacetamide; ethers such as dioxane and tetrahydrofuran; water and a mixed solvent thereof. Particularly preferred is a mixed solvent of an alcohol such as methanol and ethanol and water.

The base to be used includes a hydroxide of an alkyl metal such as sodium hydroxide and potassium hydroxide;
Examples thereof include carbonates of alkyl metals such as sodium carbonate and potassium carbonate, and preferred are hydroxides of alkyl metals such as sodium hydroxide and potassium hydroxide.

The reaction temperature varies depending on the compound, solvent and the like, but is usually 0 to 40 ° C., preferably 10 to 3 ° C.
The reaction temperature is 0 ° C., and the reaction time varies depending on the compound, the reaction temperature and the like, but is usually 1 to 24 hours, and preferably 1 to 5 hours.

After the completion of the reaction, for example, the reaction solution is poured into water,
After washing with a water-immiscible solvent, for example, benzene, ether, dichloromethane, etc., the aqueous layer is acidified with hydrochloric acid,
It is obtained by extracting with a water-immiscible solvent, for example, benzene, ethyl acetate, dichloromethane, etc., washing the extract with water and then with saturated saline, drying over anhydrous sodium sulfate, and distilling off the solvent. If desired, it can be isolated and purified by various chromatography or recrystallization methods.

(Twenty-third Step) Amidation This step is a step of producing a compound (3d) from a compound (18) and an aminopyridine (30). That is, in an inert solvent in the presence of a condensing agent and a base, compound (18)
Is reacted with aminopyridine (30) to give compound (3d)
Is a way to get

The solvent to be used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. Hydrogen; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform, and particularly preferred are halogenated hydrocarbons such as dichloromethane and chloroform.

As the base used, triethylamine, tributylamine, diisopropylethylamine,
Organic bases such as N-methylmorpholine, pyridine, N, N-dimethylaminopyridine, and 1,8-diazabicyclo [5.4.0] undec-7-ene are preferred.
Triethylamine, N-methylmorpholine.

Examples of the condensing agent used include carbodiimides such as dicyclohexylcarbodiimide (DCC) and N-ethyl-N'-dimethylaminopropylcarbodiimide (WSC); carbonyldiimidazole and disuccinimidyl carbonate. Acid carbonates such as oxalyl chloride and thionyl chloride; and phosphoric acid derivatives such as diethyl phosphate cyanide and diphenyl phosphate azide. Preferred are cyanide diethyl phosphate and diphenyl phosphate azide. And phosphoric acid derivatives such as

When carbodiimides such as dicyclohexylcarbodiimide (DCC) and N-ethyl-N'-dimethylaminopropylcarbodiimide (WSC) are used as the condensing agent, 1-hydroxybenzotriazole can be used together.

The reaction temperature varies depending on the compound, solvent and the like, but is usually 0 to 40 ° C., preferably 10 to 30 ° C.
° C, and the reaction time varies depending on the compound, the reaction temperature and the like, but is usually 1 to 24 hours, preferably 1 to 5 hours.

After the completion of the reaction, for example, the reaction solution was poured into water,
Extracted with a water-immiscible solvent, for example, benzene, ether, ethyl acetate, etc., and the extract is washed with water, then with saturated saline, dried over anhydrous sodium sulfate, and evaporated to remove the solvent. Can be If desired, it can be isolated and purified by various chromatography or recrystallization methods.

<Step H> (Step 24) Sulfonylation In this step, compound (19) and sulfonyl chloride (2
This is a step of producing a compound (20) from 8). That is, the compound (19) is reacted with the sulfonyl chloride (28) in an inert solvent in the presence of a base to give the compound (20)
And can be performed in the same manner as in the seventeenth step.

(Step 25) Alkylation In this step, compound (20) and alkyl halide (26)
This is a step of synthesizing compound (21) from That is,
This is a method of reacting the compound (20) with the alkyl halide (26) in the presence of a base in an inert solvent to obtain the compound (21), which can be carried out in the same manner as in the first step.

(Step 26) Heck Reaction This step is a step of producing a compound (3e) from the compound (21) and the compound (10). That is, in an inert solvent in the presence of a palladium catalyst and phosphine, compound (2)
This is a method of reacting 1) with compound (10) to obtain compound (3e), and can be carried out in the same manner as in the fifteenth step.

<Step I> (Step 27) Sulfonylation In this step, compound (22) and sulfonyl chloride (2
This is a step of producing a compound (23) from 8). That is, the compound (22) is reacted with the sulfonyl chloride (28) in an inert solvent in the presence of a base to give the compound (23)
And can be performed in the same manner as in the seventeenth step.

(Step 28) Reduction This step is a step of producing compound (24) from compound (23). That is, compound (2) in an inert solvent
In this method, compound (24) is obtained by reacting 3) with a reducing agent.

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, but is preferably an aliphatic solvent such as hexane, hebutane, ligroin or petroleum ether. Hydrocarbons; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether and tetrahydrofuran; alcohols such as methanol and ethanol. Particularly preferred are ethers such as diethyl ether and tetrahydrofuran.

The reducing agents used include hydrides such as lithium aluminum hydride and sodium borohydride.

The reaction temperature varies depending on the compound, the solvent and the like, but is usually -78 to 40 ° C, preferably -10 ° C.
To 30 ° C., and the reaction time varies depending on the compound, the reaction temperature and the like, but is usually 1 to 24 hours, preferably 1 to 5 hours.

After the completion of the reaction, for example, the reaction solution is poured into water,
Extracted with a water-immiscible solvent, for example, benzene, ether, ethyl acetate, etc., and the extract is washed with water, then with saturated saline, dried over anhydrous sodium sulfate, and evaporated to remove the solvent. Can be If desired, it can be isolated and purified by various chromatography or recrystallization methods.

(Step 29) Oxidation This step is a step of producing compound (25) from compound (24). That is, compound (2) in an inert solvent
In this method, compound (25) is obtained by reacting 4) with an oxidizing agent.

The solvent to be used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent. Hydrogens; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as methyl acetate and ethyl acetate; Esters such as ethyl acetate.

The oxidizing agent used includes manganese dioxide, pyridinium dichromate and pyridinium chlorochromate, and preferably manganese dioxide.

The reaction temperature varies depending on the compound, solvent and the like, but is usually 0 to 40 ° C., preferably 10 to 3 ° C.
The temperature is 0 ° C., and the reaction time varies depending on the compound, the reaction temperature and the like, but is usually 1 to 24 hours, preferably 1 to 10 hours.

After completion of the reaction, for example, insolubles are filtered, the filtrate is poured into water, and a water-immiscible solvent such as benzene,
It is obtained by extracting with ether, ethyl acetate, etc., washing the extract with water, then with saturated saline, drying over anhydrous sodium sulfate, and distilling off the solvent. If desired, it can be isolated and purified by various chromatography or recrystallization methods.

(Step 30) Condensation This step is a step for producing a compound (32) from the compound (25) and the compound (31). That is, this is a method of reacting compound (25) with compound (31) in an inert solvent in the presence of an acid to obtain compound (32).

The solvent to be used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent. Hydrocarbons; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; and acid anhydrides such as acetic anhydride. Such acid anhydrides.

Examples of the acid to be used include a mineral acid such as hydrochloric acid; a carboxylic acid such as acetic acid; an acid anhydride such as acetic anhydride; a Lewis acid such as zinc chloride; can give.

The reaction temperature varies depending on the compound, the solvent and the like, but is usually from 0 to 200 ° C., preferably from 10 to 150 ° C. The reaction time varies depending on the compound, the reaction temperature and the like. It is 30 minutes to 24 hours, preferably 1 to 10 hours.

After the completion of the reaction, for example, the reaction solution is poured into water,
Extracted with a water-immiscible solvent, for example, benzene, ether, ethyl acetate, etc., and the extract is washed with water, then with saturated saline, dried over anhydrous sodium sulfate, and evaporated to remove the solvent. Can be If desired, it can be isolated and purified by various chromatography or recrystallization methods.

(Step 31) Hydrolysis This step is a step of producing compound (2c) from compound (32). That is, compound (3) in an inert solvent
In this method, compound (2c) is obtained by treating 2) with an acid or a base.

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, but is preferably an aliphatic solvent such as hexane, hebutane, ligroin or petroleum ether. Hydrocarbons; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether and dioxane; Ethers such as dioxane.

Examples of the acid used include a mineral acid such as hydrochloric acid; a sulfonic acid such as trifluoromethanesulfonic acid, and preferably hydrochloric acid.

The base to be used includes a hydroxide of an alkyl metal such as sodium hydroxide and potassium hydroxide;
Sodium carbonate, carbonates of alkyl metals such as potassium carbonate and the like, preferably sodium hydroxide,
It is a hydroxide of an alkyl metal such as potassium hydroxide.

The reaction temperature varies depending on the compound, the solvent and the like, but is usually from 0 to 150 ° C., preferably from 10 to 100 ° C. The reaction time varies depending on the compound, the reaction temperature and the like. It is 30 minutes to 24 hours, preferably 1 to 10 hours.

After the completion of the reaction, for example, the reaction solution is poured into water,
It is obtained by extracting with a water-immiscible solvent, for example, benzene, ether, ethyl acetate, etc., washing the extract with water, then with saturated saline, drying over anhydrous sodium sulfate, and distilling off the solvent. . If desired, it can be isolated and purified by various chromatography or recrystallization methods.

When the compound of the present invention is used as a medicine (eg, an antitumor agent), it is administered in various forms. As the administration form, for example, tablets, capsules, granules,
Oral administration such as powder or syrup or parenteral administration such as injection or suppository,
These preparations are produced by known methods using additives such as excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents, diluents and the like. The amount used varies depending on symptoms, age, administration method and the like.
0.5mg as the lower limit and 3000m as the upper limit
In the case of intravenous administration of g, it is desirable to administer 0.1 mg as a lower limit and 1000 mg as an upper limit once per day, depending on symptoms, once or several times.

[0169]

The present invention will be described more specifically with reference to the following examples, preparation examples and test examples.

(Example 1) (E) -4- (2- (2-
(N- (hydroxylaminocarbonylmethyl) -N-
(4-methoxybenzenesulfonyl) amino) phenyl
B) vinyl) pyridine 1-oxide (exemplary compound number 1-3) (1-1) (E) -4- (2- (2-aminophenyl)
Vinyl) pyridine To a suspension of 4-vinylpyridine (20.28 g) and 2-bromoaniline (25 g) in triethylamine (250 ml), palladium acetate (330 mg) and tri-o-
Tolylphosphine (1.79 g) was added,
Stirred for hours. After completion of the reaction, the reaction mixture was added with ethyl acetate 5
00 ml and 150 ml of water were added. The obtained insolubles were collected by filtration and dried to obtain the target compound (22.07 g). Further, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with dichloromethane to obtain 4.00 g of the desired compound. ^{1 H-NMR (400MHz, DMSO} -d 6) 5.51 (2H, br s), 6.57 (1H, t, J = 7.9Hz), 6.68 (1H, d,
J = 8.1Hz), 6.95-7.05 (2H, m), 7.49 (1H, d, J = 7.9Hz),
7.58 (2H, d, J = 4.6Hz), 7.70 (1H, d, J = 16.2Hz), 8.51 (2
H, d, J = 4.6 Hz) (1-2) (E) -4- (2- (2- (4-methoxy)
Nzensulfonyl) amino) phenyl) vinyl) pyridi
To a solution of (E) -4- (2- (2-aminophenyl) vinyl) pyridine (2.00 g) in pyridine (80 ml),
p-methoxybenzenesulfonyl chloride (2.21
g) was added and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the residue obtained by distilling off pyridine under reduced pressure was extracted with ethyl acetate, washed with water and then with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. did. The obtained residue was recrystallized from ethyl acetate-hexane to obtain the desired compound (3.50 g). ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 3.65 (3H, s), 6.68 (1H, d, J = 16.1 Hz), 6.73 (2H, d, J =
9.0Hz), 7.2-7.3 (5H, m), 7.47 (1H, d, J = 16.1Hz), 7.5
-7.6 (3H, m), 8.54 (2H, d, J = 6.1 Hz), 9.20 (1H, brs) (1-3) (E) -4- (2- (2- (N- (t- Buto
Xycarbonylmethyl) -N- (4-methoxybenzene
Sulfonyl) amino) phenyl) vinyl) pyridine (E) -4- (2- (2- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (3.5
To a solution of 0 g) in dimethylformamide (DMF) (30 ml) were added potassium carbonate (1.98 g) and then t-butyl bromoacetate (1.5 ml), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the insoluble matter was filtered using Celite,
DMF was distilled off under reduced pressure. The obtained residue was extracted with ethyl acetate, washed with water and then with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 100: 1) to obtain the desired compound (2.80 g). ¹ H-NMR (400 MHz, CDCl ₃ ) 1.32 (9H, s), 3.76 (3H, s), 4.23 (2H, s), 6.84-6.91 (3
H, m), 7.17 (1H, d, J = 8.0Hz), 7.24-7.30 (3H, m), 7.3
6 (1H, t, J = 7.4Hz), 7.57-7.64 (3H, m), 7.72 (1H, d, J
= 7.4Hz), 8.56 (2H, d, J = 5.5Hz) (1-4) (E) -4- (2- (2- (N- (t-but
Xycarbonylmethyl) -N- (4-methoxybenzene
Sulfonyl) amino) phenyl) vinyl) pyridine 1
-Oxide (E) -4- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (1.75)
g) in dichloromethane (20 ml), m-chloroperbenzoic acid (mCPBA) (0.63 g) was added, and the solution was added at room temperature for 1 hour.
Stirred for hours. Since the raw material remained, mCPBA was added little by little until the raw material disappeared (total 0.54 g). After completion of the reaction, the reaction mixture was treated with an aqueous solution of sodium hydrogen carbonate,
After washing with water and then with a saturated saline solution, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 100: 1 to 100: 5). The obtained crystals were recrystallized from ethyl acetate-hexane to obtain the desired compound (1.32 g). ¹ H-NMR (400 MHz, CDCl ₃ ) 1.37 (9H, s), 3.82 (3H, s), 4.09 (1H, br d, J = 16.7H
z), 4.35 (1H, br d, J = 16.7Hz), 6.86-6.91 (3H, m), 7.
00 (1H, d, J = 7.0Hz), 7.21-7.27 (1H, m), 7.34-7.39 (3
H, m), 7.61 (2H, d, J = 9.0Hz), 7.71-7.77 (2H, m), 8.2
0 (2H, d, J = 7.2Hz) (1-5) (E) -4- (2- (2- (N- (
Cimethyl) -N- (4-methoxybenzenesulfonyl)
Amino) phenyl) vinyl) pyridine 1-oxide (E) -4- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1 To a solution of -oxide (1.32 g) in dichloromethane (15 ml) was added trifluoroacetic acid (6.6 ml), and the mixture was stirred at room temperature for 3.5 hours. After completion of the reaction, the residue obtained by evaporating the solvent under reduced pressure was recrystallized from dichloromethane to obtain the desired compound (1.13 g). ¹ H-NMR (400 MHz, DMSO-d ₆ ) 3.73 (3H, s), 4.35 (2H, s), 7.00 (2H, d, J = 8.9 Hz), 7.
07-7.17 (2H, m), 7.31 (1H, t, J = 7.2Hz), 7.37-7.47 (4
H, m), 7.57 (2H, d, J = 8.9Hz), 7.83 (1H, d, J = 9.2Hz),
8.21 (2H, d, J = 7.1 Hz) (1-6) (E) -4- (2- (2- (N- (hydroxy
Silaminocarbonylmethyl) -N- (4-methoxy)
Nzensulfonyl) amino) phenyl) vinyl) pyridi
1-oxide (E) -4- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide (4.50
g) in dichloromethane (44 ml), N-methylmorpholine (4.9 ml), water-soluble carbodiimide
Hydrochloride (2.56 g), hydroxybenzotriazole (1.26 g) and O-tetrahydropyranylhydroxylamine (1.59 g) were added, and the mixture was stirred at room temperature for 16 hours. After the completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 6: 1 to 3: 1). The obtained colorless powder was dissolved in a methanol (40 ml) -dichloromethane (20 ml) solution, p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solvent was concentrated to one tenth under reduced pressure, water, ethyl acetate and diethyl ether were added. The resulting crystals were collected by filtration and dried to obtain the desired compound (2.38 g). ^{1 H-NMR (400MHz, DMSO} -d 6) 3.77 (3H, s), 3.98 (1H, d, J = 15.7Hz), 4.26 (1H, d, J =
15.7Hz), 6.92 (1H, d, J = 7.8Hz), 7.04 (2H, d, J = 8.8H
z), 7.13 (1H, d, J = 16.6Hz), 7.28 (1H, m), 7.39 (1H,
t, J = 7.8Hz), 7.45 (2H, d, J = 7.0Hz), 7.58 (2H, d, J =
8.8Hz), 7.61 (1H, d, J = 16.6Hz), 7.83 (1H, d, J = 7.2H)
z), 8.23 (2H, d, J = 7.0Hz), 8.94 (1H, s), 10.54 (1H,
s).

Example 2 (E) -4- (2- (2-
(N- (hydroxylaminocarbonylmethyl) -N-
(4-methoxybenzenesulfonyl) amino) phenyl
Ru) vinyl) pyridine (Exemplary Compound No. 1-4) (2-1) (E) -4- (2- (2- (N- (carboxy)
Cimethyl) -N- (4-methoxybenzenesulfonyl)
(Amino) phenyl) vinyl) pyridine (E) -4- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (5.00
g) in dioxane (30 ml) was added to concentrated hydrochloric acid (10 m
l) was added and the mixture was heated under reflux for 1 hour. After cooling, the residue obtained by evaporating the solvent under reduced pressure was washed with diethyl ether to obtain the desired compound (3.50 g). ^{1 H-NMR (400MHz, DMSO} -d 6) 3.74 (3H, s), 4.34 (1H, br d, J = 17.2Hz), 4.52 (1H, br
d, J = 17.2Hz), 7.01 (2H, d, J = 8.8Hz), 7.10 (1H, d, J =
8.0Hz), 7.42-7.52 (3H, m), 7.55 (2H, d, J = 8.8Hz), 7.
98 (1H, d, J = 8.0Hz), 8.05 (2H, d, J = 6.7Hz), 8.17 (1H,
d, J = 16.5 Hz), 8.88 (2H, d, J = 6.7 Hz) (2-2) (E) -4- (2- (2- (N- (hydroxy
Silaminocarbonylmethyl) -N- (4-methoxy)
Nzensulfonyl) amino) phenyl) vinyl) pyridi
Emissions (E) -4- (2- (2- (N- ( carboxymethyl)
To a suspension of -N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (1.50 g) in dichloromethane (80 ml) was added N-methylmorpholine (1.79 ml), a water-soluble carbodiimide hydrochloride (6.
86 mg), hydroxybenzotriazole (484 m
g) and O-tetrahydropyranylhydroxylamine (400 mg) were added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into water, and the organic layer was washed with an aqueous solution of sodium hydrogen carbonate, water, and then with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 100: 5).
The obtained solid was dissolved in methanol (30 ml) and p-
Toluenesulfonic acid monohydrate (1.23 g) was added,
Stirred at room temperature for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Dichloromethane was added to the obtained residue, and the resulting precipitate was collected by filtration. This precipitate was suspended in methanol, a saturated aqueous solution of sodium hydrogen carbonate was added, and ultrasonic waves were applied. The remaining powder was collected by filtration, washed with dichloromethane, isopropyl alcohol, and then with water, and then dried to obtain the desired compound (9).
90 mg). ¹ H-NMR (400 MHz, DMSO-d ₆ ) 3.75 (3 H, s), 3.99 (1 H, d, J = 15.6 Hz), 4.24 (1 H, d, J =
15.6Hz), 6.92 (1H, d, J = 8.0Hz), 7.03 (2H, d, J = 8.8H
z), 7.14 (1H, d, J = 16.6Hz), 7.30 (1H, t, J = 7.3Hz),
7.32-7.43 (3H, m), 7.59 (2H, d, J = 8.8Hz), 7.78 (1H,
d, J = 16.6Hz), 7.87 (1H, d, J = 7.3Hz), 8.57 (2H, d, J =
6.0Hz), 8.93 (1H, s), 10.53 (1H, s).

Example 3 (E) -4- (2- (2-
(N-((O-methyl) hydroxylaminocarbonyl
Methyl) -N- (4-methoxybenzenesulfonyl) a
Mino) phenyl) vinyl) pyridine 1-oxide (Exemplified Compound No. 1-9) (E) -4- (2- (2- (N- (carboxymethyl))
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide (100 m
g), a solution of water-soluble carbodiimide hydrochloride (65 mg), hydroxybenzotriazole (32 mg) and O-methylhydroxylamine hydrochloride (28 mg) in dichloromethane (2 ml) was added to N-methylmorpholine (11
0 ml) and stirred at room temperature for 2.5 hours. After completion of the reaction, the reaction mixture was poured into water, and the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is washed with ethyl acetate to give the desired compound (51 m
g) was obtained. ¹ H-NMR (400MHz, CDCl ₃ ) 3.72 (3H, s), 3.82 (3H, s), 3.9-4.1 (1H, m), 4.2-4.4
(1H, m), 6.8-7.0 (4H, m), 7.2-7.5 (5H, m), 7.63 (2H,
d, J = 9.0Hz), 7.69 (1H, d, J = 7.9Hz), 8.15 (2H, d, J =
7.9Hz), 9.29 (1H, br s).

Example 4 (E) -4- (2- (2-
(N-((Op-methoxybenzyl) hydroxyl
Minocarbonylmethyl) -N- (4-methoxybenzene
Sulfonyl) amino) phenyl) vinyl) pyridine 1
-Oxide (Exemplified Compound No. 1-17) (E) -4- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide (88 m
g), water-soluble carbodiimide hydrochloride (57 mg), hydroxybenzotriazole (28 mg) and O- (p
-Methoxybenzyl) hydroxylamine hydrochloride (5
Using 6 mg) and N-methylmorpholine (97 ml), the target compound was obtained in the same manner as in Example 3. ^{1 H-NMR (400MHz, CDCl} 3) 3.82 (6H, s), 3.9-4.1 (1H, m), 4.2-4.4 (1H, m), 4.78
(2H, br s), 6.80 (1H, d, J = 16.4Hz), 6.85-7.0 (5H, m),
7.15-7.5 (5H, m), 7.60 (2H, d, J = 8.3Hz), 7.67 (1H,
d, J = 7.8Hz), 8.11 (2H, d, J = 6.7Hz), 8.93 (1H, br
s).

(Example 5) (E) -4- (2- (2-
(N- (aminocarbonylmethyl) -N- (4-methoxy
Sibenzenesulfonyl) amino) phenyl) vinyl) pi
Lysine 1-oxide (Exemplified Compound No. 1-1) (E) -4- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide (69 m
g), water-soluble carbodiimide hydrochloride (45 mg), hydroxybenzotriazole (22 mg), aqueous ammonia (28%, 20 ml) and N-methylmorpholine (51 ml) in the same manner as in Example 3 to give the target compound. Obtained. However, washing was performed with a mixture of dichloromethane and methanol. ^{1 H-NMR (400MHz, DMSO} -d 6) 3.76 (3H, s), 4.08 (1H, br d, J = 16.0Hz), 4.28 (1H, br
d, J = 16.0Hz), 7.0-7.07 (3H, m), 7.11 (1H, d, J = 16.5
Hz), 7.28 (1H, m), 7.39 (1H, t, J = 7.6Hz), 7.44 (2H,
d, J = 7.0Hz), 7.55-7.63 (3H, m), 7.82 (1H, d, J = 7.0H
z), 8.21 (2H, d, J = 7.0Hz).

(Example 6) (E) -4- (2- (2-
(N-((N ', O-dimethyl) hydroxylaminoca
Rubonylmethyl) -N- (4-methoxybenzenesulfo
Nyl) amino) phenyl) vinyl) pyridine 1-oxo
Sid (Exemplified Compound No. 1-19) (E) -4- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide (69 m
g), water-soluble carbodiimide hydrochloride (45 mg), hydroxybenzotriazole (22 mg) and N, O-
Using dimethylhydroxylamine hydrochloride (23 mg) and N-methylmorpholine (77 ml), the target compound was obtained in the same manner as in Example 3. ¹ H-NMR (400 MHz, CDCl ₃ ) 3.15 (3H, s), 3.68 (3H, s), 3.78 (3H, s), 4.35-4.45 (1
H, m), 4.70-4.80 (1H, m), 6.82 (1H, d, J = 16.5Hz), 6.
85 (2H, d, J = 8.8Hz), 7.12 (1H, d, J = 7.9Hz), 7.2-7.3
(1H, m), 7.35 (1H, t, J = 7.9Hz), 7.39 (2H, d, J = 7.1H
z), 7.63 (2H, d, J = 8.8Hz), 7.70 (1H, d, J = 7.1Hz), 7.
96 (1H, d, J = 16.5Hz), 8.16 (2H, d, J = 7.1Hz).

Example 7 (E) -4- (2-((2-
(N- (hydroxylaminocarbonylmethyl) -N-
(4-methoxybenzenesulfonyl) amino) -5-meth
(Tyl) phenyl) vinyl) pyridine 1-oxide (exemplified compound number 1-43) (7-1) (E) -4- (2- (2-amino-5-methyl)
Ruphenyl) vinyl) pyridine 4-vinylpyridine ( 9.9 ml) , 2-bromo-4-
Methylaniline (8.7 ml), triethylamine (8
7 ml), palladium acetate (157.1 mg), and o
Example 1 using tolylphosphine (0.85 g)
In the same manner as in Example 1, the target compound (2.73 g) was obtained. ^{1 H-NMR (400MHz, DMSO} -d 6) 2.18 (3H, s), 5.36 (2H, br s), 6.58 (1H, d, J = 8.1Hz),
6.97 (1H, d, J = 16.1Hz), 7.32 (1H, s), 7.58 (2H, d, J =
5.9 Hz), 7.66-7.72 (2H, m), 8.51 (2H, d, J = 5.9 Hz) (7-2) (E) -4- (2-((2- (4-methoxy
Benzenesulfonyl) amino-5-methyl) phenyl)
( Vinyl) pyridine (E) -4- (2- (2-amino-5-methylphenyl) vinyl) pyridine (2.73 g), p-methoxybenzenesulfonyl chloride (2.68 g), and pyridine (27 ml) were used. In the same manner as in Example 1-2, the target compound (3.30 g) was obtained. ¹ H-NMR (400MHz, CDCl ₃ ) 2.43 (3H, s), 3.81 (3H, s), 6.70 (1H, d, J = 16.2Hz),
6.79 (2H, d, J = 8.5Hz), 7.06-7.28 (5H, m), 7.37 (1H,
s), 7.64 (2H, d, J = 8.5Hz), 8.34 (1H, br s), 8.48 (2H,
m) (7-3) (E) -4- (2-((2- (N- (t-
Toxylcarbonylmethyl) -N- (4-methoxybenze
Sulphonyl) amino) -5-methyl) phenyl) vinyl
Pyridine) (E) -4- (2-((2- (4-methoxybenzenesulfonyl) amino-5-methyl) phenyl) vinyl) pyridine (3.30 g), dimethylformamide (17 m
l), potassium carbonate (2.40 g) and bromoacetic acid t
Using -butyl (1.5 ml), the target compound (1.69 g) was obtained in the same manner as in Example 1-3. ¹ H-NMR (400 MHz, CDCl ₃ ) 1.38 (9H, s), 2.39 (3H, s), 3.75 (3H, s), 4.21 (2H, s),
6.86 (2H, d, J = 8.9Hz), 6.87 (1H, d, J = 16.5Hz), 7.07
(2H, s), 7.28 (2H, d, J = 6.1Hz), 7.52 (1H, s), 7.55 (1
H, d, J = 16.5Hz), 7.63 (2H, d, J = 8.9Hz), 8.56 (2H, d,
J = 6.1 Hz) (7-4) (E) -4- (2-((2- (N- (t-bu
Toxylcarbonylmethyl) -N- (4-methoxybenze
Sulphonyl) amino) -5-methyl) phenyl) vinyl
Ru) pyridine 1-oxide (E) -4- (2-((2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) -5-methyl) phenyl) vinyl) Pyridine (1.0 g), m-chloroperbenzoic acid (0.95
g) and dichloromethane (16 ml) in the same manner as in Example 1-4 to obtain the desired compound (0.65 g). ¹ H-NMR (400 MHz, CDCl ₃ ) 1.37 (9H, s), 2.04 (3H, s), 3.81 (3H, s), 4.06-4.34 (2
H, m), 6.85-6.90 (4H, m), 7.05 (1H, d, J = 8.1Hz), 7.3
6 (2H, d, J = 7.0Hz), 7.52 (1H, s), 7.62 (2H, d, J = 8.9H
z), 7.68 (1H, d, J = 16.4 Hz), 8.18 (2H, d, J = 7.0 Hz) (7-5) (E) -4- (2-((2- (N-((O −
Tetrahydropyran-2-yl) hydroxylaminoca
Rubonylmethyl) -N- (4-methoxybenzenesulfo
Nyl) amino) -5-methyl) phenyl) vinyl) pyri
Gin 1-oxide (E) -4- (2-((2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) -5-methyl) phenyl) vinyl) pyridine 1 -Powder (0.83 g) as in Example 1-5 using oxide (0.65 g), trifluoroacetic acid (1.95 ml) and dichloromethane (6.5 ml)
I got The obtained powder (0.79 g), water-soluble carbodiimide hydrochloride (0.35 g), hydroxybenzotriazole (0.17 g), O-tetrahydropyranylhydroxylamine (0.21 g), N-methylmorpholine (0 .33 ml) and dichloromethane (7.9 ml)
And the target compound (0.46
g) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 1.53-1.73 (6H.m), 2.36 (3H, s), 3.45-4.41 (7H, m),
4.86 (1H, m), 6.82-6.90 (4H, m), 7.03 (1H, d, J = 8.0H
z), 7.38 (2H, m), 7.50 (1H, s), 7.64 (3H, m), 8.11 (2
H, d, J = 6.8 Hz), 10.47-10.57 (1H, m) (7-6) (E) -4- (2-((2- (N- (hydro
Xylaminocarbonylmethyl) -N- (4-methoxy
Benzenesulfonyl) amino) -5-methyl) phenyl
Ru) vinyl) pyridine 1-oxide (E) -4- (2-((2- (N-((O-tetrahydropyran-2-yl) hydroxylaminocarbonylmethyl) -N- (4-methoxybenzenesulfonyl) Amino) -5-methyl) phenyl) vinyl) pyridine 1-
To a solution of the oxide (0.46 g) in methanol (5 ml) was added p-toluenesulfonic acid monohydrate (0.16 g), and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water and ethyl acetate were added to the reaction solution, and the resulting precipitate was collected by filtration. After washing with water and then with ethyl acetate, drying was performed to obtain the target compound (3
00 mg). ^{1 H-NMR (400MHz, DMSO} -d 6) 2.33 (3H, s), 3.77 (3H, s), 3.94 (1H, d, J = 15.6Hz),
4.23 (1H, d, J = 15.6Hz), 6.79 (1H, d, J = 8.0 Hz), 7.02-
7.14 (4H, m), 7.44 (2H, d, J = 6.9 Hz), 7.54-7.64 (4H,
m), 8.22 (2H, d, J = 6.9Hz), 8.91 (1H, s).

Example 8 (E) -4- (2-((2-
(N- (hydroxylaminocarbonylmethyl) -N-
(4-methoxybenzenesulfonyl) amino) -5-meth
Tyl) phenyl) vinyl) pyridine (Exemplary Compound No. 1)
-44) (8-1) (E) -4- (2-((2- (N-((O-
Tetrahydropyran-2-yl) hydroxylaminoca
Rubonylmethyl) -N- (4-methoxybenzenesulfo
Nyl) amino) -5-methyl) phenyl) vinyl) pyri
Zin (E) -4- (2-((2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) -5-methyl) phenyl) vinyl) pyridine (0.70 g ) In dichloromethane (7 ml) solution
Under stirring at room temperature, trifluoroacetic acid (7 ml) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated at room temperature, dissolved in ethyl acetate, and neutralized by adding a saturated aqueous solution of sodium hydrogen carbonate. Separate, dry the organic layer over anhydrous magnesium sulfate, evaporate the solvent under reduced pressure, and dry.
A powder was obtained. The obtained powder (0.25 g), water-soluble carbodiimide hydrochloride (0.15 g), hydroxybenzotriazole (75.2 mg), O-tetrahydropyranylhydroxylamine (95.3 mg), N-methylmorpholine (0 .29 ml) and dichloromethane (2.
In the same manner as in Example 3, the desired compound (0.24 g) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 1.61-1.87 (6H, m), 2.43 (3H, s), 3.59-3.61 (1H, m), 3.
79-3.95 (4H, m), 4.17-4.28 (2H, m), 4.90-4.97 (1H,
m), 6.94-6.96 (4H, m), 7.13 (1H, d, J = 8.0Hz), 7.27-
7.31 (2H, m), 7.41-7.46 (1H, m), 7.55 (1H, s), 7.70 (2
H, d, J = 8.6Hz), 8.60 (2H, d, J = 6.0Hz), 9.41-9.45 (1
H, m) (8-2) (E) -4- (2-((2- (N- (hydro
Xylaminocarbonylmethyl) -N- (4-methoxy
Benzenesulfonyl) amino) -5-methyl) phenyl
Ru) vinyl) pyridine (E) -4- (2-((2- (N-((O-tetrahydropyran-2-yl) hydroxylaminocarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino)- 5-methyl) phenyl) vinyl) pyridine (0.
P-toluenesulfonic acid / 1 in a mixed solution of methanol (2.4 ml) and dichloromethane (12 ml).
A hydrate (84.9 mg) was added, and the mixture was stirred at room temperature for 8 hours. After the reaction, water and ethyl acetate were added to the reaction solution,
The resulting precipitate was collected by filtration. After washing with water and then with ethyl acetate, drying was performed to obtain the target compound (59 mg). ^{1 H-NMR (400MHz, DMSO} -d 6) 2.27 (3H, s), 3.68-3.78 (4H, m), 4.28-4.32 (1H, m), 6.
64 (1H, d, J = 8.4Hz), 6.95 (2H, d, J = 7.1Hz), 7.10-7.3
1 (2H, m), 7.47 (2H, d, 8.8Hz), 7.68 (1H, m), 7.86-7.
91 (2H, m), 8.14-8.18 (1H, m), 8.75-8.89 (2H, m), 10.
51 (1H, m).

(Embodiment 9)(E) -4- (2-((2-
(N- (hydroxylaminocarbonylmethyl) -N-
(4-methoxybenzenesulfonyl) amino) -3-me
Toxi) phenyl) vinyl) pyridine 1-oxide
(Exemplary Compound No. 1-47) (9-1)(E) -4- (2- (3-methoxy-2-ni)
Trophenyl) vinyl) pyridine 3-methoxy-2-nitrobenzaldehyde (5 g)
Dissolve in acetic anhydride (5.3 ml) and add 4-picoline (2.
7 ml) and stirred at 160 ° C. for 8 hours. End of reaction
Thereafter, the reaction solution was cooled to room temperature, and ethyl acetate, water and a small amount of
Methanol was added and the layers were separated. The organic layer is made of ammonia water,
Then, after washing with saturated saline, anhydrous magnesium sulfate was used.
After drying, the solvent was distilled off under reduced pressure. The resulting residue is
Ricagel column chromatography (hexane-acetic acid
Purification by chill 1: 1) gave 5.65 g of the desired compound.
Was.¹ H-NMR (400MHz, CDCl_Three) 3.92 (3H, s), 7.01 (1H, d, J = 8.2Hz), 7.06 (1H, d, J
= 16.2Hz), 7.11 (1H, d, J = 16.2Hz), 7.31-7.33 (3H, m),
7.45 (1H, t, J = 8.2Hz), 8.60 (2H, d, J = 6.2Hz) (9-2)(E) -4- (2- (2-amino-3-metho
Xyphenyl) vinyl) pyridine (E) -4- (2- (3-methoxy-2-nitrophenyl)
(V) vinyl) pyridine (5.65 g) in ethanol (1
50 ml), add acetic acid (150 ml), and add
While stirring at, iron powder (12.3 g) was added. Rise to 120 ° C
Warmed and stirred for 3 hours. After completion of the reaction, cool the reaction solution to room temperature.
Pour into ice water, then add 28% aqueous ammonia
The mixture was made alkaline and extracted with ethyl acetate. Saturated salt
After washing with water, drying over anhydrous magnesium sulfate, under reduced pressure,
The solvent was distilled off to obtain 3.25 g of the target compound.¹ H-NMR (400MHz, CDCl_Three) 3.87 (3H, s), 4.10 (2H, br, s), 6.75-6.79 (2H, m), 6.9
2 (1H, d, J = 16.1Hz), 7.06-7.08 (1H, m), 7.34 (2H, d,
J = 6.1Hz), 7.40 (1H, d, J = 16.1Hz), 8.55 (2H, d, J = 6.1H
z) (9-3)(E) -4- (2-((2- (4-methoxy
Benzenesulfonyl) amino-3-methoxy) phenyl
Le) vinyl) pyridine (E) -4- (2- (2-amino-3-methoxyphenyl)
L) vinyl) pyridine (3.25 g), p-methoxybenzene
Nzensulfonyl chloride (2.697 g) and pyri
Using gin (33 ml), as in Example 1-2,
The target compound (2.37 g) was obtained.¹ H-NMR (400MHz, CDCl_Three) 3.38 (3H, s), 3.79 (3H, s), 6.47 (1H, s), 6.65 (1H, d,
 J = 8.1Hz), 6.81 (2H, d, J = 8.8Hz), 7.01 (1H, d, J = 16.5
Hz), 7.22 (1H, t, J = 8.0Hz), 7.39 (1H, d, J = 8.0Hz),
7.42 (2H, d, J = 5.4Hz), 7.55 (2H, d, J = 8.8Hz), 7.94 (1
(H, d, J = 16.5Hz), 8.57 (2H, d, J = 5.4Hz) (9-4)(E) -4- (2-((2- (N- (t-
Toxylcarbonylmethyl) -N- (4-methoxybenze
Sulphonyl) amino) -3-methoxy) phenyl) bi
Nil) pyridine (E) -4- (2-((2- (4-methoxybenzenes)
Ruphonyl) amino-3-methoxy) phenyl) vinyl)
Pyridine (2.37 g), dimethylformamide (12
ml), potassium carbonate (1.66 g), and bromoacetic acid
Same as Example 1-3 using t-butyl (0.97 ml)
Thus, the target compound (2.12 g) was obtained.¹ H-NMR (400MHz, CDCl_Three) 1.41 (9H, s), 3.45 (3H, s), 3.73 (3H, s), 3.84 (1H, d,
 J = 17.5Hz), 4.70 (1H, d, J = 17.5Hz), 6.75-6.81 (3H,
m), 6.92 (1H, d, J = 16.5Hz), 7.27-7.42 (4H, m), 7.60 (2
H, d, J = 7.3Hz), 8.28 (1H, d, J = 16.5Hz), 8.56 (2H, d,
 J = 4.6Hz) (9-5)(E) -4- (2-((2- (N- (t-
Toxylcarbonylmethyl) -N- (4-methoxybenze
Sulphonyl) amino) -3-methoxy) phenyl) bi
Nyl) pyridine 1-oxide (E) -4- (2-((2- (N- (t-butoxycal
Bonylmethyl) -N- (4-methoxybenzenesulfoni
Ru) amino) -3-methoxy) phenyl) vinyl) pyri
Gin (1.10 g), m-chloroperbenzoic acid (1.01
g) and dichloromethane (21 ml)
The target compound (0.74 g) was obtained in the same manner as in 1-4.
Was.¹ H-NMR (400MHz, CDCl_Three) 1.41 (9H, s), 3.37 (3H, s), 3.79-3.83 (4H, m), 4.65 (1
H, d, J = 18.0Hz), 6.74 (1H, d, J = 8.0Hz), 6.85 (2H, d,
 J = 8.9Hz), 6.91 (1H, d, J = 16.5Hz), 7.30 (1H, t, J = 8.
0Hz), 7.37 (1H, d, J = 8.0Hz), 7.47 (2H, d, J = 7.0Hz),
7.57 (2H, d, J = 8.9Hz), 8.17 (2H, d, J = 7.0Hz), 8.32 (1
H, d, J = 16.5Hz), (9-6)(E) -4- (2-((2- (N-((O-
Tetrahydropyran-2-yl) hydroxylaminoca
Rubonylmethyl) -N- (4-methoxybenzenesulfo
Nyl) amino) -3-methoxy) phenyl) vinyl) pi
Lysine 1-oxide (E) -4- (2-((2- (N- (t-butoxycal
Bonylmethyl) -N- (4-methoxybenzenesulfoni
Ru) amino) -3-methoxy) phenyl) vinyl) pyri
Gin 1-oxide (0.74 g), trifluoroacetic acid
(7.4 ml) and dichloromethane (7.4 ml)
Used and in the same manner as in Example 1-5, powder (0.61 g)
I got The obtained powder (0.16 g), water-soluble carbodi
Imide hydrochloride (0.20 g), hydroxybenzotri
Azole (0.10 g), O-tetrahydropyranylhi
Droxylamine (0.12 g), N-methylmorpholy
(0.19 ml) and dichloromethane (1.6 ml)
And in the same manner as in Example 3, the desired compound (0.04
g) was obtained.¹ H-NMR (400MHz, CDCl_Three) 1.42-1.88 (6H, m), 3.49-4.27 (10H, m), 4.95 (1H, m),
6.96-7.00 (4H, m), 7.24-7.41 (5H, m), 7.79 (2H, m),
8.22 (2H, m), 10.05 (0.5H, br.s), 10.27 (0.5H, br.s) (9-7)(E) -4- (2-((2- (N- (hydro
Xylaminocarbonylmethyl) -N- (4-methoxy
Benzenesulfonyl) amino) -3-methoxy) phenyl
Ru) vinyl) pyridine 1-oxide (E) -4- (2-((2- (N-((O-tetrahydro
Ropyran-2-yl) hydroxylaminocarbonyl
Tyl) -N- (4-methoxybenzenesulfonyl) ami
No) -3-Methoxy) phenyl) vinyl) pyridine 1
-Oxide (0.04 g) in methanol (0.4 ml)
Add p-toluenesulfonic acid monohydrate (13.4) to the solution.
mg) and stirred at room temperature for 3 hours. After the reaction,
Water and ethyl acetate were added to the reaction solution, and the resulting precipitate was collected by filtration.
Was. After washing with water and then with ethyl acetate, drying and drying
The compound (20.9 mg) was obtained.¹ H-NMR (400MHz, DMSO-d₆) 3.33 (3H, s), 3.70-3.80 (4H, m), 4.46 (1H, d, J = 17.2H
z), 6.95-7.14 (4H, m), 7.35-7.58 (6H, m), 8.10-8.25
(3H, m), 8.94-8.96 (1H, m).

Example 10 (E) -4- (2-((2
-(N- (hydroxylaminocarbonylmethyl) -N
-(4-methoxybenzenesulfonyl) amino) -3-
(Methoxy) phenyl) vinyl) pyridine (Exemplary Compound No. 1-48) (10-1) (E) -4- (2-((2- (N-((O
-Tetrahydropyran-2-yl) hydroxylamino
Carbonylmethyl) -N- (4-methoxybenzenesul
(Honyl) amino) -3-methoxy) phenyl) vinyl)
Pyridine (E) -4- (2-((2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) -3-methoxy) phenyl) vinyl) pyridine (1.00 g) ), Trifluoroacetic acid (10 ml),
A powder was obtained in the same manner as in Example 1-5 using dichloromethane (10 ml). The obtained powder (0.20 g),
Water-soluble carbodiimide hydrochloride (0.12 g), hydroxybenzotriazole (56.8 mg), O-tetrahydropyranylhydroxylamine (72.7 mg),
Using N-methylmorpholine (0.22 ml) and dichloromethane (2 ml), the target compound (0.23 g) was obtained in the same manner as in Example 3. ¹ H-NMR (400 MHz, CDCl ₃ ) 1.56-1.82 (6H, m), 3.49-4.35 (10H, m), 4.87 (1H, m),
6.81-6.92 (4H, m), 7.12-7.22 (3H, m), 7.29-7.35 (2H, m
m), 7.71-7.75 (2H, m), 8.53 (2H, d, J = 5.4Hz), 10.16
(0.5H, br, s), 10.42 (0.5H, br, s) (10-2) (E) -4- (2-((2- (N- (hydr
Roxylaminocarbonylmethyl) -N- (4-methoxy
Sibenzenesulfonyl) amino) -3-methoxy) fe
Nyl) vinyl) pyridine (E) -4- (2-((2- (N-((O-tetrahydropyran-2-yl) hydroxylaminocarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino)- To a mixed solution of 3-methoxy) phenyl) vinyl) pyridine (0.23 g) in methanol (1.2 ml) and dichloromethane (1.2 ml) was added p-toluenesulfonic acid monohydrate (76.1 mg). 8 at room temperature
Stirred for hours. After completion of the reaction, water and ethyl acetate were added to the reaction solution, and the resulting precipitate was collected by filtration. After washing with water and then with ethyl acetate, drying was performed to obtain the target compound (17.6 mg).
I got ^{1 H-NMR (400MHz, DMSO} -d 6) 3.30 (3H, s), 3.71 (3H, s), 3.99-4.02 (1H, m), 4.39-
4.44 (1H, m), 6.91-7.13 (4H, m), 7.33-7.58 (6H, m),
8.27-8.35 (1H, m), 8.51-8.57 (2H, m), 8.91 (1H, br,
s), 10.56 (1H, br, s).

Example 11 (E) -4- (2-((2
-(N- (hydroxylaminocarbonylmethyl) -N
-(4-methoxybenzenesulfonyl) amino) -4-
Methoxy) phenyl) vinyl) pyridine 1-oxide
(Exemplified Compound No. 1-99) (11-1) (E) -4- (2- (2-Nitro-4- meth)
Toxylphenyl) vinyl) pyridine 4-vinylpyridine (7.1 ml), 4-bromo-3-
Nitroanisole (11.6 g), triethylamine (116 ml), palladium acetate (110 mg) and o
Example 1 using tolylphosphine (0.61 g)
In the same manner as 1, a target compound (2.35 g) was obtained. ^{1 H-NMR (400MHz, CDCl} 3) 3.91 (3H, s), 6.89 (1H, d, J = 16.2Hz), 7.19 (1H, dd, J
= 2.7, 8.7Hz), 7.37 (2H, d, J = 4.7Hz), 7.51 (1H, d, J
= 2.7Hz), 7.68 (1H, d, J = 8.7Hz), 7.73 (1H, d, J = 16.2H
z), 8.60 (2H, d, J = 4.7Hz) (11-2) (E) -4- (2-((2- (N- (t-
Butoxycarbonylmethyl) -N- (4-methoxybenz)
Zensulfonyl) amino) -4-methoxy) phenyl)
Vinyl) pyridine (E) -4- (2- (2-nitro-4-methoxyphenyl) vinyl) pyridine (2.35 g), ethanol (7
0), acetic acid (70 ml) and iron powder (5.12 g) in the same manner as in Example 9-2, (E) -4- (2-
(2-Amino-4-methoxyphenyl) vinyl) pyridine was obtained, but at this time, a dihydro compound in which the double bond was saturated, which was difficult to remove, was also produced. The obtained (E) -4- (2-
Example 1-2 was prepared using a mixture of (2-amino-4-methoxyphenyl) vinyl) pyridine and a dihydro compound (1.80 g), p-methoxybenzenesulfonyl chloride (1.64 g), and pyridine (18 ml). (E) -4- (2-((2- (4-methoxybenzenesulfonyl) amino-4-methoxy) phenyl) vinyl) pyridine was obtained in the same manner as described above, but also in this case, the dihydro form was difficult to remove. Met. The obtained (E) -4- (2-((2- (4
-Methoxybenzenesulfonyl) amino-4-methoxy) phenyl) vinyl) pyridine and a mixture of dihydro form (2.94 g), dimethylformamide (15 m
l), potassium carbonate (2.05 g) and bromoacetic acid t-
Using butyl (1.2 ml), the target compound (0.46 g) was obtained in the same manner as in Example 1-3. ¹ H-NMR (400 MHz, CDCl ₃ ) 1.41 (9H, s), 3.74 (3H, s), 3.75 (3H, s), 4.11-4.25 (2
H, m), 6.75 (1H, d, J = 16.5Hz), 6.78-6.79 (1H, m), 6.8
6 (2H, d, J = 8.9Hz), 6.91-6.95 (1H, m), 7.22 (2Hd, J =
6.1Hz), 7.39 (1H, d, J = 16.5Hz), 7.62-7.67 (3H, m),
8.53 (2H d, J = 6.1 Hz) (11-3) (E) -4- (2-((2- (N- (t-
Butoxycarbonylmethyl) -N- (4-methoxybenz)
Zensulfonyl) amino) -4-methoxy) phenyl)
Vinyl) pyridine 1-oxide (E) -4- (2-((2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) -4-methoxy) phenyl) vinyl) Pyridine (0.3 g), m-chloroperbenzoic acid (0.56
g) and dichloromethane (8.6 ml) in the same manner as in Example 1-4 to obtain the desired compound (0.18 g). ¹ H-NMR (400 MHz, CDCl ₃ ) 1.39 (9H, s), 3.71 (3H, s), 3.80 (3H, s), 4.15-4.27 (2
H, m), 6.61 (1H, d, J = 2.6Hz), 6.74 (1H, d, J = 16.4H
z), 6.90 (2H, d, J = 8.9Hz), 6.91-6.93 (1H, m), 7.29 (2
H, d, J = 7.1Hz), 7.53 (1H, d, J = 16.4Hz), 7.62-7.66 (3
H, m), 8.14 (2H, d, J = 7.1 Hz) (11-4) (E) -4- (2-((2- (N-((O
-Tetrahydropyran-2-yl) hydroxylamino
Carbonylmethyl) -N- (4-methoxybenzenesul
(Honyl) amino) -4-methoxy) phenyl) vinyl)
Pyridine 1-oxide (E) -4- (2-((2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) -4-methoxy) phenyl) vinyl) pyridine 1 A powder (0.15 g) was obtained in the same manner as in Example 1-5, using -oxide (0.18 g), trifluoroacetic acid (1.8 ml) and dichloromethane (1.8 ml). The obtained powder (0.15 g), water-soluble carbodiimide hydrochloride (91.7 mg), hydroxybenzotriazole (45.4 mg), O-tetrahydropyranylhydroxylamine (51.2 mg), N-methylmorpholine (88 μl) ) And dichloromethane (1.5 ml)
And in the same manner as in Example 3, the desired compound (0.10
g) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 1.58-1.84 (6H, m), 3.56-3.90 (8H, m), 4.11-4.31 (2H,
m), 4.92 (1H, m), 6.48-6.54 (1H, m), 6.76 (1H, d, J = 1
6.0Hz), 6.93-7.01 (3H, m), 7.33-7.48 (3H, m), 7.63-7.
69 (3H, m), 8.13 (2H, d, J = 6.8H), 9.87 (0.5H, br, s),
9.88 (0.5H, br, s) (11-5) (E) -4- (2-((2- (N- (
Roxylaminocarbonylmethyl) -N- (4-methoxy
Sibenzenesulfonyl) amino) -4-methoxy) fe
Nyl) vinyl) pyridine 1-oxide (E) -4- (2-((2- (N-((O-tetrahydropyran-2-yl) hydroxylaminocarbonylmethyl) -N- (4-methoxybenzenesulfonyl) Amino) -4-methoxy) phenyl) vinyl) pyridine 1
-Poxide (0.10 g) in methanol (1 ml) was added to p-toluenesulfonic acid monohydrate (33.4 m
g) was added and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water and ethyl acetate were added to the reaction solution, and the resulting precipitate was collected by filtration.
After washing with water and then with ethyl acetate, drying was performed to obtain the target compound (50 mg). ^{1 H-NMR (400MHz, DMSO} -d 6) 3.65 (3H, s), 3.78 (3H, s), 3.99 (1H, d, J = 15.7Hz),
4.23 (1H, d, J = 15.7Hz), 6.42 (1H, s), 6.98-7.02 (2H,
m), 7.06 (2H, d, J = 8.8Hz), 7.41 (2H, d, J = 6.9Hz), 7.
51 (1H, d, J = 16.6Hz), 7.61 (2H, d, J = 8.8Hz), 7.76 (1
H, d, J = 8.8Hz), 8.20 (2H, d, J = 6.9Hz), 8.95 (1H, br,
s), 10.52 (1H, br, s).

(Example 12) (E) -4- (2-((2
-(N- (hydroxylaminocarbonylmethyl) -N
-(4-methoxybenzenesulfonyl) amino) -4-
(Methoxy) phenyl) vinyl) pyridine (Exemplary Compound No. 1-100) (12-1) (E) -4- (2-((2- (N-((O
-Tetrahydropyran-2-yl) hydroxylamino
Carbonylmethyl) -N- (4-methoxybenzenesul
(Honyl) amino) -4-methoxy) phenyl) vinyl)
Pyridine (E) -4- (2-((2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) -4-methoxy) phenyl) vinyl) pyridine (0.16 g ), Concentrated hydrochloric acid (0.8 ml) and dioxane (1.6 ml), to obtain a powder in the same manner as in Example 2-1. The obtained powder, water-soluble carbodiimide hydrochloride (89.1 mg), hydroxybenzotriazole (46.1 mg), O-tetrahydropyranylhydroxylamine (56.0 mg), N-methylmorpholine (0.34 ml) and dichloromethane (2.0ml)
And in the same manner as in Example 3, the desired compound (0.10
g) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 1.44-1.94 (6H, m), 3.48-3.87 (8H, m), 4.20 (2H, m),
4.86-4.93 (1H, m), 6.58-6.62 (1H, m), 6.77 (1H, d, J =
15.8Hz), 6.89-6.98 (3H, m), 7.19-7.27 (3H, m), 7.63 (1
H, d, J = 8.9Hz), 7.69 (2H, d, J = 8.6Hz), 8.50 (2H, m),
9.77-9.88 (1H, br, s) (12-2) (E) -4- (2- (2- (N- (hydro-
Xylaminocarbonylmethyl) -N- (4-methoxy
Benzenesulfonyl) amino-4-methoxy) phenyl
Ru) vinyl) pyridine (E) -4- (2- (2- (N- (O-tetrahydropyran-2-ylhydroxylaminocarbonylmethyl))
-N- (4-methoxybenzenesulfonyl) amino-4
-Methoxy) phenyl) vinyl) pyridine (0.10
g) methanol (1 ml) dichloromethane (1 ml)
In a mixed solution of p-toluenesulfonic acid monohydrate (6
8.8 mg) and stirred at room temperature for 8 hours. After completion of the reaction, water and ethyl acetate were added to the reaction solution, and the resulting precipitate was collected by filtration. After washing with water and then with ethyl acetate, drying was performed to obtain the target compound (29 mg). ¹ H-NMR (400 MHz, DMSO-d ₆ ) 3.68 (3H, s), 3.78 (3H, s), 4.00-4.26 (2H, m), 6.45 (1
H, s), 7.02-7.12 (4H, m), 7.40-7.44 (2H, m), 7.63-7.
74 (3H, m), 7.82-7.87 (1H, m), 8.56 (2H, d, J = 4.2Hz),
8.95-9.00 (1H, br, s). (Example 13) (E) -4- (2- (3- (N- (hydr
Roxylaminocarbonylmethyl) -N- (4-methoxy
Sibenzenesulfonyl) amino) thienyl) vinyl) pi
Lysine 1-oxide (Exemplified Compound No. 6-3) (13-1) 2-methoxycarbonyl- (3- (4-meth
Toxibenzenesulfonyl ) amino) thiophene As in Example 1-2, using 3-amino-2-methoxycarbonyl-thiophene (6.29 g), p-methoxybenzenesulfonyl chloride (8.27 g), and pyridine (63 ml). To give the desired compound (9.58)
g) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 3.84 (6H, m), 6.91 (2H, d, J = 9.0 Hz), 7.38-7.40 (2H,
m), 7.79 (2H, d, J = 9.0 Hz), 9.55 (1H, br, s) (13-2) 2-formyl- (3- (4-methoxybenz)
(Zensulfonyl ) amino) thiophene 2-methoxycarbonyl- (3- (4-methoxybenzenesulfonyl) amino) thiophene (9.58 g) was dissolved in tetrahydrofuran, and lithium aluminum hydride was added little by little under ice-cooling and stirring. . After stirring for 30 minutes under ice cooling and 1 hour at room temperature, the reaction solution was cooled to -78 ° C, and a saturated aqueous ammonium chloride solution was slowly added dropwise. afterwards,
The temperature was raised to room temperature, tetrahydrofuran was added, insolubles were filtered off, and the filtrate was evaporated under reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography (ethyl acetate). Next, the obtained target compound is dissolved in ethyl acetate and activated manganese dioxide (19.2) is stirred at room temperature.
g) was added. After stirring at room temperature for 6 hours, the reaction solution was filtered,
The solvent was distilled off from the filtrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the desired compound (1.96 g). ^{1 H-NMR (400MHz, CDCl} 3) 3.84 (3H, s), 6.93 (2H, d. J = 9.0Hz), 7.42 (1H, d, J =
5.4Hz), 7.62 (1H, d, J = 5.4Hz), 7.81 (2H, d.J = 9.0H
z), 9.60 (1H, s), 10.10 (1H, br, s) (13-3) (E) -4- (2- (3- (N- (acetyl
) -N- (4-methoxybenzenesulfonyl) ami
No) thienyl) vinyl) pyridine 2-formyl- (3- (4-methoxybenzenesulfonyl) amino) thiophene (5 g), acetic anhydride (1.2 m
Using l) and 4-picoline (0.61 ml), the target compound (0.38 g) was obtained in the same manner as in Example 9-1. ^{1 H-NMR (400MHz, CDCl} 3) 1.91 (3H, s), 3.82 (3H, s), 6.86 (1H, d, J = 16.1Hz),
6.92-6.97 (3H, m), 6.99 (1H, d, J = 5.3Hz), 7.12 (2H,
d, J = 6.1Hz), 7.36 (1H, d, J = 5.3Hz), 8.03 (2H, d, J = 9.
0 Hz), 8.54 (2H, d, J = 6.1 Hz) (13-4) (E) -4- (2- (3- (4-methoxy
Benzenesulfonyl) amino) thienyl) vinyl) pyri
Gin (E) -4- (2- (3- (N- (acetyl) -N-
(4-Methoxybenzenesulfonyl) amino) thienyl) vinyl) pyridine (0.87 g) was suspended in dioxane (8.7 ml), concentrated hydrochloric acid (0.87 ml) was added, and the mixture was heated under reflux for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature, dissolved in ethyl acetate, and neutralized by adding a saturated aqueous solution of sodium hydrogen carbonate. After liquid separation, the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and
The solvent was distilled off. Drying yielded the target compound (0.79 g). ^{1 H-NMR (400MHz, CDCl} 3) 3.71 (3H, s), 6.60 (1H, d, J = 16.0Hz), 6.87 (2H, d, J =
9.0Hz), 6.93 (1H, d, J = 5.4Hz), 7.06-7.11 (3H, m), 7.
16 (1H, d, J = 5.4Hz), 7.71 (2H, d, J = 9.0Hz), 8.47 (2H,
d, J = 4.8 Hz) (13-5) (E) -4- (2- (3- (N- (t-bu
Toxylcarbonylmethyl) -N- (4-methoxybenze
(Sulfonyl) amino) thienyl) vinyl) pyridine (E) -4- (2- (3- (4-methoxybenzenesulfonyl) amino) thienyl) vinyl) pyridine (0.7
9 g), dimethylformamide (4 ml), potassium carbonate (0.27 g), and t-butyl bromoacetate (4 m
Using l) and in the same manner as in Example 1-3, the target compound (0.30 g) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 1.40 (9H, s), 3.71 (3H, s), 4.20 (2H, s), 6.68-6.74 (2
H, m), 6.87 (2H, d, J = 9.0Hz), 7.14 (1H, d, J = 5.4Hz),
7.22 (2H, d, J = 6.1Hz), 7.39 (1H, d, J = 16.4Hz), 7.64
(2H, d, J = 9.0 Hz), 8.54 (2H, d, J = 6.1 Hz) (13-6) (E) -4- (2- (3- (N- (t-bu
Toxylcarbonylmethyl) -N- (4-methoxybenze
Sulphonyl) amino) thienyl) vinyl) pyridine
1-oxide (E) -4- (2- (3- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) thienyl) vinyl) pyridine (0.20
g), m-chloroperbenzoic acid (0.35 g), and dichloromethane (3.4 ml), and the target compound (0.16 g) was obtained in the same manner as in Example 1-4. ¹ H-NMR (400 MHz, CDCl ₃ ) 1.40 (9H, s), 3.79 (3H, s), 4.19 (2H, s), 6.63 (1H, d,
J = 5.4Hz), 6.69 (1H, d, J = 16.3Hz), 6.90 (2H, d, J = 8.3
Hz), 7.15 (1H, d, J = 5.4Hz), 7.30 (2H, d, J = 6.2Hz),
7.47 (1H, d, J = 16.3Hz), 7.63 (2H, d, J = 8.3Hz), 8.17
(2H, d, J = 6.2 Hz) (13-7) (E) -4- (2- (3- (N-((O-
Tetrahydropyran-2-yl) hydroxylaminoca
Rubonylmethyl) -N- (4-methoxybenzenesulfo
Nyl) amino) thienyl) vinyl) pyridine 1-oxo
Sid (E) -4- (2- (3- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) thienyl) vinyl) pyridine 1-oxide (0.16 g), tri Examples 1-5 using fluoroacetic acid (0.8 ml) and dichloromethane (1.6 ml).
A powder ((0.14 g) was obtained in the same manner as described above. The obtained powder (0.14 g), water-soluble carbodiimide hydrochloride (92.0 mg), and hydroxybenzotriazole (4
7.6 mg), O-tetrahydropyranylhydroxylamine (57.2 mg), N-methylmorpholine (0.5 mg).
18 ml) and dichloromethane (1.4 ml),
In the same manner as in Example 3, the target compound (0.10 g) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 1.57-1.80 (6H, m), 3.56-3.58 (1H, m), 3.81 (3H, s),
3.88 (1H, m), 4.13-4.23 (2H, m), 4.89 (1H, m), 6.56 (1
H, m), 6.72 (1H, d, J = 16.2Hz), 6.92 (2H, d, J = 8.6H
z), 7.16 (1H, d, J = 5.3Hz), 7.34-7.40 (3H, m), 7.64 (2
H, d, J = 8.6Hz), 8.13 (2H, d, J = 7.0Hz), 9.67 (1H, br,
s) (13-8) (E) -4- (2- (3- (N- (hydro
Xylaminocarbonylmethyl) -N- (4-methoxy
Benzenesulfonyl) amino) thienyl) vinyl) pyri
Gin 1-oxide (E) -4- (2- (3- (N-((O-tetrahydropyran-2-yl) hydroxylaminocarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) thienyl) vinyl ) Pyridine 1-oxide (0.
To a solution of 10 g) in methanol (1 ml) was added p-toluenesulfonic acid monohydrate (34.4 mg), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, water and ethyl acetate were added to the reaction solution, and the resulting precipitate was collected by filtration. After washing with water and then with ethyl acetate, drying was performed to obtain the target compound (38 mg). ^{1 H-NMR (400MHz, DMSO} -d 6) 3.77 (3H, s), 4.12 (2H, s), 6.66 (1H, s, J = 5.4Hz), 6.
83 (1H, d, J = 16.4Hz), 7.07 (2H, d, J = 8.9Hz), 7.35 (1
H, d, J = 16.4Hz), 7.45 (2H, d, J = 7.0Hz), 7.49 (1H, s,
J = 5.4Hz), 7.64 (2H, d, J = 8.9Hz), 8.22 (2H, d, J = 7.0
Hz), 8.98 (1H, br, s).

(Example 14) (E) -4- (2- (3-
(N- (hydroxylaminocarbonylmethyl) -N-
(4-methoxybenzenesulfonyl) amino) thieni
) Vinyl) pyridine (Exemplified Compound No. 6-4) (14-1) (E) -4- (2- (3- (N-((O-
Tetrahydropyran-2-yl) hydroxylaminoca
Rubonylmethyl) -N- (4-methoxybenzenesulfo
Yl) amino) thienyl) vinyl) pyridine (E) -4- (2- (3- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) thienyl) vinyl) pyridine (0 .10
g), concentrated hydrochloric acid (2.5 ml), and dioxane (1 m
Using 1), a powder was obtained in the same manner as in Example 2-1.
The obtained powder, water-soluble carbodiimide hydrochloride (80.
5 mg), hydroxybenzotriazole (42.6 m
g), O-tetrahydropyranylhydroxylamine (50.0 mg), N-methylmorpholine (0.23 m
l) and dichloromethane (1.0 ml), and the target compound (90 mg) was obtained in the same manner as in Example 3. ¹ H-NMR (400 MHz, CDCl ₃ ) 1.53-1.77 (6H, m), 3.52-3.64 (1H, m), 3.73 (3H, s),
3.82-3.87 (1H, m), 4.09-4.21 (2H, m), 4.88 (1H, m),
6.65-6.74 (2H, m), 6.89 (2H, d, J = 8.7Hz), 7.15 (1H,
d, J = 5.4Hz), 7.22-7.33 (3H, m), 7.66 (2H, 8.7Hz), 8.
51 (2H, d, J = 4.9 Hz), 10.09 (1H, br, s) (14-2) (E) -4- (2- (3- (N- (hydro
Xylaminocarbonylmethyl) -N- (4-methoxy
Benzenesulfonyl) amino) thienyl) vinyl) pyri
Zin (E) -4- (2- (3- (N-((O-tetrahydropyran-2-yl) hydroxylaminocarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) thienyl) vinyl) pyridine ( 90 mg) of a mixed solution of methanol (0.9 ml) and dichloromethane (0.9 ml) was added to p-toluenesulfonic acid monohydrate (32.3).
mg) and stirred at room temperature for 8 hours. After completion of the reaction, water and ethyl acetate were added to the reaction solution, and the resulting precipitate was collected by filtration. After washing with water and then with ethyl acetate, drying was performed to obtain the target compound (26 mg). ^{1 H-NMR (400MHz, DMSO} -d 6) 3.71 (3H, s), 4.09 (2H, s), 6.65 (1H, d, J = 5.4Hz), 6.
81 (1H, d, J = 16.4Hz), 7.05 (2H, d, J = 8.8Hz), 7.39 (2
H, m), 7.46-7.49 (1H, m), 7.49 (1H, d, J = 5.4Hz), 7.6
2 (2H, d, J = 8.8Hz), 8.55-8.56 (2H, m), 8.95 (1H, br,
s), 10.59 (1H, br, s).

(Example 15) (E) -4- (2- (2-
(N- (aminocarbonylmethyl) -N- (4-methoxy
Sibenzenesulfonyl) amino) phenyl) vinyl) pi
Lysine (Exemplified Compound No. 1-2) (E) -4- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine hydrochloride (84.9 mg), water-soluble carbodiimide hydrochloride (57.5 mg), hydroxybenzotriazole (29.7 mg), 28% aqueous ammonia (3 ml), N-methylmorpholine (0.15
ml) and dichloromethane (3.8 ml), and the target compound (28.1 mg) was obtained in the same manner as in Example 3. ¹ H-NMR (400 MHz, CDCl ₃ ) 3.79 (3H, s), 4.16-4.18 (2H, m), 5.66 (1H, br, s), 6.
63 (1H, br, s), 6.81-6.96 (3H, m), 7.05 (1H, d, J = 7.7
Hz), 7.19 (2H, d, J = 4.9Hz), 7.27-7.40 (3H, m), 7.64 (2
H, d, J = 9.0Hz), 7.70 (1H, d, J = 7.7Hz), 8.56 (2H, d,
J = 4.9Hz).

(Example 16) (E) -4- (2- (2-
(N-((N ', O-dimethyl) hydroxylaminoca
Rubonylmethyl) -N- (4-methoxybenzenesulfo
Nyl) amino) phenyl) vinyl) pyridine (Exemplary Compound No. 1-20) (E) -4- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine hydrochloride (84.9 mg), water-soluble carbodiimide hydrochloride (57.5 mg), hydroxybenzotriazole (29.7 mg), N, O- Dimethylhydroxyamine hydrochloride (39.0 mg), N-
Using methylmorpholine (0.15 ml) and dichloromethane (3.8 ml), the target compound (12.7 mg) was obtained in the same manner as in Example 3. ¹ H-NMR (400 MHz, CDCl ₃ ) 3.14 (3H, s), 3.66 (3H, s), 3.71 (3H, s), 4.57-4.62 (2
H, m), 6.74-6.87 (3H, m), 7.24-7.27 (2H, m), 7.31-7.
35 (3H, m), 7.65 (2H, d, J = 8.9Hz), 7.70 (1H, d, J = 7.6H
z), 7.83 (1H, d, J = 16.4Hz), 8.57 (2H, d, J = 4.6Hz).

(Example 17) (E) -4- (2- (2-
(N- (methylaminocarbonylmethyl) -N- (4-
Methoxybenzenesulfonyl) amino) phenyl) vinyl
B) pyridine (Exemplified Compound No. 1-6) (E) -4- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine hydrochloride (0.21 g), water-soluble carbodiimide hydrochloride (0.10 g), hydroxybenzotriazole (74.3 mg), methylamine hydrochloride (67.5 mg), N-methylmorpholine (0.3
In the same manner as in Example 3 using 8 ml) and dichloromethane (2.1 ml), the target compound (58.6 mg) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 2.75 (3H, d, J = 4.9 Hz), 3.81 (3H, s), 4.09-4.13 (2H,
m), 6.65 (1H, br, s), 6.66-6.96 (4H, m), 7.22 (2H, d,
J = 6.1Hz), 7.26-7.44 (3H, m), 7.64 (2H, d, J = 8.9Hz),
7.68 (1H, d, J = 6.5Hz), 8.58 (2H, d, J = 6.1Hz). (Example 18) (E) -4- (2- (2- (N- (dimethyl
Tylaminocarbonylmethyl) -N- (4-methoxy
Nzensulfonyl) amino) phenyl) vinyl) pyridi
Down (Compound No. 1-8) (E) -4- (2- (2- (N- ( carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine hydrochloride (0.21 g), water-soluble carbodiimide hydrochloride (0.10 g), hydroxybenzotriazole (74.3 mg), dimethylamine hydrochloride (81.5 mg), N-methylmorpholine (0.
38 ml) and dichloromethane (2.1 ml)
In the same manner as in Example 3, the target compound (47.1 mg) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 2.84 (3H, s), 3.01 (3H, s), 3.76 (3H, s), 4.20-4.60 (2
H, m), 6.84-6.88 (3H, m), 7.17-7.26 (2H, m), 7.31-7.
35 (3H, m), 7.67 (2H, d, J = 8.9Hz), 7.69 (1H, d, J = 7.2H
z), 7.82 (1H, d, J = 16.3Hz), 8.58 (2H, d, J = 5.7Hz).

(Example 19) (E) -4- (2- (2-
(N-((O-benzyl) hydroxylaminocarboni
Methyl) -N- (4-methoxybenzenesulfonyl)
Amino-5-methyl) phenyl) vinyl) pyridine 1
-Oxide (Exemplified Compound No. 1-15) (E) -4- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide (0.15
g), water-soluble carbodiimide hydrochloride (71.9 m
g), hydroxybenzotriazole (37.2 m
g), O-benzylhydroxyamine hydrochloride (79.8
mg), N-methylmorpholine (0.19 ml) and dichloromethane (1.5 ml) in the same manner as in Example 3 to obtain the desired compound (88.8 mg). ¹ H-NMR (400 MHz, CDCl ₃ ) 3.80 (3H, s), 4.03-4.31 (2H, m), 4.82 (2H, s), 6.81 (1
H, d, J = 16.4Hz), 6.84-6.91 (3H, m), 7.21-7.39 (9H,
m), 7.48-7.62 (3H, m), 7.68 (1H, d, J = 7.9Hz), 8.00 (2
H, d, J = 7.0Hz), 9.89 (1H, br, s).

(Example 20) (E) -4- (2- (2-
(N- (benzylaminocarbonylmethyl) -N- (4
-Methoxybenzenesulfonyl) amino) phenyl) bi
Nil) pyridine 1-oxide (Exemplary Compound No. 1-1)
1) (E) -4- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide (0.10
g), water-soluble carbodiimide hydrochloride (48.9 m
g), hydroxybenzotriazole (25.3 m
g), benzylamine (37.1 μl), N-methylmorpholine (0.13 ml) and dichloromethane (1 m
l) and in the same manner as in Example 3, the target compound (5
4.1 mg). ¹ H-NMR (400 MHz, CDCl ₃ ) 1.90-1.99 (1 H, m), 3.85 (3 H, s), 4.03-4.15 (1 H, m),
4.36-4.38 (3H, m), 6.69 (1H, d, J = 16.3Hz), 6.80 (1H,
d, J = 8.0Hz), 6.86-6.88 (1H, m), 6.94 (2H, d, J = 9.0H
z), 7.07-7.12 (4H, m), 7.23-7.27 (3H, m), 7.38 (1H,
t, J = 7.8Hz), 7.52 (1H, d, J = 16.3Hz), 7.61 (2H, d, J =
9.0Hz), 7.65 (1H, t, J = 7.8Hz), 8.03 (2H, d, J = 7.1H
z).

(Example 21) (E) -4- (2- (2-
(N- (benzylaminocarbonylmethyl) -N- (4
-Methoxybenzenesulfonyl) amino) phenyl) bi
Nyl) pyridine (Exemplified Compound No. 1-12) (E) -4- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine hydrochloride (0.21 g), water-soluble carbodiimide hydrochloride (0.10 g), hydroxybenzotriazole (74.3 mg), benzylamine (0 .11 ml), N-methylmorpholine (0.38 m
1) and dichloromethane (2.1 ml), and the desired compound (86.5 mg) was obtained in the same manner as in Example 3. ¹ H-NMR (400MHz, CDCl ₃ ) 3.82 (3H, s), 4.08-4.13 (1H, m), 4.28-4.37 (3H, m),
6.73 (1H, d, J = 16.3Hz), 6.84-6.87 (2H, m), 6.93 (2H,
d, J = 8.9Hz), 7.06-7.07 (2H, m), 7.11 (2H, d, J = 6.0H
z), 7.22-7.26 (3H, m), 7.38 (1H, t, J = 7.7Hz), 7.48 (1
H, d, J = 16.3Hz), 7.62 (2H, d, J = 8.9Hz), 7.66 (1H, d,
J = 7.7Hz), 8.51 (2H, d, J = 6.0Hz).

(Example 22) (E) -4- (2- (2-
(N-((O-cyclopropylmethyl) hydroxyl
Minocarbonylmethyl) -N- (4-methoxybenzene
Sulfonyl) amino) phenyl) vinyl) pyridine 1
-Oxide (Exemplified Compound No. 1-31) (E) -4- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide (0.18
g), water-soluble carbodiimide hydrochloride (86.2 m
g), hydroxybenzotriazole (44.6 m
g), O-cyclopropylmethylhydroxylamine (74.2 mg), N-methylmorpholine (0.23 m
l) and dichloromethane (1.8 ml), in the same manner as in Example 3, to obtain the desired compound (75.9 mg). ¹ H-NMR (400 MHz, CDCl ₃ ) 0.30-0.34 (2H, m), 0.62-0.66 (2H, m), 1.10-1.16 (1H,
m), 3.67-3.84 (2H, m), 3.87 (3H, s), 4.03-4.05 (1H,
m), 4.34-4.35 (1H, m), 6.85-7.05 (4H, m), 7.25-7.53
(5H, m), 7.68 (2H, d, J = 9.0Hz), 7.74 (1H, d, J = 7.0H
z), 8.20 (2H, d, J = 7.1 Hz), 9.35 (1H, br, s).

(Example 23) (E) -4- (2- (2-
(N-((O-cyclopropylmethyl) hydroxyl
Minocarbonylmethyl) -N- (4-methoxybenzene
Sulfonyl) amino) phenyl) vinyl) pyridine (Exemplary Compound No. 1-32) (E) -4- (2- (2- (N- (carboxymethyl))
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine hydrochloride (0.21 g), water-soluble carbodiimide hydrochloride (0.10 g), hydroxybenzotriazole (74.3 mg), O-cyclopropyl Using methylhydroxylamine (0.12 g), N-methylmorpholine (0.38 ml) and dichloromethane (2.1 ml), the target compound (23.6 mg) was obtained in the same manner as in Example 3. ¹ H-NMR (400 MHz, CDCl ₃ ) 0.23 (2H, m), 0.54-0.57 (2H, m), 1.03-1.09 (1H, m),
3.65-3.66 (2H, m), 3.79 (3H, s), 4.10-4.21 (2H, m),
6.83-7.02 (4H, m), 7.22-7.41 (5H, m), 7.64 (2H, d, J =
8.9Hz), 7.70 (1H, d, J = 8.1Hz), 8.57 (2H, d, J = 6.1H
z), 9.25 (1H, br, s).

(Example 24) ( E) -4- (2- (2-
(N- (methylaminocarbonylmethyl) -N- (4-
Methoxybenzenesulfonyl) amino) phenyl) vinyl
B) pyridine 1-oxide (exemplified compound number 1-5) (E) -4- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide (0.10
g), water-soluble carbodiimide hydrochloride (48.9 m
g), hydroxybenzotriazole (25.3 m
g), methylamine hydrochloride (22.3 mg), N-methylmorpholine (0.13 ml) and dichloromethane (1
ml) of the desired compound (6)
9.0 mg). ¹ H-NMR (400 MHz, CDCl ₃ ) 2.76 (3H, d, J = 5.0 Hz), 3.84 (3H, s), 3.90-4.13 (1H,
m), 4.14-4.24 (1H, m), 6.54 (1H, m), 6.85 (1H, d, J = 1
6.4Hz), 6.92-6.95 (1H, m), 6.94 (2H, d, J = 9.1Hz), 7.
25-7.30 (3H, m), 7.38 (1H, t, J = 7.0Hz), 7.41 (1H, d,
J = 16.4Hz), 7.64 (2H, d, J = 9.1Hz), 7.67 (1H, d, J = 8.1
Hz), 8.15 (2H, d, J = 7.1Hz).

(Example 25) (E) -4- (2- (2-
(N- (dimethylaminocarbonylmethyl) -N- (4
-Methoxybenzenesulfonyl) amino) phenyl) bi
Nyl) pyridine 1-oxide (exemplified compound number 1-7) (E) -4- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide (0.10
g), water-soluble carbodiimide hydrochloride (48.9 m
g), hydroxybenzotriazole (25.3 m
g), dimethylamine hydrochloride (26.9 mg), N-methylmorpholine (0.13 ml) and dichloromethane (1 ml), in the same manner as in Example 3, to obtain the desired compound (76.2 mg). ¹ H-NMR (400 MHz, CDCl ₃ ) 2.87 (3H, s), 2.99 (3H, s), 3.79 (3H, s), 4.24-4.28 (1
H, m), 4.62-4.66 (1H, m), 6.83 (1H, d, J = 16.4Hz), 6.
86 (2H, d, J = 8.9Hz), 7.10 (1H, d, J = 8.0Hz), 7.22-7.2
6 (1H, m), 7.34 (1H, t, J = 7.5Hz), 7.39 (2H, d, J = 7.0H
z), 7.64 (2H, d, J = 8.9Hz), 7.69 (1H, d, J = 8.0Hz), 7.9
2 (1H, d, J = 16.4Hz), 8.16 (2H, d, J = 7.0Hz).

(Example 26) (E) -4- (2- (2-
(N- (aminosulfonylmethyl) -N- (4-methoxy
Sibenzenesulfonyl) amino) phenyl) vinyl) pi
Lysine (Exemplified Compound No. 1-36) (E) -4- (2- (2- (4-methoxybenzenesulfonylamino) phenyl) vinyl) pyridine (0.18
g) was dissolved in dimethylformamide (4 ml), potassium carbonate (0.28 g) and bromomethanesulfonamide (0.26 g) were added, and the mixture was stirred at 70 ° C. for 12 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (hexane: ethyl acetate =
1: 4). The obtained target compound was recrystallized from a mixed solution of ethyl acetate and hexane (1:10), and the obtained crystals were collected by filtration, dried, and dried to give the target compound (18.3 m 2).
g) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 3.74 (3H, s), 4.92-4.94 (4H, m), 6.83-6.87 (3H, m),
7.15-7.20 (4H, m), 7.31-7.35 (1H, m), 7.40-7.44 (1H,
m), 7.59 (2H, d, J = 9.0Hz), 7.68 (1H, d, J = 8.0Hz), 8.
56 (2H, d, J = 4.5Hz).

(Example 27) (E) -2- (2- (2-
(N- (hydroxylaminocarbonylmethyl) -N)
-(4-methoxybenzenesulfonyl) amino) phenyl
B) vinyl) pyridine 1-oxide (Exemplified Compound No. 1-67) (27-1) (E) -2- (2- (2-aminophenyl)
(Vinyl) pyridine Using 2-vinylpyridine (6.57 g), 2-bromoaniline (8.6 g), triethylamine (25 ml), palladium acetate (112.2 mg) and O-tolylphosphine (608.3 mg). The target compound (6.65 g) was obtained in the same manner as in Example 1-1. ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 3.95 (2 H, br s), 6.73 (1 H, d, J = 7.8 Hz), 6.81 (1 H, t,
J = 7.8Hz), 7.06 (1H, d, J = 16.6Hz), 7.09-7.14 (2H, m),
7.35 (1H, d, J = 7.8Hz), 7.48 (1H, d, J = 6.5Hz), 7.65 (1
H, t, J = 7.8Hz), 7.78 (1H, d, J = 16.6Hz), 8.60 (1H, d,
(27-2) (E) -2- (2- (2- (4-methoxy)
Benzenesulfonyl) amino) phenyl) vinyl) pyri
Gin (E) -2- (2- (2-aminophenyl) vinyl) pyridine (6.65 g), pyridine (4.5 ml) and 4
-Methoxybenzenesulfonyl chloride (8.4 g)
And the target compound (8.73 g) was obtained in the same manner as in Example 1-2. ¹ H-NMR (400 MHz, CDCl ₃ ) 3.74 (3H, s), 6.75 (2H, d, J = 8.2 Hz), 6.90 (1H, d, J =
7.8Hz), 7.19-7.36 (2H, m), 7.40 (1H, d, J = 16.2Hz),
7.61 (2H, d, J = 8.2Hz), 7.66 (1H, t, J = 7.8Hz), 7.74 (1H
H, d, J = 7.8Hz), 7.93 (1H, d, J = 7.1Hz), 8.11 (1H, d,
J = 16.2Hz), 8.29 (1H, t, J = 7.8Hz), 8.67 (1H, d, J = 6.
(27 Hz), 9.18 (1H, s). (27-3) (E) -2- (2- (2- (N- (t-
Toxylcarbonylmethyl) -N- (4-methoxybenze
(Sulfonyl) amino) phenyl) vinyl) pyridine (E) -2- (2- (2- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (3.0
0 g), bromoacetic acid t-butyl ester (2.39 g)
And Example 1-3 using potassium carbonate (3.39 g).
In a similar manner to the above, the target compound (3.13 g) was obtained. 1H-NMR (400MHz, CDCl ₃ ) 1.39 (9H, s), 3.74 (3H, s), 4.04-4.21 (1H, m), 4.32-
4.48 (1H, m), 6.82 (1H, d, J = 7.7Hz), 6.83 (2H, d, J =
8.7Hz), 7.07 (1H, d, J = 16.3Hz), 7.16 (1H, t, J = 7.7H
z), 7.24-7.33 (2H, m), 7.37 (1H, t, J = 7.7Hz), 7.45 (2H
H, d, J = 7.7Hz), 7.57 (1H, d, J = 16.3Hz), 7.65 (2H, d,
J = 8.7Hz), 7.66 (1H, d, J = 7.2Hz), 7.74 (1H, d, J = 7.7H
z), 8.57 (1H, d, J = 4.0 Hz). (27-4) (E) -2- (2- (2- (N- (carbo
Xymethyl) -N- (4-methoxybenzenesulfoni
Ru) amino) phenyl) vinyl) pyridine 1-oxy
De (E) -2- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (710 m
g) and m-chloroperbenzoic acid (595 mg)
By the same method as in Example 1-4, (E) -2- (2-
(2- (N- (t-butoxycarbonylmethyl) -N-
(4-Methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide was synthesized, and the target compound (403) was obtained in the same manner as in Example 1-5 using trifluoroacetic acid (3.0 ml). .2m
g) was obtained. (E) -2- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide ¹ H-NMR (400 MHz, CDCl ₃ ) 1.41 (9H, s), 3.87 (3H, s), 4.18-4.22 (1H, m), 4.24-4.
36 (1H, m), 6.92 (2H, d, J = 8.9Hz), 7.06 (1H, d, J = 8.0H
z), 7.11-7.34 (2H, m), 7.19 (1H, t, J = 8.0Hz), 7.39 (1
H, t, J = 8.0Hz), 7.66 (2H, d, J = 8.9Hz), 7.75 (1H, d,
J = 7.3Hz), 7.78-7.88 (2H, m), 7.95 (1H, d, J = 8.0Hz),
8.30 (1H, d, J = 6.3Hz). (E) -2- (2- (2- (N- (carboxymethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1- Oxide ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 3.87 (3 H, s), 3.88-3.97 (1 H, m), 4.66-4.78 (1 H, m),
6.74 (1H, d, J = 8.0Hz), 6.92 (2H, d, J = 8.9Hz), 7.12-
7.19 (3H, m), 7.27 (1H, t, J = 8.0Hz), 7.55 (1H, d, J = 1
7.0Hz), 7.56 (2H, d, J = 8.9Hz), 7.57 (1H, d, J = 7.3H
z), 7.74 (1H, d, J = 8.0Hz), 8.18 (1H, d, J = 17.0Hz),
8.26 (1H, d, J = 6.6 Hz). (27-5) (E) -2- (2- (2- (N- (hydro-
Xylaminocarbonylmethyl) -N- (4-methoxy
Benzenesulfonyl) amino) phenyl) vinyl) pyri
Gin 1-oxide (E) -2- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide (150 m
g), water-soluble carbodiimide hydrochloride (130.4 m
g), hydroxybenzotriazole (57.5 m
g), N-methylmorpholine (103.2 mg) and O
-Tetrahydropyranylhydroxylamine (79.7
mg), and for the deprotection of the tetrahydropyranyl group, p-toluenesulfonic acid monohydrate (67.9 m
Using g), a target compound (109.8 mg) was obtained in the same manner as in Example 1-6. ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 3.82 (3H, S), 3.85-4.08 (1H, br s), 4.30-4.51 (1H, br
s), 6.88 (2H, d, J = 8.8Hz), 6.96 (1H, d, J = 8.1Hz),
7.14-7.19 (2H, m), 7.26 (1H, t, J = 8.1Hz), 7.30 (1H,
t, J = 8.1Hz), 7.36 (1H, d, J = 16.8Hz), 7.64 (2H, d, J =
8.8Hz), 7.65 (1H, d, J = 8.1Hz), 7.82 (1H, d, J = 7.7H
z), 7.90 (1H, d, J = 16.8Hz), 8.23 (1H, d, J = 6.4Hz),
8.62 (1H, br s), 10.2 (1H, br s).

(Example 28) (E) -2- (2- (2- (2-
(N- (hydroxylaminocarbonylmethyl) -N-
(4-methoxybenzenesulfonyl) amino) phenyl
Ru) vinyl) pyridine (Exemplary Compound No. 1-68) (28-1) (E) -2- (2- (2- (N- (carbo)
Xymethyl) -N- (4-methoxybenzenesulfoni
L) amino) phenyl) vinyl) pyridine (E) -2- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (473 .8
mg) and trifluoroacetic acid (3.0 ml) in the same manner as in Example 1-5.
mg). ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 3.74 (3H, s), 4.26 (1H, br s), 4.38 (1H, br s), 6.84
(2H, d, J = 9.0Hz), 7.05 (1H, d, J = 16.3Hz), 7.17 (1H,
d, J = 7.8Hz), 7.25 (1H, t, J = 7.8Hz), 7.36 (1H, t, J =
7.8Hz), 7.48 (1H, d, J = 7.1Hz), 7.61-7.78 (6H, m), 8.
57 (1H, brs). (28-2) (E) -2- (2- (2- (N- (hydro
Xylaminocarbonylmethyl) -N- (4-methoxy
Benzenesulfonyl) amino) phenyl) vinyl) pyri
Gin (E) -2- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (431.6 mg), water-soluble carbodiimide hydrochloride (389.3 mg), hydroxybenzotriazole (164.9 mgmg), N-methylmorpholine (308 0.5 mg) and O-tetrahydropyranylhydroxylamine (237.8 mg).
Using toluenesulfonic acid monohydrate (107.7 mg), the target compound (1) was obtained in the same manner as in Example 2-2.
37.6 mg). ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 3.67 (1H, d, J = 14.2 Hz), 3.82 (3H, s), 4.62 (1H, d, J =
14.2Hz), 6.71 (1H, d, J = 6.9Hz), 6.97 (2H, d, J = 8.8H
z), 7.15 (1H, d, J = 16.1Hz), 7.18-7.29 (2H, m), 7.32
7.41 (2H, m), 7.68 (2H, d, J = 8.8Hz), 7.75 (1H, t, J =
7.5Hz), 7.80 (1H, d, J = 7.5Hz), 8.04 (1H, d, J = 16.1H
z), 8.53 (1H, d, J = 4.3Hz), 9.88 (1H, br s).

(Example 29) (E) -2- (2- (2-
(N- (aminocarbonylmethyl) -N- (4-methoxy
Sibenzenesulfonyl) amino) phenyl) vinyl) pi
Lysine 1-oxide (Exemplified Compound No. 1-65) (E) -2- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide (100 m
g), water-soluble carbodiimide hydrochloride (87.1 m
g), hydroxybenzotriazole (38.3 m
g), N-methylmorpholine (68.9 mg) and aqueous ammonia (28%, 0.1 ml) were obtained in the same manner as in Example 5 to obtain the desired compound (40.1 mg). ¹ H-NMR (400MHz, CDCl ₃ + DMSO-d ₆ ) 3.71 (1H, d, J = 12.3Hz), 3.84 (3H, s), 4.36 (1H, d, J =
12.3Hz), 6.46 (1H, s), 6.89 (1H, d, J = 7.3Hz), 6.92 (2H
H, d, J = 8.8Hz), 7.00 (1H, d, J = 18.8Hz), 7.17 (1H, d
d, J = 6.3, 7.3Hz), 7.25 (1H, br s), 7.37 (1H, dd, J =
6.3, 7.3Hz), 7.40 (1H, t, J = 8.0Hz), 7.53 (1H, d, J =
8.0Hz), 7.62 (2H, d, J = 8.8Hz), 7.63 (1H, t, J = 8.0H
z), 7.65 (1H, d, J = 18.8Hz), 7.86 (1H, d, J = 8.0Hz),
8.26 (1H, d, J = 6.3Hz).

(Example 30) (E) -2- (2- (2-
(N- (aminocarbonylmethyl) -N- (4-methoxy
Sibenzenesulfonyl) amino) phenyl) vinyl) pi
Lysine (Exemplified Compound No. 1-66) (E) -2- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (180.9 mg), water-soluble carbodiimide hydrochloride (163.4 mg), hydroxybenzotriazole (69.1 mg), N-methylmorpholine (150 .8 mg) and aqueous ammonia (28
%, 0.2 ml) to give the desired compound (177.0 mg) in the same manner as in Example 5. ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 3.78 (3H, s), 4.00-4.46 (2H, m), 5.51 (1H, s), 6.83 (1
H, s), 6.90 (2H, d, J = 9.0Hz), 6.98 (1H, d, J = 7.7Hz),
7.06 (1H, d, J = 16.1Hz), 7.17 (1H, dd, J = 5.1,7.3Hz),
7.26 (1H, t, J = 7.7Hz), 7.30 (1H, d, J = 7.7Hz), 7.37
(1H, t, J = 7.7Hz), 7.64 (2H, d, J = 9.0Hz), 7.65 (1H, d
d, J = 5.1, 7.7Hz), 7.72 (1H, d, J = 16.1Hz), 7.75 (1H,
d, J = 7.3Hz), 8.57 (1H, d, J = 5.1Hz).

(Example 31) ( Z) -2- (2- (2-
(N- (hydroxylaminocarbonylmethyl) -N-
(4-methoxybenzenesulfonyl) amino) phenyl
B) vinyl) pyridine 1-oxide (exemplified compound number 2-11) (31-1) (Z) -2- (2- (2-nitrophenyl)
B) vinyl) pyridine 2-nitrobenzyltriphenylphosphonium bromide (20.0 g) in tetrahydrofuran (300 ml)
And cooled to -60 ° C. Here, lithium hexamethyldisilazide (1.0 M in hexane, 48.4)
ml) was added dropwise and stirred at this temperature for 40 minutes. Next, a solution of pyridine-2-aldehyde (4.75 g) in tetrahydrofuran (20 ml) was added dropwise, and the mixture was stirred at room temperature for 6 hours. Water was added to the system to stop the reaction, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the desired compound (5.09 g). ^{1 H-NMR (400MHz, CDCl} 3) 6.84 (1H, d, J = 12.3Hz), 6.90 (1H, d, J = 8.0Hz), 7.05
(1H, t, J = 7.6Hz), 7.11 (1H, d, J = 12.3Hz), 7.25 (1H,
t, J = 8.0Hz), 7.35-7.56 (3H, m), 8.13 (1H, d, J = 8.0H
z), 8.48 (1H, d, J = 6.3 Hz). (31-2) (Z) -2- (2- (2-aminophenyl)
Iv) vinyl) pyridine (Z) -2- (2- (2-nitrophenyl) vinyl) pyridine (2.5 g) was added to ethanol (20 ml) and water (1
0 ml) in a mixed solvent, and ammonium chloride (29
5 mg) and iron (1.29 g) were added, and the mixture was heated under reflux for 2 hours and 30 minutes. After completion of the reaction, insolubles were filtered off by celite filtration, the solvent was distilled off under reduced pressure, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain the desired compound (1.72 g). ¹ H-NMR (400 MHz, CDCl ₃ ) 6.68 (1 H, d, J = 7.7 Hz), 6.70 (1 H, d, J = 8.2 Hz), 7.76 (1
H, d, J = 12.3Hz), 6.82 (1H, d, J = 12.3Hz), 7.04-7.20
(2H, m), 7.21 (1H, t, J = 7.8Hz), 7.25 (1H, d, J = 7.8H
z), 7.41 (1H, d, J = 7.8 Hz), 8.56 (1H, d, J = 6.5 Hz). (31-3) (Z) -2- (2- (2- (4-methoxy
Benzenesulfonyl) amino) phenyl) vinyl) pyri
Zin (Z) -2- (2- (2-aminophenyl) vinyl) pyridine (1.71 g), pyridine (3.2 ml) and 4-
Methoxybenzenesulfonyl chloride (2.70 g)
And the target compound (1.58 g) was obtained in the same manner as in Example 1-2. ^{1 H-NMR (400MHz, CDCl} 3) 3.81 (3H, s), 6.18 (1H, d, J = 12.5Hz), 6.65 (1H, d, J =
12.5Hz), 6.83 (2H, d, J = 9.0Hz), 6.88 (1H, d, J = 7.6H
z), 7.06-7.10 (2H, m), 7.11 (1H, dd, J = 4.8, 8.2Hz),
7.25 (1H, d, J = 7.6Hz), 7.44 (1H, t, J = 7.6Hz), 7.57 (1
H, d, J = 8.2Hz), 7.60 (2H, d, J = 9.0Hz), 8.26 (1H, s),
8.51 (1H, d, J = 4.8Hz). (31-4) (Z) -2- (2- (2- (N- (t-bu
Toxylcarbonylmethyl) -N- (4-methoxybenze
(Sulfonyl) amino) phenyl) vinyl) pyridine (Z) -2- (2- (2- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (1.5
8 g), bromoacetic acid t-butyl ester (1.09 g)
And Example 1-3 using potassium carbonate (2.98 g).
By the same method as in the above, the target compound (2.02 g) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 1.38 (9H, s), 3.86 (3H, s), 4.27 (2H, br s), 6.72 (1H,
d, J = 12.4Hz), 6.89 (1H, d, J = 12.4Hz), 6.94 (2H, d,
J = 8.9Hz), 7.08 (1H, t, J = 7.8Hz), 7.11 (1H, d, J = 7.2H
z), 7.13 (1H, d, J = 7.8Hz), 7.16-7.19 (3H, m), 7.40 (1
H, t, J = 7.8Hz), 7.70 (2H, d, J = 8.9Hz), 8.55 (1H, d, J
= 4.9Hz). (31-5) (Z) -2- (2- (2- (N- (t-
Toxylcarbonylmethyl) -N- (4-methoxybenze
Sulphonyl) amino) phenyl) vinyl) pyridine
1-oxide (Z) -2- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (500 m
g) and m-chloroperbenzoic acid (418.9 mg) in the same manner as in Example 1-4, using the target compound (38).
3.3 mg). ¹ H-NMR (400 MHz, CDCl ₃ ) 1.37 (9H, s), 3.88 (3H, s), 4.23 (2H, br s), 6.74 (1H,
d, J = 12.5Hz), 6.88 (1H, d, J = 12.5Hz), 6.98 (2H, d,
J = 8.9Hz), 7.10 (1H, t, J = 7.9Hz), 7.12 (1H, d, J = 7.9H
z), 7.12-7.23 (4H, m), 7.37 (1H, t, J = 7.9Hz), 7.70 (2
(H, d, J = 8.9 Hz), 8.27 (1H, d, J = 6.6 Hz). (31-6) (Z) -2- (2- (2- (N- (carbo
Xymethyl) -N- (4-methoxybenzenesulfoni
Ru) amino) phenyl) vinyl) pyridine 1-oxy
De (Z) -2- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide (380 mg) in dichloromethane (12 2.0 ml), trifluoroacetic acid (4.0 ml) was added, and the mixture was stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, toluene (5.0 ml) was added, and trifluoroacetic acid remaining in the system was azeotropically removed. This operation was repeated three times to obtain the crudely purified target compound (about 225 mg), which was used for the condensation reaction with the amine without further purification. (31-7) (Z) -2- (2- (2- (N- (hydro
Xylaminocarbonylmethyl) -N- (4-methoxy
Benzenesulfonyl) amino) phenyl) vinyl) pyri
Gin 1-oxide (Z) -2- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide (about 110 m
g), water-soluble carbodiimide hydrochloride (85.3 m
g), hydroxybenzotriazole (36.0 m
g), N-methylmorpholine (78.7 mg) and O-
Tetrahydropyranyl hydroxylamine (52.1m
g), and for the deprotection of the tetrahydropyranyl group, p-toluenesulfonic acid monohydrate (47.4 m
Using g) and in the same manner as in Example 1-6, the target compound (32.0 mg) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 3.31-3.82 (1H, br s), 3.89 (3H, s), 4.09-4.52 (1H, br
s), 6.60 (1H, d, J = 8.0Hz), 6.98 (2H, d, J = 8.8Hz),
7.02-7.11 (2H, m), 7.16 (1H, t, J = 6.3Hz), 7.17-7.28
(2H, m), 7.21 (1H, d, J = 12.5Hz), 7.29-7.36 (2H, m),
7.39 (1H, d, J = 12.5Hz), 7.58 (2H, d, J = 8.8Hz), 8.28
(1H, d, J = 6.3Hz), 9.24-9.88 (1H, m).

(Example 32) (Z) -2- (2- (2-
(N- (hydroxylaminocarbonylmethyl) -N-
(4-methoxybenzenesulfonyl) amino) phenyl
(3 ) Vinyl) pyridine (Exemplified Compound No. 2-12) (32-1) (Z) -2- (2- (2- (N- (carbo)
Xymethyl) -N- (4-methoxybenzenesulfoni
L) amino) phenyl) vinyl) pyridine (Z) -2- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (500 m
g) was dissolved in dichloromethane (12.0 ml), trifluoroacetic acid (8.0 ml) was added, and the mixture was stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, toluene (7.0 m
1) was added to remove trifluoroacetic acid remaining in the system azeotropically. This operation was repeated three times to obtain a crudely purified target compound (about 300 mg), which was used for the condensation reaction with the amine without further purification. (32-2) (Z) -2- (2- (2- (N- (hydro
Xylaminocarbonylmethyl) -N- (4-methoxy
Benzenesulfonyl) amino) phenyl) vinyl) pyri
Zin (Z) -2- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (about 200 mg), water-soluble carbodiimide hydrochloride (180.9 mg), hydroxybenzotriazole (76.5 mg), N-methylmorpholine (167. 0 mg) and O-tetrahydropyranylhydroxylamine (110.5 mg), and the deprotection of the tetrahydropyranyl group was performed using p-toluenesulfonic acid monohydrate (73.7 mg). The target compound (83.0) was obtained in the same manner as in Example 2-2.
mg). ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 3.90 (3H, s), 4.06-4.67 (2H, brs), 6.61 (1H, d, J = 7.
5Hz), 6.84 (1H, d, J = 7.5Hz), 6.98 (1H, d, J = 12.1Hz),
7.00 (2H, d, J = 8.8Hz), 7.03 (1H, t, J = 7.5Hz), 7.06 (1
H, t, J = 7.5Hz), 7.17 (1H, dd, J = 5.1, 7.9Hz), 7.32 (1
H, d, J = 12.1Hz), 7.35 (1H, d, J = 7.9Hz), 7.72 (1H, t,
J = 7.9Hz), 7.76 (2H, d, J = 8.8Hz), 8.33 (1H, d, J = 5.1
Hz), 9.81-11.02 (1H, m).

(Example 33) (Z) -2- (2- (2- (2-
(N- (aminocarbonylmethyl) -N- (4-methoxy
Sibenzenesulfonyl) amino) phenyl) vinyl) pi
Lysine 1-oxide (Exemplified Compound No. 2-9) (Z) -2- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide (about 170 m
g) Water-soluble carbodiimide hydrochloride (148.0 m
g), hydroxybenzotriazole (62.6 m
g), N-methylmorpholine (175.7 mg) and aqueous ammonia (28%, 0.2 ml) were obtained in the same manner as in Example 5 to obtain the target compound (42.8 mg). ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 3.84-4.55 (2H, m), 3.91 (3H, s), 5.60 (1H, br s), 6.8
6 (1H, d, J = 7.8Hz), 6.89 (1H, d, J = 7.8Hz), 7.00 (2H,
d, J = 8.8Hz), 7.04 (1H, d, J = 12.2Hz), 7.05 (1H, br s),
7.06-7.25 (5H, m), 7.20 (1H, d, J = 12.2Hz), 7.65 (2H,
d, J = 8.8Hz), 8.25 (1H, d, J = 6.5Hz).

(Example 34) (Z) -2- (2- (2-
(N- (aminocarbonylmethyl) -N- (4-methoxy
Sibenzenesulfonyl) amino) phenyl) vinyl) pi
Lysine (Exemplified Compound No. 2-10) (Z) -2- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (about 147 mg), water-soluble carbodiimide hydrochloride (133.1 mg), hydroxybenzotriazole (56.3 mg), N-methylmorpholine (157. 9 mg) and aqueous ammonia (28%,
0.3 ml) to give the target compound (107.7 mg) in the same manner as in Example 5. ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 3.90 (3H, s), 3.99-4.46 (2H, m), 5.43 (1H, s), 6.78 (1
H, d, J = 8.8Hz), 6.83 (1H, d, J = 12.4Hz), 6.93-7.03 (2
H, m), 6.99 (2H, d, J = 8.9Hz), 7.06 (1H, dd, J = 5.5,
8.8Hz), 7.10-7.22 (3H, m), 7.16 (1H, d, J = 12.4Hz),
7.41 (1H, t, J = 7.9Hz), 7.66 (2H, d, J = 8.9Hz), 8.49 (1
H, d, J = 5.5Hz).

(Example 35) (Z) -3- (2- (2-
(N- (hydroxylaminocarbonylmethyl) -N-
(4-methoxybenzenesulfonyl) amino) phenyl
B) vinyl) pyridine 1-oxide (exemplified compound number 2-7) (35-1) (Z) -3- (2- (2-nitrophenyl)
B) vinyl) pyridine 2-nitrobenzyltriphenylphosphonium bromide (20.0 g) in tetrahydrofuran (300 ml)
And cooled to -60 ° C. Here, lithium hexamethyldisilazide (1.0 M in hexane, 48.4)
ml) was added dropwise and stirred at this temperature for 40 minutes. Next, a solution of pyridine-3-aldehyde (4.75 g) in tetrahydrofuran (20 ml) was added dropwise, and the mixture was stirred at room temperature for 6 hours. Water was added to the system to stop the reaction, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the desired compound (6.52 g). ¹ H-NMR (400 MHz, CDCl ₃ ) 6.84 (1 H, d, J = 11.9 Hz), 7.16 (1 H, d, J = 11.9 Hz), 7.19
(1H, d, J = 7.9Hz), 7.33 (1H, t, J = 7.9Hz), 7.42 (1H,
d, J = 7.9Hz), 7.52-7.67 (2H, m), 8.24 (1H, dd, J = 4.3,
7.4Hz), 8.44 (1H, s), 8.49 (1H, d, J = 4.3Hz). (35-2) (Z) -3- (2- (2-aminophenyl
(V ) Vinyl) pyridine (Z) -3- (2- (2-nitrophenyl) vinyl) pyridine (2.80 g) was dissolved in acetic acid (53 ml), immersed in a water bath, and cooled. Zinc powder (20.2 g) was divided into small portions and stirred at room temperature for 2 hours. The insoluble matter was separated by filtration through Celite, and the solvent was distilled off under reduced pressure.
Acetic acid was removed azeotropically (three times) with toluene (15 ml), then ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain the desired compound (2.
37 g) were obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 3.72 (2H, br s), 6.62 (1H, d, J = 12.1 Hz), 6.67 (1H, d,
J = 12.1Hz), 6.69 (1H, d, J = 8.0Hz), 6.71 (1H, d, J = 7.
5Hz), 7.02 (1H, d, J = 7.5Hz), 7.09 (1H, t, J = 7.5Hz),
7.10 (1H, t, J = 7.5Hz), 7.49 (1H, dd, J = 4.9, 8.0Hz),
8.38 (1H, d, J = 4.9 Hz), 8.47 (1H, brs). (35-3) (Z) -3- (2- (2- (4-methoxy)
Benzenesulfonyl) amino) phenyl) vinyl) pyri
Gin (Z) -3- (2- (2-aminophenyl) vinyl) pyridine (2.37 g) and pyridine (3.1 ml) were dissolved in dichloromethane (50 ml) and cooled to 0 ° C. Next, 4-methoxybenzenesulfonyl chloride (3.74 g) was added, and the mixture was stirred at room temperature for 3 hours and 30 minutes. Then, a saturated aqueous ammonium chloride solution was added to stop the reaction. The organic layer extracted with ethyl acetate was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain the desired compound (4.39 g). ¹ H-NMR (400 MHz, CDCl ₃ ) 3.79 (3H, s), 6.35 (1H, d, J = 12.0 Hz), 6.53 (1H, br
s), 6.63 (1H, d, J = 12.0Hz), 6.81 (2H, d, J = 8.9Hz),
6.96-7.07 (3H, m), 7.10 (1H, d, J = 7.8Hz), 7.27 (1H,
t, J = 7.8Hz), 7.54 (1H, d, J = 7.8Hz), 7.64 (2H, d, J =
(35 Hz), 8.26 (1H, brs), 8.38 (1H, brs). (35-4) (Z) -3- (2- (2- (N- (t-
Toxylcarbonylmethyl) -N- (4-methoxybenze
(Sulfonyl) amino) phenyl) vinyl) pyridine (Z) -3- (2- (2- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (1.0
g), bromoacetic acid t-butyl ester (692.3 m
g) and potassium carbonate (1.12 g).
Target compound (357.6 mg) in the same manner as in -3
I got ¹ H-NMR (400 MHz, CDCl ₃ ) 1.38 (9H, s), 3.86 (3H, s), 4.25 (2H, br s), 6.61 (1H,
d, J = 12.3Hz), 6.92 (1H, d, J = 8.0Hz), 6.94 (2H, d, J
= 8.8Hz), 7.02-7.18 (5H, m), 7.49 (1H, d, J = 8.0Hz),
7.69 (2H, d, J = 8.8Hz), 8.39 (1H, d, J = 3.9Hz), 8.45 (1
H, br s). (35-5) (Z) -3- (2- (2- (N- (t-Bu)
Toxylcarbonylmethyl) -N- (4-methoxybenze
Sulphonyl) amino) phenyl) vinyl) pyridine
1-oxide (Z) -3- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (350 m
g) and m-chloroperbenzoic acid (256.8 mg) in the same manner as in Example 1-4, using the target compound (30).
7.7 mg). ¹ H-NMR (400 MHz, CDCl ₃ ) 1.37 (9H, s), 3.89 (3H, s), 4.20 (2H, br s), 6.52 (1H,
d, J = 12.3Hz), 6.89 (1H, d, J = 8.1Hz), 6.97 (2H, d, J
= 8.9Hz), 7.09-7.23 (5H, m), 7.27 (1H, t, J = 8.1Hz),
7.67 (2H, d, J = 8.9Hz), 8.05 (1H, d, J = 6.5Hz), 8.16 (1
H, br s). (35-6) (Z) -3- (2- (2- (N- (carbo)
Xymethyl) -N- (4-methoxybenzenesulfoni
Ru) amino) phenyl) vinyl) pyridine 1-oxy
De (Z) -3- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide (307 mg) was added to dichloromethane (6 2.0 ml), trifluoroacetic acid (2.0 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. After evaporating the solvent under reduced pressure, toluene (6 ml) was added to remove trifluoroacetic acid remaining in the system by azeotropic distillation. This operation was repeated three times to obtain a crudely purified target compound (about 280 mg), which was used for a condensation reaction with an amine without further purification. (35-7) (Z) -3- (2- (2- (N- (hydro-
Xylaminocarbonylmethyl) -N- (4-methoxy
Benzenesulfonyl) amino) phenyl) vinyl) pyri
Gin 1-oxide (Z) -3- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide (about 136 m
g), water-soluble carbodiimide hydrochloride (118.9 m
g), hydroxybenzotriazole (50.3 m
g), N-methylmorpholine (141.1 mg) and O
-Tetrahydropyranylhydroxylamine (63.6
mg), and for deprotection of the tetrahydropyranyl group, p-toluenesulfonic acid monohydrate (25.3 m
Using g) and in the same manner as in Example 1-6, the target compound (78.0 mg) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 3.73-4.11 (1H, m), 3.89 (3H, s), 4.11-4.48 (1H, m),
6.56 (1H, d, J = 12.1Hz), 6.78 (1H, d, J = 7.8Hz), 6.99 (2
H, d, J = 8.9Hz), 7.08 (1H, d, J = 8.1Hz), 7.14-7.22 (3
H, m), 7.24 (1H, d, J = 7.8Hz), 7.38 (1H, d, J = 12.1H
z), 7.66 (2H, d, J = 8.9Hz), 7.89 (1H, s), 7.98 (1H, d,
J = 6.3Hz), 9.23 (1H, br s), 10.37 (1H, br s).

(Example 36) (Z) -3- (2- (2-
(N- (hydroxylaminocarbonylmethyl) -N-
(4-methoxybenzenesulfonyl) amino) phenyl
(3 ) Vinyl) pyridine (Exemplified Compound No. 2-8) (36-1) (Z) -3- (2- (2- (N- (carbo)
Xymethyl) -N- (4-methoxybenzenesulfoni
L) amino) phenyl) vinyl) pyridine (Z) -3- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (287 .7
mg) was dissolved in dichloromethane (6.0 ml), trifluoroacetic acid (2.0 ml) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, and then toluene (6.0 ml) was added to remove trifluoroacetic acid remaining in the system azeotropically. This operation was repeated three times to obtain the crudely purified target compound (about 260 mg), which was used for the condensation reaction with the amine without further purification. (36-2) (Z) -3- (2- (2- (N- (hydro-
Xylaminocarbonylmethyl) -N- (4-methoxy
Benzenesulfonyl) amino) phenyl) vinyl) pyri
Gin (Z) -3- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (about 127 mg), water-soluble carbodiimide hydrochloride (115 mg), hydroxybenzotriazole (48.6 mg), N-methylmorpholine (136.6 mg) And O-tetrahydropyranylhydroxylamine (61.5 mg), and p-toluenesulfonic acid monohydrate (68.5 mg) was used for the deprotection of the tetrahydropyranyl group. −
In a similar manner to 2, the desired compound (63.8 mg) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 3.88 (3H, s), 4.07-4.28 (2H, m), 6.61 (1H, d, J = 12.2H
z), 6.91 (1H, d, J = 6.6Hz), 6.98 (2H, d, J = 8.8Hz), 7.
04-7.16 (5H, m), 7.54 (1H, d, J = 8.0Hz), 7.69 (2H, d,
J = 8.8Hz), 8.37 (1H, d, J = 4.5Hz), 8.44 (1H, br s), 8.
60-9.16 (1H, m), 10.42 (1H, br s).

(Example 37) (Z) -3- (2- (2-
(N- (aminocarbonylmethyl) -N- (4-methoxy
Sibenzenesulfonyl) amino) phenyl) vinyl) pi
Lysine 1-oxide (Exemplified Compound No. 2-5) (Z) -3- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide (about 136 m
g), water-soluble carbodiimide hydrochloride (118.9 m
g), hydroxybenzotriazole (50.3 m
g), N-methylmorpholine (141.4 mg) and aqueous ammonia (28%, 0.2 ml) were obtained in the same manner as in Example 5 to obtain the desired compound (69.6 mg). ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 3.77-4.46 (2H, m), 3.91 (3H, s), 6.55 (1H, d, J = 12.2H
z), 6.74 (1H, d, J = 7.3Hz), 7.00 (2H, d, J = 9.1Hz), 7.
03 (1H, d, J = 7.9Hz), 7.08 (1H, d, J = 7.9Hz), 7.13-7.2
6 (3H, m), 7.23 (1H, d, J = 12.2Hz), 7.64 (2H, d, J = 9.1
Hz), 8.03 (1H, d, J = 6.3Hz), 8.10 (1H, br s).

(Example 38) (Z) -3- (2- (2-
(N- (aminocarbonylmethyl) -N- (4-methoxy
Sibenzenesulfonyl) amino) phenyl) vinyl) pi
Lysine (Exemplified Compound No. 2-6) (Z) -3- (2- (2- (N- (carboxymethyl)
-N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (about 127 mg), water-soluble carbodiimide hydrochloride (115.1 mg), hydroxybenzotriazole (48.6 mg), N-methylmorpholine (136. 6 mg) and aqueous ammonia (28%,
0.2 ml), and the target compound (110.1 mg) was obtained in the same manner as in Example 5. ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 3.90 (3H, m), 3.99-4.52 (2H, m), 5.52 (1H, s), 6.69 (1
H, d, J = 12.3Hz), 6.76 (1H, d, J = 7.5Hz), 6.90 (1H,
s), 6.99 (2H, d, J = 9.1Hz), 7.07 (1H, dd, J = 4.9,8.0H
z), 7.13 (1H, d, J = 12.3Hz), 7.13-7.22 (3H, m), 7.37
(1H, d, J = 7.5Hz), 7.64 (2H, d, J = 9.1Hz), 8.37-8.44 (2
H, m).

Example 39 4- (2- (N- (hydro-
Xylaminocarbonylmethyl) -N- (4-methoxy
Benzenesulfonyl) amino) phenylcarbonylamido
No.) Pyridine 1-oxide (Exemplified Compound No. 4-3) (39-1) 4-Nitrobenzyl 2-aminobenzoate
Ester 2-Aminobenzoic acid (2.74 g), 4-nitrobenzyl alcohol (5.36 g), dimethylaminopyridine (4.88 g) and hydroxybenzotriazole (2.97 g) in dichloromethane (60 ml) were dissolved in 0 ml.
° C, and water-soluble carbodiimide (6.71
g) was added and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water was added to the system, extracted with diethyl ether and tetrahydrofuran, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, ethyl acetate was added to the obtained crude product,
The mixture was washed with ultrasonic waves, and the precipitated solid was separated by filtration and dried under reduced pressure to obtain the target compound (1.96 g). ^{1 H-NMR (400MHz, CDCl} 3) 5.42 (2H, s), 5.74 (2H, br s), 6.68 (1H, d, J = 7.6Hz),
6.69 (1H, t, J = 7.6Hz), 7.31 (1H, t, J = 7.6Hz), 7.60 (2
H, d, J = 8.2Hz), 7.93 (1H, d, J = 7.6Hz), 8.26 (2H, d,
J = 8.2Hz). (39-2) 2- (N- (4-methoxybenzenesulfo )
Nyl) amino) benzoic acid-4-nitrobenzyl ester 2-aminobenzoic acid-4-nitrobenzyl ester (5
44.5 mg) and pyridine (0.44 ml) were dissolved in dichloromethane (7.0 ml) and cooled to 0 ° C. Here, 4-methoxybenzenesulfonyl chloride (6
20 mg), and the mixture was stirred at room temperature for 1 hour. Then, a saturated aqueous ammonium chloride solution was added to stop the reaction. The organic layer extracted with ethyl acetate was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The crude product obtained was subjected to silica gel column chromatography (hexane: ethyl acetate =
Purification with 4: 1, then hexane: ethyl acetate: tetrahydrofuran = 3: 2: 2 yields the desired compound (8
84 mg). ¹ H-NMR (400 MHz, CDCl ₃ ) 3.80 (3H, s), 5.41 (2H, s), 6.98 (2H, d, J = 8.3 Hz), 7.
06 (1H, t, 7.7Hz), 7.50 (1H, t, J = 7.7Hz), 7.57 (2H,
d, J = 8.3Hz), 7.71 (1H, d, J = 7.7Hz), 7.79 (2H, d, J =
8.5Hz), 7.98 (1H, d, J = 7.7Hz), 8.27 (2H, d, J = 8.5H
z). (39-3) 2- (N- (t-butoxycarbonylmethyl )
) -N- (4-methoxybenzenesulfonyl) ami
D) Benzoic acid-4-nitrobenzyl ester 2- (N- (4-methoxybenzenesulfonyl) amino) benzoic acid-4-nitrobenzyl ester (880 m
g), bromoacetic acid t-butyl ester (780.2 m
g) and potassium carbonate (829.3 mg) in the same manner as in Example 1-3, using the desired compound (898.4 m).
g) was obtained. ^{1 H-NMR (400MHz, CDCl} 3) 1.44 (9H, s), 3.86 (3H, s), 4.11 (1H, d, J = 16.8Hz),
4.64 (1H, d, J = 16.8Hz), 5.42 (2H, s), 6.82 (1H, d, J =
7.7Hz), 6.88 (2H, d, J = 8.5Hz), 7.14 (1H, t, J = 7.7H
z), 7.55 (2H, d, J = 8.5Hz), 7.71 (1H, d, J = 7.7Hz), 7.
81 (2H, d, J = 8.5Hz), 7.87 (1H, d, J = 7.7Hz), 8.28 (2H,
d, J = 8.5 Hz). (39-4) 2- (N- (t-butoxycarbonylmethyl )
) -N- (4-methoxybenzenesulfonyl) ami
G) Benzoic acid 2- (N- (t-butoxycarbonylmethyl) -N-
(4-methoxybenzenesulfonyl) amino) benzoic acid-4-nitrobenzyl ester (690.5 mg)
It was dissolved in a mixed solution of methanol (15.0 ml) and tetrahydrofuran (1.5 ml), palladium carbon (10%, about 50 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. After completion of the reaction, insolubles were filtered off through celite, the solvent was distilled off under reduced pressure, diethyl ether and an aqueous sodium hydrogen carbonate solution were added, and the aqueous layer was acidified by adding concentrated hydrochloric acid (pH = 1.5). . After the aqueous layer was extracted with ethyl acetate and dried over sodium sulfate, the solvent was distilled off under reduced pressure to obtain the desired compound (524 mg). ¹ H-NMR (400 MHz, CDCl ₃ ) 1.42 (9 H, s), 3.87 (3 H, s), 4.16 (1 H, br s), 4.67 (1 H,
br s), 6.72 (1H, d, J = 8.0Hz), 6.93 (2H, d, J = 8.8H
z), 7.36-7.51 (2H, m), 7.50 (2H, d, J = 8.8Hz), 8.02 (1
H, d, J = 8.0 Hz). (39-5) 4- (2- (N- (t-butoxycarboni )
Methyl) -N- (4-methoxybenzenesulfonyl)
Amino) phenylcarbonylamino) pyridine 2- (N- (t-butoxycarbonylmethyl) -N-
A solution of (4-methoxybenzenesulfonyl) amino) benzoic acid (500 mg) in tetrahydrofuran (3.0 ml) was cooled to -10 ° C, and triethylamine (0.33
ml), diethoxyphosphonium cyanide (386.9)
mg) and stirred for 20 minutes. Then, 4-aminopyridine (334.8 mg) was added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction system, and extracted with ethyl acetate.
After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 15: 1) to obtain the desired compound (565.9 mg). ^{1 H-NMR (400MHz, CDCl} 3) 1.44 (9H, s), 3.84 (3H, s), 4.05 (1H, d, J = 16.7Hz),
4.59 (1H, d, J = 16.7Hz), 6.65 (1H, d, J = 7.9Hz), 6.93 (2
H, d, J = 9.1Hz), 7.17 (1H, t, J = 7.9Hz), 7.24 (2H, d,
J = 9.1Hz), 7.25 (1H, t, J = 7.9Hz), 7.78 (2H, d, J = 6.1H
z), 8.04 (1H, d, J = 7.9 Hz), 8.46 (2H, d, J = 6.1 Hz). (39-6) 4- (2- (N- (t-butoxycarboni )
Methyl) -N- (4-methoxybenzenesulfonyl)
Amino) phenylcarbonylamino) pyridine 1-oxo
Side 4- (2- (N- (t-butoxycarbonylmethyl)-
Using N- (4-methoxybenzenesulfonyl) amino) phenylcarbonylamino) pyridine (373.4 mg) and m-chloroperbenzoic acid (145.6 mg)
The target compound (383 m) was prepared in the same manner as in Example 1-4.
g) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 1.45 (9 H, s), 3.87 (3 H, s), 4.03 (1 H, d, J = 17.3 Hz),
4.64 (1H, d, J = 17.3Hz), 6.59 (1H, d, J = 7.9Hz), 6.92 (2
H, d, J = 8.7Hz), 7.38 (1H, t, J = 7.9Hz), 7.41 (2H, d,
J = 8.7Hz), 7.44 (1H, t, J = 7.9Hz), 7.87 (2H, d, J = 7.1H
z), 8.04 (1H, d, J = 7.9 Hz), 8.21 (2H, d, J = 7.1 Hz). (39-7) 4- (2- (N- (carboxymethyl)-
N- (4-methoxybenzenesulfonyl) amino) fe
Nylcarbonylamino) pyridine 1-oxide 4- (2- (N- (t-butoxycarbonylmethyl)-
N- (4-methoxybenzenesulfonyl) amino) phenylcarbonylamino) pyridine 1-oxide (38
0 mg) and trifluoroacetic acid (2.0 ml).
The target compound (318 m) was obtained in the same manner as in Example 1-5.
g) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 3.90 (3H, s), 4.12 (1H, d, J = 16.6 Hz), 4.73 (1H, d, J =
16.6Hz), 6.63 (1H, d, J = 7.8Hz), 6.93 (2H, d, J = 8.3H
z), 7.35-7.54 (4H, m), 8.06 (1H, d, J = 7.8Hz), 8.13 (2
H, d, J = 7.0 Hz), 8.52 (2H, d, J = 7.0 Hz). (39-8) 4- (2- (N- (hydroxylaminoca )
Rubonylmethyl) -N- (4-methoxybenzenesulfo
Nyl) amino) phenylcarbonylamino) pyridine
1-oxide 4- (2- (N- (carboxymethyl) -N- (4-methoxybenzenesulfonyl) amino) phenylcarbonylamino) pyridine 1-oxide (230.6 m
g), water-soluble carbodiimide hydrochloride (191.8 m
g), hydroxybenzotriazole (74.3 m
g), N-methylmorpholine (151.7 mg) and O
-Tetrahydropyranylhydroxylamine (118.
1 mg), and p-toluenesulfonic acid monohydrate (19.0) was used for deprotection of the tetrahydropyranyl group.
mg) to give the target compound (25 mg) in the same manner as in Example 1-6. ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 3.88 (3H, s), 4.05 (1H, d, J = 17.4 Hz), 4.68 (1H, d, J =
17.4Hz), 5.98 (1H, s), 6.61 (1H, d, J = 7.8Hz), 6.95 (2
H, d, J = 8.3Hz), 7.28 (1H, t, J = 7.8Hz), 7.36 (2H, d,
J = 8.3Hz), 7.43 (1H, t, J = 7.8Hz), 7.83 (2H, d, J = 7.2H
z), 8.11 (1H, d, J = 7.8Hz), 8.24 (2H, d, J = 7.2Hz), 10.
88 (1H, br s), 11.47 (1H, br s).

Example 40 4- (2- (N- (hydro)
Xylaminocarbonylmethyl) -N- (4-methoxy
Benzenesulfonyl) amino) phenylcarbonylamido
D) Pyridine (Exemplified Compound No. 4-4) (40-1) 4- (2- (N- (carboxymethyl)-
N- (4-methoxybenzenesulfonyl) amino) fe
Nylcarbonylamino) pyridine 4- (2- (N- (t-butoxycarbonylmethyl)-
Example 1 was prepared using N- (4-methoxybenzenesulfonyl) amino) phenylcarbonylamino) pyridine (565.9 mg) and trifluoroacetic acid (4.0 ml).
In a similar manner to 5, the desired compound (500 mg) was obtained. ^{1 H-NMR (400MHz, DMSO} -d 6) 3.64 (3H, s), 4.43 (1H, d, J = 17.2Hz), 5.22 (1H, d, J =
17.2Hz), 6.87-6.90 (3H, m), 7.13 (1H, t, J = 7.9Hz), 7.
38 (2H, d, J = 8.8Hz), 7.46 (2H, d, J = 8.8Hz), 7.75 (1H,
d, J = 7.9Hz), 7.99 (2H, d, J = 6.2Hz), 8.68 (2H, d, J =
6.2Hz). (40-2) 4- (2- (N- (hydroxylaminoca )
Rubonylmethyl) -N- (4-methoxybenzenesulfo
Nyl) amino) phenylcarbonylamino) pyridine 4- (2- (N- (carboxymethyl) -N- (4-methoxybenzenesulfonyl) amino) phenylcarbonylamino) pyridine (87.7 mg), water-soluble carbodiimide hydrochloride (76.7 mg), hydroxybenzotriazole (29.6 mg), N-methylmorpholine (60.7 mg) and O-tetrahydropyranylhydroxylamine (46.9 mg), and for deprotection of the tetrahydropyranyl group. Using p-toluenesulfonic acid monohydrate (21.6 mg), a target compound (12 mg) was obtained in the same manner as in Example 2-2. ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 3.84 (3H, s), 4.07 (1H, d, J = 16.8 Hz), 4.59 (1H, d, J =
16.8Hz), 5.84 (1H, s), 6.62 (1H, d, J = 7.8Hz), 6.90 (2H
H, d, J = 7.8Hz), 7.14 (1H, t, J = 7.8Hz), 7.30 (1H, t,
J = 7.8Hz), 7.36 (2H, d, J = 8.9Hz), 7.81 (2H, d, J = 6.1H
z), 8.08 (1H, d, J = 7.8Hz), 8.51 (2H, d, J = 6.1Hz), 9.5
6 (1H, br s), 10.74 (1H, br s).

Example 41 4- (2- (N- (amino)
Carbonylmethyl) -N- (4-methoxybenzenesul
Honyl) amino) phenylcarbonylamino) pyridine
(Exemplified Compound No. 4-2) 4- (2- (N- (carboxymethyl) -N- (4-methoxybenzenesulfonyl) amino) phenylcarbonylamino) pyridine (251.8 mg), water-soluble carbodiimide hydrochloride ( 214 mg), hydroxybenzotriazole (113.1 mg), N-methylmorpholine (225.7 mg) and aqueous ammonia (28%, 0.5
ml) and the target compound was obtained in the same manner as in Example 5. ^{1 H-NMR (400MHz, CDCl} 3 + DMSO-d 6) 3.87 (3H, s), 4.08 (1H, d, J = 15.8Hz), 4.65 (1H, d, J =
15.8Hz), 6.67 (1H, s), 6.72 (1H, d, J = 7.8Hz), 6.91 (2
H, d, J = 8.8Hz), 7.38 (1H, dd, J = 7.5, 7.8Hz), 7.44 (2
H, d, J = 8.8Hz), 7.45 (1H, dd, J = 7.5, 7.8Hz), 7.81 (2
H, d, J = 6.1Hz), 7.90 (1H, d, J = 7.5Hz), 7.98 (1H, br
s), 8.48 (2H, d, J = 6.1 Hz), 11.68 (1H, brs).

Example 42 4- (2- (N- (hydro-
Xylaminocarbonylmethyl) -N- (4-methoxy
Benzenesulfonyl) amino) phenylaminocarboni
B) pyridine 1-oxide (Exemplified Compound No. 5-3) (42-1) 4- (2- (N- (4-methoxybenzene)
Sulfonyl) amino) phenylaminocarbonyl) pyri
Gin O-phenylenediamine (3.24 g) was dissolved in dichloromethane (30 ml), cooled to 0 ° C., and pyridine (2.4 ml) and 4-methoxybenzenesulfonyl chloride (6.2 g) were sequentially added. Stir at room temperature for 3 hours. The reaction was stopped by adding a saturated aqueous solution of ammonium chloride to the reaction system, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. A part (2.58 g) of the crude product obtained by evaporating the solvent under reduced pressure was dissolved in dichloromethane (50 ml), cooled to 0 ° C, and N-methylmorpholine (3. 0 ml), isonicotinic acid (1.0 g), hydroxybenzotriazole (5
After adding 50 mg) and water-soluble carbodiimide (1.37 g), the mixture was stirred at room temperature for 4 hours. After completion of the reaction, water was added to the reaction system, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to 0: 1) to obtain the desired compound (584.6 mg). ¹ H-NMR (400 MHz, CDCl ₃ ) 3.87 (3 H, s), 6.39 (1 H, s), 6.55 (1 H, d, J = 7.6 Hz), 6.
92 (2H, d, J = 8.5Hz), 6.98 (1H, t, J = 7.6Hz), 7.35 (1H,
t, J = 7.6Hz), 7.60 (2H, d, J = 8.5Hz), 7.86 (2H, d, J =
6.6Hz), 8.30 (1H, d, J = 7.6Hz), 8.83 (2H, d, J = 6.6H
z), 9.48 (1H, brs). (42-2) 4- (2- (N- (t-butoxycarboni )
Methyl) -N- (4-methoxybenzenesulfonyl)
Amino) phenylaminocarbonyl) pyridine 4- (2- (N- (4-methoxybenzenesulfonyl)
Amino) phenylaminocarbonyl) pyridine (580
mg), bromoacetic acid t-butyl ester (446 mg)
Example 1-3 using potassium carbonate and potassium carbonate (632 mg).
The target compound (752 mg) was obtained in the same manner as in the above. ¹ H-NMR (400MHz, CDCl ₃ ) 1.43 (9H, s), 3.74 (1H, d, J = 17.9Hz), 3.82 (3H, s),
4.75 (1H, d, J = 17.9Hz), 6.74 (1H, d, J = 7.9Hz), 6.81 (2
H, d, J = 7.8Hz), 7.04 (1H, t, J = 7.9Hz), 7.40 (1H, t,
J = 7.9Hz), 7.54 (2H, d, J = 7.8Hz), 7.85 (2H, d, J = 6.9H
z), 8.48 (1H, d, J = 7.9 Hz), 8.81 (2H, d, J = 6.9 Hz). (42-3) 4- (2- (N- (t-butoxycarboni )
Methyl) -N- (4-methoxybenzenesulfonyl)
Amino) phenylaminocarbonyl) pyridine 1-oxo
Side 4- (2- (N- (t-butoxycarbonylmethyl)-
N- (4-methoxybenzenesulfonyl) amino) phenylaminocarbonyl) pyridine (401 mg) and m
Example 1 using chloroperbenzoic acid (308 mg)
The target compound (316 mg) was obtained in the same manner as in Example 4. ^{1 H-NMR (400MHz, CDCl} 3) 1.45 (9H, s), 3.70 (1H, d, J = 17.9Hz), 3.85 (3H, s),
4.73 (1H, d, J = 17.9Hz), 6.67 (1H, d, J = 8.0Hz), 6.87 (2
H, d, J = 9.0Hz), 7.02 (1H, t, J = 8.0Hz), 7.40 (1H, t,
J = 8.0Hz), 7.55 (2H, d, J = 9.0Hz), 8.04 (2H, d, J = 7.3H
z), 8.29 (2H, d, J = 7.3 Hz), 8.46 (1H, d, J = 8.0 Hz). (42-4) 4- (2- (N- (carboxymethyl)-
N- (4-methoxybenzenesulfonyl) amino) fe
Nylaminocarbonyl) pyridine 1-oxide 4- (2- (N- (t-butoxycarbonylmethyl)-
N- (4-methoxybenzenesulfonyl) amino) phenylaminocarbonyl) pyridine 1-oxide (21
7 mg) and trifluoroacetic acid (6.0 ml),
By the same method as in Example 1-5, the target compound (100.
2 mg). ^{1 H-NMR (400MHz, DMSO} -d 6) 3.31 (3H, s), 3.92-4.29 (1H, m), 4.58-4.93 (1H, m),
6.80 (1H, d, J = 8.0Hz), 7.05 (2H, d, J = 8.8Hz), 7.10 (1
H, t, J = 8.0Hz), 7.42 (1H, t, J = 8.0Hz), 6.59 (2H, d,
J = 8.8Hz), 7.93 (2H, d, J = 7.2Hz), 8.23 (1H, d, J = 8.0H
z), 8.42 (2H, d, J = 7.2 Hz). (42-5) 4- (2- (N- (hydroxylaminoca )
Rubonylmethyl) -N- (4-methoxybenzenesulfo
Nyl) amino) phenylaminocarbonyl) pyridine
1-oxide 4- (2- (N- (carboxymethyl) -N- (4-methoxybenzenesulfonyl) amino) phenylaminocarbonyl) pyridine 1-oxide (137.2 mg),
Water-soluble carbodiimide hydrochloride (115 mg), hydroxybenzotriazole (60.8 mg), N-methylmorpholine (121.4 mg) and O-tetrahydropyranylhydroxylamine (70.3 mg) were used. For the deprotection of p-toluenesulfonic acid monohydrate (61.6 mg), the target compound (71.1 m
g) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 3.79 (1 H, br d, J = 16.6 Hz), 3.81 (3 H, s), 4.66 (1 H, br
d, J = 16.6Hz), 6.83 (1H, d, J = 8.1Hz), 7.04 (2H, d, J
= 8.9Hz), 7.13 (1H, d, J = 8.1Hz), 7.42 (1H, t, J = 8.1H)
z), 7.56 (2H, d, J = 8.9Hz), 8.01 (2H, d, J = 7.2Hz), 8.
18 (1H, d, J = 8.1Hz), 8.40 (2H, d, J = 7.2Hz), 9.27 (1H,
br s), 10.94 (1H, br s), 10.98 (1H, br s).

Example 43 4- (2- (N- (amino)
Carbonylmethyl) -N- (4-methoxybenzenesul
Honyl) amino) phenylaminocarbonyl) pyridine
1-oxide (exemplified compound number 5-1) 4- (2- (N- (carboxymethyl) -N- (4-methoxybenzenesulfonyl) amino) phenylaminocarbonyl) pyridine 1-oxide (80 mg), water-soluble carbodiimide -Hydrochloride (67.1 mg), hydroxybenzotriazole (35.4 mg), N-methylmorpholine (0.07 ml) and aqueous ammonia (28%,
0.1 ml) to give the desired compound (46.2 mg) in the same manner as in Example 5. ^{1 H-NMR (400MHz, CDCl} 3 + DMSO-d 6) 3.81 (3H, s), 3.87 (1H, br d, J = 17.5Hz), 4.72 (1H, br
d, J = 17.5Hz), 6.84 (1H, d, J = 7.5Hz), 7.04 (2H, d, J
= 9.0Hz), 7.12 (1H, t, J = 7.5Hz), 7.42 (1H, t, J = 7.5H
z), 7.55 (2H, d, J = 9.0Hz), 7.67 (1H, br s), 7.87 (1H,
br s), 8.00 (2H, d, J = 7.1Hz), 8.19 (1H, d, J = 7.5Hz),
8.39 (2H, d, J = 7.1Hz), 11.24 (1H, br s).

Example 44 4- (2- (N- (Hydrogen)
Roxylaminocarbonylmethyl) -N- (4-methoxy
Sibenzenesulfonyl) amino) phenylaminocarbo
Nyl) pyridine (Exemplified Compound No. 5-4) (44-1) 4- (2- (N- (carboxymethyl)-
N- (4-methoxybenzenesulfonyl) amino) fe
Nylaminocarbonyl) pyridine 4- (2- (N- (t-butoxycarbonylmethyl)-
Using N- (4-methoxybenzenesulfonyl) amino) phenylaminocarbonyl) pyridine (400 mg) and trifluoroacetic acid (6.0 ml), the target compound (335 mg) was obtained in the same manner as in Example 1-5. . ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 3.78 (1 H, m), 3.86 (3 H, s), 3.97 (1 H, m), 6.71 (1 H, d,
J = 7.9Hz), 6.90 (2H, d, J = 8.2Hz), 7.07 (1H, t, J = 7.9H
z), 7.42 (1H, t, J = 7.9Hz), 7.58 (2H, d, J = 8.2Hz), 8.
32 (2H, d, J = 6.8Hz), 8.38 (1H, d, J = 7.9Hz), 8.59 (2H,
d, J = 6.8 Hz). (44-2) 4- (2- (N- (hydroxylaminoca )
Rubonylmethyl) -N- (4-methoxybenzenesulfo
Nyl) amino) phenylaminocarbonyl) pyridine 4- (2- (N- (carboxymethyl) -N- (4-methoxybenzenesulfonyl) amino) phenylaminocarbonyl) pyridine (110.3 mg), water-soluble carbodiimide hydrochloride (95.9 mg), hydroxybenzotriazole (43.9 mg), N-methylmorpholine (101.2 mg) and O-tetrahydropyranylhydroxylamine (58.6 mg), and used for deprotection of the tetrahydropyranyl group. Was prepared using p-toluenesulfonic acid monohydrate (44.2 mg) in Example 2-2.
By the same method as in the above, the target compound (56.0 mg) was obtained. ¹ H-NMR (400MHz, CDCl ₃ + DMSO-d ₆ ) 3.78 (1H, br d, J = 16.5Hz), 3.81 (3H, s), 4.64 (1H, br
d, J = 16.5Hz), 6.79 (1H, d, J = 8.0Hz), 7.04 (2H, d, J
= 8.8Hz), 7.13 (1H, t, J = 8.0Hz), 7.44 (1H, t, J = 8.0H
z), 7.57 (2H, d, J = 8.8Hz), 7.99 (2H, d, J = 5.9Hz), 8.
24 (1H, d, J = 8.0Hz), 8.84 (2H, d, J = 5.9Hz), 9.25 (1H,
br s), 10.92 (1H, br s), 11.02 (1H, br s).

Example 45 4- (2- (N- (amido)
Noncarbonylmethyl) -N- (4-methoxybenzenes)
Ruphonyl) amino) phenylaminocarbonyl) pyridi
Down (Compound No. 5-2) 4-(2-(N-(carboxymethyl) -N- (4- methoxybenzenesulfonyl) amino) phenyl aminocarbonyl) pyridine (110.3Mg), water soluble carbodiimide hydrochloride (95.9 mg), hydroxybenzotriazole (43.9 mg), N-methylmorpholine (101.2 mg) and aqueous ammonia (28%, 0.1
1 ml) to give the target compound (85.6 mg) in the same manner as in Example 5. ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 3.78 (1H, br d, J = 17.3 Hz), 3.79 (3H, s), 4.91 (1H, br
d, J = 17.3Hz), 6.47 (1H, br s), 6.78 (2H, d, J = 8.9),
6.88 (1H, d, J = 7.9Hz), 7.07 (1H, t, J = 7.9Hz), 7.34 (1
H, br s), 7.39 (1H, t, J = 7.9Hz), 7.54 (2H, d, J = 8.9H
z), 7.99 (2H, d, J = 5.9Hz), 8.35 (1H, d, J = 7.9Hz), 8.7
7 (2H, d, J = 5.9Hz), 11.12 (1H, br s).

(Example 46) 4- (2- (2- (N-
(Hydroxylaminocarbonylmethyl) -N- (4-
Methoxybenzenesulfonyl) amino) phenyl) ethyl
Len) pyridine 1-oxide (Exemplified Compound No. 3-3) (46-1) 4- (2- (2- (N- (t-butoxyca)
Rubonylmethyl) -N- (4-methoxybenzenesulfo
Yl) amino) phenyl) ethylene) pyridine (E) -4- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (569 .4
mg) was dissolved in acetic acid (15 ml), zinc powder (1.55 g) was added to a system immersed in a water bath, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, insolubles were removed from the reaction solution by filtration through celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the desired compound (372.0 mg). ^{1 H-NMR (400MHz, CDCl} 3) 1.36 (9H, s), 2.90-3.00 (1H, m), 3.00-3.08 (1H, m),
3.08-3.24 (2H, m), 3.87 (3H, s), 4.06 (1H, d, J = 17.3H
z), 4.19 (1H, d, J = 17.3Hz), 6.86 (1H, d, J = 8.0Hz),
6.94 (2H, d, J = 8.8Hz), 7.09 (1H, d, J = 8.0Hz), 7.24 (2
H, d, J = 3.7Hz), 7.29 (1H, d, J = 8.0Hz), 7.31 (1H, d,
J = 8.0Hz), 7.63 (2H, d, J = 8.9Hz), 8.51 (2H, d, J = 3.7H
z). (46-2) 4- (2- (2- (N- (t-butoxyca)
Rubonylmethyl) -N- (4-methoxybenzenesulfo
Nyl) amino) phenyl) ethylene) pyridine 1-oxo
Sid 4- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) ethylene) pyridine (186.8 mg)
And m-chloroperbenzoic acid (155.8 mg)
By the same method as in Example 1-4, the target compound (171.
6 mg). ¹ H-NMR (400 MHz, CDCl ₃ ) 1.35 (9H, s), 2.87-3.26 (4H, m), 3.86 (3H, s), 4.04 (1
H, d, J = 17.1Hz), 4.22 (1H, d, J = 17.1Hz), 6.82 (1H,
d, J = 7.8Hz), 6.95 (2H, d, J = 8.9Hz), 7.03 (1H, t, J =
7.8Hz), 7.12 (2H, d, J = 6.9Hz), 7.31 (1H, t, J = 7.8H
z), 7.35 (1H, t, J = 7.8Hz), 7.58 (2H, d, J = 8.9Hz), 8.
25 (2H, d, J = 6.9 Hz). (46-3) 4- (2- (2- (N- (carboxymethyl
) -N- (4-methoxybenzenesulfonyl) ami
(No) phenyl) ethylene) pyridine 1-oxide 4- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) ethylene) pyridine 1-oxide (1
71.6 mg) was dissolved in dichloromethane (4.0 ml), trifluoroacetic acid (2.0 ml) was added, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and toluene (7.0 ml) was added to remove trifluoroacetic acid remaining in the system azeotropically. This operation was repeated three times to obtain the crudely purified target compound (about 140 mg), which was used for the condensation reaction with the amine without further purification. (46-4) 4- (2- (2- (N- (hydroxyl)
Minocarbonylmethyl) -N- (4-methoxybenzene
Sulfonyl) amino) phenyl) ethylene) pyridine
1-oxide 4- (2- (2- (N- (carboxymethyl) -N-
(4-methoxybenzenesulfonyl) amino) phenyl) ethylene) pyridine 1-oxide (about 69 m
g), water-soluble carbodiimide hydrochloride (60.0 m
g), hydroxybenzotriazole (31.7 m
g), N-methylmorpholine (63.3 mg) and O-
Tetrahydropyranyl hydroxylamine (36.7m
g), and for the deprotection of the tetrahydropyranyl group, p-toluenesulfonic acid monohydrate (32.6 m
Using g) and in the same manner as in Example 1-6, the target compound (12.5 mg) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 2.82-2.97 (3H, m), 3.12-3.29 (1H, m), 3.83 (1H, br d,
J = 15.2Hz), 3.85 (3H, s), 4.18 (1H, br d, J = 15.2Hz),
6.61 (1H, d, J = 7.9Hz), 7.10 (1H, t, J = 7.9Hz), 7.11 (2
H, d, J = 9.0Hz), 7.28 (1H, t, J = 7.9Hz), 7.35 (2H, d,
J = 6.8Hz), 7.39 (1H, d, J = 7.9Hz), 7.58 (2H, d, J = 9.0H
z), 8.16 (2H, d, J = 6.8Hz), 8.91 (1H, brs), 10.51 (1H,
br s).

(Example 47) 4- (2- (2- (N-
(Hydroxylaminocarbonylmethyl) -N- (4-
Methoxybenzenesulfonyl) amino) phenyl) ethyl
Len) pyridine (Exemplified Compound No. 3-4) (47-1) 4- (2- (2- (N- (carboxymethyl)
) -N- (4-methoxybenzenesulfonyl) ami
(No) phenyl) ethylene) pyridine 4- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) ethylene) pyridine (186.8 mg)
Was dissolved in dichloromethane (5.0 ml), trifluoroacetic acid (2.0 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and toluene (7.0 ml) was added to remove trifluoroacetic acid remaining in the system azeotropically. This operation was repeated three times to obtain a crudely purified target compound (about 165 mg), which was used for the condensation reaction with an amine without further purification. (47-2) 4- (2- (2- (N- (hydroxyl)
Minocarbonylmethyl) -N- (4-methoxybenzene
Sulfonyl) amino) phenyl) ethylene) pyridine 4- (2- (2- (N- (carboxymethyl) -N-
(4-methoxybenzenesulfonyl) amino) phenyl) ethylene) pyridine (about 72 mg), water-soluble carbodiimide hydrochloride (57.4 mg), hydroxybenzotriazole (30.4 mg), N-methylmorpholine (68.3 mg) and Example 2 was carried out using O-tetrahydropyranylhydroxylamine (35.2 mg) and deprotection of the tetrahydropyranyl group using p-toluenesulfonic acid monohydrate (34.2 mg). In a similar manner to 2, the desired compound (34.2 mg) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 2.73-3.28 (4H, m), 3.86 (1H, br d, J = 16.1 Hz), 3.88 (3
H, s), 4.32 (1H, br d, J = 16.1Hz), 6.56 (1H, d, J = 7.8H
z), 6.96 (2H, d, J = 8.6Hz), 7.08 (1H, t, J = 7.8Hz), 7.
11-7.21 (2H, m), 7.23-7.37 (2H, m), 7.59 (2H, d, J = 8.
6Hz), 8.31-8.40 (2H, m).

(Example 48) 4- (2- (2- (N-
(Aminocarbonylmethyl) -N- (4-methoxybenz
Zensulfonyl) amino) phenyl) ethylene) pyridi
1-oxide (Exemplified Compound No. 3-1) 4- (2- (2- (N- (carboxymethyl) -N-
(4-methoxybenzenesulfonyl) amino) phenyl) ethylene) pyridine 1-oxide (about 69 m
g), water-soluble carbodiimide hydrochloride (60.0 m
g), hydroxybenzotriazole (31.7 m
g), N-methylmorpholine (63.3 mg) and aqueous ammonia (28%, 0.15 ml) were obtained in the same manner as in Example 5 to obtain the desired compound (11.2 mg). ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 2.81-2.95 (3H, m), 3.13-3.29 (1H, m), 3.85 (3H, s),
3.96 (1H, d, J = 16.0Hz), 4.21 (1H, d, J = 16.0Hz), 6.71
(1H, d, J = 8.0Hz), 7.01 (1H, br s), 7.10 (2H, d, J = 8.8
Hz), 7.12 (1H, t, J = 8.0Hz), 7.29 (1H, t, J = 8.0Hz),
7.32 (1H, br s), 7.34 (2H, d, J = 6.9Hz), 7.39 (1H, d,
J = 8.0Hz), 7.57 (2H, d, J = 8.8Hz), 8.15 (2H, d, J = 6.9H
z).

(Example 49) 4- (2- (2- (N-
(Aminocarbonylmethyl) -N- (4-methoxybenz
Zensulfonyl) amino) phenyl) ethylene) pyridi
Down (Compound No. 4-2) 4- (2- (2- ( N- ( carboxymethyl) -N-
(4-methoxybenzenesulfonyl) amino) phenyl) ethylene) pyridine (about 72 mg), water-soluble carbodiimide hydrochloride (57.5 mg), hydroxybenzotriazole (30.4 mg), N-methylmorpholine (68.3 mg) and Ammonia water (28%, 0.2m
Using l) and in the same manner as in Example 5, the target compound (43.7 mg) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 2.85-3.09 (2H, m), 3.09-3.16 (2H, m), 3.85 (1H, br d,
J = 16.6Hz), 3.89 (3H, s), 4.23 (1H, br d, J = 16.6Hz),
5.47 (1H, s), 6.64 (1H, d, J = 8.0Hz), 6.66 (1H, br s),
6.97 (2H, d, J = 8.8Hz), 7.12 (1H, t, J = 8.0Hz), 7.18
(2H, d, J = 5.7Hz), 7.30 (1H, t, J = 8.0Hz), 7.34 (1H,
d, J = 8.0Hz), 7.60 (2H, d, J = 8.8Hz), 8.53 (2H, d, J =
5.7Hz).

(Example 50) 2- (2- (2- (N-
(Hydroxylaminocarbonylmethyl) -N- (4-
Methoxybenzenesulfonyl) amino) phenyl) ethyl
Len) pyridine 1-oxide (exemplary compound number 3-1)
1) (50-1) 2- (2- (2- (N- (t-butoxyca)
Rubonylmethyl) -N- (4-methoxybenzenesulfo
Nil) amino) phenyl) ethylene) pyridine (Z) -2- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (479) .8
mg) was dissolved in acetic acid (15 ml), and zinc powder (1.31 g) was added to the system immersed in a water bath. Then at room temperature
Stir for 30 minutes. After completion of the reaction, insolubles were removed by filtration through Celite, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to 0: 1) to obtain the desired compound (413.0 mg). ¹ H-NMR (400 MHz, CDCl ₃ ) 1.36 (9H, s), 3.08-3.24 (4H, m), 3.86 (3H, s), 3.99 (1
H, d, J = 17.4Hz), 4.34 (1H, d, J = 17.4Hz), 6.92 (2H,
d, J = 9.0Hz), 6.96 (1H, d, J = 8.0Hz), 7.07 (1H, d, J =
8.0Hz), 7.12 ((1H, dd, J = 5.0, 7.4Hz), 7.23-7.32 (2H,
m), 7.36 (1H, d, J = 8.0Hz), 7.60 (1H, t, J = 8.0Hz),
7.66 (2H, d, J = 9.0Hz), 8.55 (1H, d, J = 5.0Hz). (50-2) 2- (2- (2- (N- (t-butoxyca)
Rubonylmethyl) -N- (4-methoxybenzenesulfo
Nyl) amino) phenyl) ethylene) pyridine 1-oxo
Sid 2- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) ethylene) pyridine (206.5 mg)
And m-chloroperbenzoic acid (147.7 mg)
The target compound (18) was obtained in the same manner as in Example 1-4.
8.2 mg). ¹ H-NMR (400 MHz, CDCl ₃ ) 1.34 (9H, s), 3.02-3.42 (4H, s), 3.88 (3H, s), 4.02 (1
H, d, J = 17.8Hz), 4.40 (1H, d, J = 17.8Hz), 6.84 (2H,
d, J = 9.1Hz), 6.90 (1H, d, J = 7.9Hz), 7.06 (1H, t, J =
7.9Hz), 7.22 (1H, dd, J = 6.0, 7.0Hz), 7.20-7.34 (2H,
m), 7.39 (1H, d, J = 7.9Hz), 7.63 (1H, d, J = 7.9Hz), 8.
23 (1H, d, J = 6.0Hz). (50-3) 2- (2- (2- (N- (carboxymethyl
) -N- (4-methoxybenzenesulfonyl) ami
(No) phenyl) ethylene) pyridine 1-oxide 2- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) ethylene) pyridine 1-oxide (1
88.2 mg) was dissolved in dichloromethane (5.0 ml), trifluoroacetic acid (2.5 ml) was added, and the mixture was stirred at room temperature for 4 hours. After evaporating the solvent under reduced pressure, toluene (5.0 ml) was added, and trifluoroacetic acid remaining in the system was azeotropically removed. This operation was repeated three times to obtain the crudely purified target compound (about 131 mg), which was used for the condensation reaction with the amine without further purification. (50-4) 2- (2- (2- (N- (hydroxyl)
Minocarbonylmethyl) -N- (4-methoxybenzene
Sulfonyl) amino) phenyl) ethylene) pyridine
1-oxide 2- (2- (2- (N- (carboxymethyl) -N-
(4-methoxybenzenesulfonyl) amino) phenyl) ethylene) pyridine 1-oxide (about 66 mg),
Water-soluble carbodiimide hydrochloride (57.1 mg), hydroxybenzotriazole (30.2 mg), N-methylmorpholine (60.2 mg) and O-tetrahydropyranylhydroxylamine (34.9 mg) were used. For the deprotection of the benzyl group, the target compound (42 m
g) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 2.89-3.04 (1H, m), 3.26-3.38 (1H, m), 3.38-3.47 (1H,
m), 3.48 (1H, br d, J = 15.6Hz), 3.88-4.02 (1H, m), 3.
89 (3H, s), 4.45 (1H, br d, J = 15.6Hz), 6.46 (1H, d, J
= 8.0Hz), 6.97 (2H, d, J = 8.8Hz), 7.09 (1H, t, J = 8.0H
z), 7.19-7.30 (3H, m), 7.34 (1H, t, J = 8.0Hz), 7.52 (1
H, d, J = 8.0Hz), 7.56 (2H, d, J = 8.8Hz), 8.34 (1H, d,
J = 5.3Hz), 9.70 (1H, br s), 9.97 (1H, br s).

(Example 51) 2- (2- (2- (N-
(Hydroxylaminocarbonylmethyl) -N- (4-
Methoxybenzenesulfonyl) amino) phenyl) ethyl
Len) pyridine (Exemplified Compound No. 3-12) (51-1) 2- (2- (2- (N- (carboxymethyl)
) -N- (4-methoxybenzenesulfonyl) ami
(No) phenyl) ethylene) pyridine 2- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) ethylene) pyridine (206.5 mg)
Was dissolved in dichloromethane (5.0 ml), trifluoroacetic acid (2.5 ml) was added, and the mixture was stirred at room temperature for 3 hours.
After the solvent was distilled off under reduced pressure, toluene (7.0 ml) was added, and trifluoroacetic acid remaining in the system was azeotropically removed. This operation was repeated three times to obtain a crudely purified target compound (about 180 mg).
Subsequently, it was used for a condensation reaction with an amine. (51-2) 2- (2- (2- (N- (hydroxyl)
Minocarbonylmethyl) -N- (4-methoxybenzene
Sulfonyl) amino) phenyl) ethylene) pyridine 2- (2- (2- (N- (carboxymethyl) -N-
(4-methoxybenzenesulfonyl) amino) phenyl) ethylene) pyridine (about 94 mg), water-soluble carbodiimide hydrochloride (82.1 mg), hydroxybenzotriazole (43.4 mg), N-methylmorpholine (86.6 mg) and Example 2 was carried out using O-tetrahydropyranylhydroxylamine (50.1 mg) and p-toluenesulfonic acid monohydrate (58.4 mg) for the deprotection of the tetrahydropyranyl group. In a similar manner to 2, the target compound (91.4 mg) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 2.88-3.14 (3H, m), 3.14-3.28 (1H, m), 3.85 (3H, s),
3.95 (1H, br d, J = 15.3Hz), 4.09 (1H, br d, J = 15.3H)
z), 6.69 (1H, d, J = 7.9Hz), 7.09 (2H, d, J = 8.8Hz), 7.1
1 (1H, t, J = 7.9Hz), 7.20-7.36 (3H, m), 7.38 (1H, d, J
= 7.9Hz), 7.60 (2H, d, J = 8.8Hz), 7.73 (1H, d, J = 7.9H
z), 8.53 (1H, d, J = 4.0Hz), 8.92 (1H, br s), 10.50 (1H,
br s).

(Example 52) 2- (2- (2- (N-
(Aminocarbonylmethyl) -N- (4-methoxybenz
Zensulfonyl) amino) phenyl) ethylene) pyridi
1-oxide (Exemplified Compound No. 3-9) 2- (2- (2- (N- (carboxymethyl) -N-
(4-methoxybenzenesulfonyl) amino) phenyl) ethylene) pyridine 1-oxide (about 66 m
g), water-soluble carbodiimide hydrochloride (57.1 m
g), hydroxybenzotriazole (30.0 m
g), N-methylmorpholine (60.2 mg) and aqueous ammonia (28%, 0.2 ml) were obtained in the same manner as in Example 5 to obtain the target compound (35.0 mg). ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 2.87-3.05 (1 H, m), 3.07-3.24 (1 H, m), 3.26-3.44 (1 H,
m), 3.66-3.87 (1H, m), 3.82 (1H, br d, J = 16.4Hz), 3.8
9 (3H, s), 4.41 (1H, br d, J = 16.4Hz), 5.57 (1H, s),
6.53 (1H, d, J = 8.1Hz), 6.95 (2H, d, J = 8.8Hz), 7.09 (1
(H, t, J = 7.4Hz), 7.18-7.37 (4H, m), 7.41 (1H, br s),
7.45 (1H, d, J = 7.4Hz), 7.55 (2H, d, J = 8.8Hz), 8.28 (1
H, d, J = 6.0Hz).

(Example 53) 2- (2- (2- (N-
(Aminocarbonylmethyl) -N- (4-methoxybenz
Zensulfonyl) amino) phenyl) ethylene) pyridi
Down (Compound No. 3-10) 2- (2- (2- ( N- ( carboxymethyl) -N-
(4-methoxybenzenesulfonyl) amino) phenyl) ethylene) pyridine (about 94 mg), water-soluble carbodiimide hydrochloride (82.1 mg), hydroxybenzotriazole (43.4 mg), N-methylmorpholine (86.6 mg) and Ammonia water (28%, 0.2m
Using 1) and in the same manner as in Example 5, the desired compound (86.5 mg) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 3.01-3.20 (3H, m), 3.44-3.54 (1H, m), 3.85 (1H, br d,
J = 16.7Hz), 3.89 (3H, s), 4.31 (1H, br d, J = 16.7Hz),
5.59 (1H, br s), 6.56 (1H, d, J = 7.9Hz), 6.96 (2H, d,
J = 8.9Hz), 7.08 (1H, t, J = 7.9Hz), 7.14 (1H, dd, J = 5.
5, 7.9Hz), 7.19 (1H, d, J = 7.9Hz), 7.24 (1H, br s),
7.28 (1H, t, J = 7.9Hz), 7.40 (1H, d, J = 7.9Hz), 7.59 (2
H, d, J = 8.9Hz), 7.61 (1H, dd, J = 5.5.7.9Hz), 8.53 (1
H, d, J = 5.5Hz).

(Example 54) (E) -4- (2- (2-
(N- (1- (hydroxylaminocarbonyl) ethyl
) -N- (4-methoxybenzenesulfonyl) ami
(No) phenyl) vinyl) pyridine 1-oxide (Exemplified Compound No. 1-39) (54-1) (E) -4- (2- (2- (N- (1-
(Ethoxycarbonyl) ethyl) -N- (4-methoxy
Benzenesulfonyl) amino) phenyl) vinyl) pyri
Gin (E) -4- (2- (2- (4-methoxybenzenesulfonyl) amino) phenyl) vinylpyridine (500 mg) in dimethylformamide (DMF) solution (40 ml), calcium carbonate (1.04 g), Ethyl α-bromopropionate (326 mg) was added, and the mixture was stirred at room temperature for 7 hours.
After completion of the reaction, insolubles were filtered through celite, and DMF was distilled off under reduced pressure. The residue was extracted with ethyl acetate, washed with water and then with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained compound was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 10).
To 1: 1) to give the desired compound (330 mg). ^{1 H-NMR (270MHz, CDCl} 3) 1.31-1.25 (5H, m), 3.75 (3H, s), 4.25-4.04 (3H, m), 4.89-4.
75 (1H, m), 6.90-6.71 (4H, m), 7.33-7.10 (2H, m), 7.48-7.35
(2H, m), 7.89-7.52 (4H, m), 8.56 (2H, d, J = 6.1Hz) (54-2) (E) -4- (2- (2- (N- (1-
(Ethoxycarbonyl) ethyl) -N- (4-methoxy
Benzenesulfonyl) amino) phenyl) vinyl) pyri
Gin 1-oxide (E) -4- (2- (2- (N- (1- (ethoxycarbonyl) ethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (330 mg)
M-chloroperbenzoic acid (mCPBA) (268 mg) was added to a solution of the above in dichloromethane (25 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed sequentially with a 10% aqueous solution of sodium thiosulfate, a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel chromatography (dichloromethane: methanol = 100: 1 to 10:
Purification in 1) gave the target compound (155 mg). ¹ H-NMR (270 MHz, CDCl ₃ ) 1.30-1.23 (5H, m), 3.75 (3H, s), 4.25-4.10 (3H, m), 4.89-4.
77 (1H, m), 6.88-6.72 (4H, m), 7.44-7.08 (4H, m), 7.69-7.50
(2H, m), 7.88-7.72 (2H, m), 8.22 (2H, d, J = 5.6Hz) (54-3) (E) -4- (2- (2- (N- (1-
Ruboxyethyl) -N- (4-methoxybenzenesulfo
Nyl) amino) phenyl) vinyl) pyridine 1-oxo
Ethyl of Sid (E) -4- (2- (2- (N- (1- (ethoxycarbonyl) ethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide (155 mg) (15ml) 1N in solution
Add sodium hydroxide aqueous solution (0.32 ml) and add
Stirred for hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and diethyl ether and water were added to the residue. The organic layer was removed, diluted aqueous hydrochloric acid was added to the aqueous layer to make it acidic, extracted with dichloromethane, washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. After washing the obtained compound with diethyl ether, the target compound (95 m
g) was obtained. ^{1 H-NMR (270MHz, DMSO} -d 6) 1.17 (3H, d, J = 8.2Hz), 3.75 (3H, s), 4.88-4.73 (1H, m), 6.89
-6.70 (4H, m), 7.45-7.00 (4H, m), 7.80-7.54 (4H, m), 8.20 (2
(H, d, J = 6.2Hz) (54-4) (E) -4- (2- (2- (N- (1-
(Hydroxylaminocarbonyl) ethyl) -N- (4
-Methoxybenzenesulfonyl) amino) phenyl) bi
Nil) pyridine 1-oxide (E) -4- (2- (2- (N- (1-carboxyethyl) -N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide (95 m
g) in dichloromethane (20 ml) suspension, N-methylmorpholine (106 mg), water-soluble carbodiimide hydrochloride (60 mg), hydroxybenzotriazole (42 m
g) and O-tetrahydropyranylhydroxylamine (24 mg) were added, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, ice water was added to the reaction solution, and the mixture was directly extracted with dichloromethane, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel chromatography (dichloromethane: methanol = 10
0: 1 to 10: 1). The obtained white powder was dissolved in methanol (10 ml), p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, water and ethyl acetate were added, and the resulting crystals were collected by filtration and washed with methanol to obtain the desired compound (12 mg). ^{1 H-NMR (270MHz, DMSO} -d 6) 1.18 (3H, d, J = 8.3Hz), 3.73 (3H, s), 4.83-4.70 (1H, m), 6.89
-6.73 (4H, m), 7.20-6.99 (2H, m), 7.53-7.26 (2H, m), 7.73-
7.61 (2H, m), 7.89-7.77 (2H, m), 11.49 (1H, d, J = 6.1Hz).

(Example 55) (E) -4- (2- (2-
(N- (hydroxylaminocarbonylmethyl) -N-
(3,4-dimethoxybenzenesulfonyl) amino)
(Enyl) vinyl) pyridine 1-oxide (Exemplified Compound No. 1-58) (55-1) (E) -4- (2- (2- (3,4-dimension)
Toxibenzenesulfonylamino) phenyl) vinyl)
To a solution of pyridine (E) -4- (2- (2-aminophenyl) vinyl) pyridine (3.00 g) in pyridine (150 ml),
4-dimethoxybenzenesulfonyl chloride (4.06
g) was added and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, pyridine was distilled off, the residue was extracted with ethyl acetate, water and then
After washing with a saturated saline solution, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained compound was washed with diethyl ether to obtain the desired compound (5.37 g). ¹ H-NMR (400 MHz, CDCl ₃ ) 3.60 (3H, s), 3.78 (3H, s), 6.78-6.69 (2H, m), 7.13-7.05 (3
H, m), 7.29-7.22 (4H, m), 7.38 (2H, d, J = 7.8Hz), 7.50 (1H, d,
J = 7.2Hz), 8.42 (2H, d, J = 5.8Hz) (55-2) (E) -4- (2- (2- (N- (t-bu
Toxylcarbonylmethyl) -N- (3,4-dimethoxy
Benzenesulfonyl) amino) phenyl) vinyl) pyri
Gin (E) -4- (2- (2- (3,4-dimethoxybenzenesulfonyl) amino) phenylvinyl) pyridine (5.37 g) in dimethylformamide (DMF) solution (100
ml), calcium carbonate (5.62 g) and then t-butyl bromoacetate (2.91 g) were added, and the mixture was stirred at room temperature for 3 hours. After the completion of the reaction, the insolubles were filtered through celite, and under reduced pressure.
DMF was distilled off. The residue was extracted with ethyl acetate, washed with water and then with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained compound is subjected to silica gel column chromatography (ethyl acetate-hexane).
1: 10-1: 1) to give the desired compound (6.30 g)
I got ¹ H-NMR (270 MHz, CDCl ₃ ) 1.42 (9H, s), 3.73 (3H, s), 3.84 (3H, s), 4.25 (2H, s), 6.95
6.78 (2H, m), 7.20-7.05 (2H, m), 7.45-7.30 (2H, m), 7.60 (1
H, d, J = 16Hz), 7.85 (1H, d, J = 7.8Hz), 8.60 (2H, d, J = 6.2Hz) (55-3) ( 55) (E) -4- (2- (2- ( N- (t-bu
Toxylcarbonylmethyl) -N- (3,4-dimethoxy
Benzenesulfonyl) amino) phenyl) vinyl) pyri
Gin 1-oxide (E) -4- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (3,4-dimethoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (6.30
To a solution of g) in dichloromethane (100 ml) was added m-chloroperbenzoic acid (mCPBA) (4.68 g), and the mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction solution was washed sequentially with a 10% aqueous solution of sodium thiosulfate, a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel chromatography (dichloromethane: methanol = 100: 1 to 1).
0: 1) to give the desired compound (4.60 g). ^{1 H-NMR (270MHz, DMSO} -d 6) 1.35 (9H, s), 3.78 (3H, s), 3.89 (3H, s), 4.10 (1H, d, J = 16.0H
z), 4.32 (1H, d, J = 16.0Hz), 6.85-6.83 (2H, m), 6.99 (1H, d, J
= 7.5Hz), 7.05 (1H, d, J = 7.7Hz), 7.25-7.21 (1H, m), 7.42-7.
31 (4H, m), 7.79-7.68 (2H, m), 8.26 (2H, d, J = 6.3Hz) (55-4) (E) -4- (2- (2- (N- (carbo
Xymethyl) -N- (3,4-dimethoxybenzenesul)
Honyl) amino) phenyl) vinyl) pyridine 1-oxo
Sid (E) -4- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (3,4-dimethoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide (4.60 g) In a dichloromethane (100 ml) solution,
Trifluoroacetic acid was added, and the mixture was stirred at room temperature for 3 hours. The residue obtained by evaporating the solvent under reduced pressure was crystallized from dichloromethane to obtain the desired compound (2.50 g). ^{1 H-NMR (270MHz, DMSO} -d 6) 3.74 (3H, s), 3.84 (3H, s), 4.25 (2H, br), 6.90-6.77 (2H, m),
7.18-7.00 (2H, m), 7.45-7.29 (2H, m), 7.65 (1H, d, J = 16Hz),
7.78 (1H, d, J = 8.0 Hz), 8.21 (2H, d, J = 5.9 Hz) (55-5) (E) -4- (2- (2- (N- (hydro-
Xylaminocarbonylmethyl) -N- (3,4-dimension
Toxibenzenesulfonyl) amino) phenyl) vinyl
Ru) pyridine 1-oxide (E) -4- (2- (2- (N- (carboxymethyl)
-N- (3,4-dimethoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine-1 oxide (1.00
g) in dichloromethane (20 ml) suspension, N-methylmorpholine (473 mg), water-soluble carbodiimide hydrochloride (611 mg), hydroxybenzotriazole (431 m)
g) and O-tetrahydropyranylhydroxylamine (274 mg) were added, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, ice water was added to the reaction solution, and the mixture was extracted with dichloromethane as it was, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (dichloromethane: methanol = 10
0: 1 to 10: 1). The obtained white powder was dissolved in methanol (30 ml), p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, water and ethyl acetate were added, and the resulting crystals were collected by filtration and washed with methanol to obtain the desired compound (70 mg). ^{1 H-NMR (400MHz, DMSO} -d 6) 3.72 (3H, s), 3.77 (3H, s), 3.98 (1H, d, J = 15.7Hz), 4.30 (1H,
d, J = 15.7Hz), 6.94 (1H, d, J = 8.0Hz), 7.21-7.02 (4H, m), 7.3
1 (1H, t, J = 7.2Hz), 7.41 (1H, t, J = 7.2Hz), 7.47 (1H, d, J = 8.0
Hz), 7.53 (2H, d, J = 7.0Hz), 7.69 (1H, d, J = 16.6Hz), 7.84 (1
H, d, J-7.8Hz), 8.34 (2H, d, J = 6.8Hz), 11.50 (1H, s).

(Example 56) (E) -4- (2- (2-
(N- (hydroxylaminocarbonylmethyl) -N-
(2,5-dimethoxybenzenesulfonyl) amino) f
(Enyl) vinyl) pyridine 1-oxide (Exemplified Compound No. 1-59) (56-1) (E) -4- (2- (2- (2,5-dimethyl)
Toxibenzenesulfonyl) amino) phenyl) vinyl
To a solution of pyridine (E) -4- (2- (2-aminophenyl) vinyl) pyridine (3.00 g) in pyridine (150 ml),
5-dimethoxybenzenesulfonyl chloride (3.80
g) was added and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, pyridine was distilled off, the residue was extracted with ethyl acetate, water and then
After washing with a saturated saline solution, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained compound was washed with diethyl ether to obtain the desired compound (5.45 g). ^{1 H-NMR (270MHz, DMSO} -d 6) 3.65 (3H, s), 3.70 (3H, s), 7.13-7.02 (4H, m), 7.29-7.17 (3
H, m), 7.42 (2H, d, J = 7.0Hz), 7.76-7.65 (2H, m), 8.52 (1H, d,
J = 5.8Hz), 9.79 (1H, s) (56-2) (E) -4- (2- (2- (N- (t-b)
Toxylcarbonylmethyl) -N- (2,5-dimethoxy
Benzenesulfonyl) amino) phenyl) vinyl) pyri
Zin (E) -4- (2- (2- (2,5-dimethoxybenzenesulfonyl) amino) phenyl) vinylpyridine (5.
45 g) of dimethylformamide (DMF) solution (60 ml)
Calcium carbonate (2.95 g), then bromoacetic acid t
-Butyl (2.95 g) was added, and the mixture was stirred at room temperature for 1 hour.
The insolubles were filtered through celite, and DMF was distilled off under reduced pressure. The residue was extracted with ethyl acetate, washed with water and then with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained compound was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10 to 1: 1) to obtain the desired compound (3.13 g). ¹ H-NMR (270 MHz, CDCl ₃ ) 1.45 (9H, s), 3.66 (3H, s), 3.70 (3H, s), 4.30 (2H, s), 6.88 (1
(H, d, J = 16.2Hz), 7.10-6.95 (3H, m), 7.30-7.20 (3H, m), 7.45
(2H, d, J = 7.5Hz), 7.77-7.67 (2H, m), 8.59 (2H, d, J = 6.0Hz) (56-3) (E) -4- (2- (2- (N -(T-bu
Toxylcarbonylmethyl) -N- (2,5-dimethoxy
Benzenesulfonyl) amino) phenyl) vinyl) pyri
Gin 1-oxide (E) -4- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (2,5-dimethoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine (1.13
To a solution of g) in dichloromethane (30 ml) was added m-chloroperbenzoic acid (mCPBA) (0.99 g), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was washed successively with a 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution, water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel chromatography (dichloromethane: methanol = 100: 1 to 10:
1) to give the desired compound ⁽¹ H-NMR (270MHz got _{950mg), CDCl 3 + DMSO-} d 6) 1.41 (9H, s), 3.66 (3H, s), 3.69 (3H, s), 4.21 (1H, d, J = 15.6H
z), 4.40 (1H, d, J = 15.6Hz), 7.10-6.85 (4H, m), 7.31-7.25 (3
H, m), 7.40 (2H, d, J = 7.1Hz), 7.77-762 (2H, m), 8.30 (2H, d, J
= 5.9Hz) (56-4) (E) -4- (2- (2- (N- (carbo
Xymethyl) -N- (2,5-dimethoxybenzenesul
Honyl) amino) phenyl) vinyl) pyridine 1-oxo
Sid (E) -4- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (2,5-dimethoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine 1-oxide (950 mg) in dichloromethane (100ml) solution,
Trifluoroacetic acid was added, and the mixture was stirred at room temperature for 3 hours. The residue obtained by evaporating the solvent under reduced pressure was crystallized from dichloromethane to obtain the desired compound (800 mg). ^{1 H-NMR (270MHz, DMSO} -d 6) 3.64 (3H, s), 3.69 (3H, s), 4.38 (2H, br), 7.08-6.90 (4H, m),
7.29-7.18 (3H, m), 7.39 (2H, d, J = 7.4Hz), 7.76-7.61 (2H, m
m), 8.28 (2H, d, J = 5.9 Hz) (56-5) (E) -4- (2- (2- (N- (hydro-
Xylaminocarbonylmethyl) -N- (2,5-dimethyl
Toxibenzenesulfonyl) amino) phenyl) vinyl
Ru) pyridine 1-oxide (E) -4- (2- (2- (N- (carboxymethyl)
-N- (2,5-dimethoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine-1-oxide (800
mg) in dichloromethane (20 ml), N-methylmorpholine (378 mg), water-soluble carbodiimide hydrochloride (489 mg), and hydroxybenzotriazole (345).
mg) and O-tetrahydropyranylhydroxylamine (220 mg) were added, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, ice water was added to the reaction solution, and the mixture was extracted with dichloromethane as it was, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (dichloromethane: methanol =
100: 1 to 10: 1). The obtained white powder was dissolved in methanol (30 ml), p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, water and ethyl acetate were added, and the resulting crystals were collected by filtration and washed with methanol to obtain the desired compound (12 mg). ^{1 H-NMR (400MHz, DMSO} -d 6) 3.65 (3H, s), 3.70 (3H, s), 4.10 (1H, d, J = 15.8Hz), 4.30 (1H,
d, J = 15.8Hz), 6.89 (1H, d, J = 15.9Hz), 7.11-6.99 (3H, m), 7.
29-7.15 (3H, m), 7.45 (2H, d, J = 7.1Hz), 7.79-7.62 (2H, m),
8.34 (2H, d, J = 6.5Hz), 11.48 (1H, s).

(Example 57) (E) -4- (2- (2-
(N- (hydroxylaminocarbonylmethyl) -N-
(2,5-dimethoxybenzenesulfonyl) amino) f
( Enyl) vinyl) pyridine (Exemplified Compound No. 1-60) (57-1) (E) -4- (2- (2- (N- (carbo)
Xymethyl) -N- (2,5-dimethoxybenzenesul
(Honyl) amino) phenyl) vinyl) pyridine hydrochloride (E) -4- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (2,5-dimethoxybenzenesulfonyl) amino) phenyl) Vinyl pyridine (1.0 g)
To a dioxane (50 ml) solution of the above was added concentrated hydrochloric acid (10 ml), and the mixture was heated under reflux for 2 hours. After cooling, the solvent was distilled off under reduced pressure, and the obtained residue was washed with diethyl ether to obtain the desired compound (858 mg). (57-2) (E) -4- (2- (2- (N- (hydro
Xylaminocarbonylmethyl) -N- (2,5-dimethyl
Toxibenzenesulfonyl) amino) phenyl) vinyl
L) pyridine (E) -4- (2- (2- (N- (carboxymethyl)
-N- (2,5-dimethoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine hydrochloride (858 mg)
N-methylmorpholine (884 mg) and a water-soluble carbodiimide hydrochloride (5
03mg), hydroxybenzotriazole (354mg)
And O-tetrahydropyranylhydroxylamine (19
8 mg) and stirred at room temperature for 5 hours. After the reaction,
Ice water was added to the reaction solution, and the mixture was directly extracted with dichloromethane, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (dichloromethane: methanol = 100:
1-10: 1). The obtained white powder was dissolved in methanol (15 ml), and p-toluenesulfonic acid / 1 was dissolved.
The hydrate was added and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, water and ethyl acetate were added, and the resulting crystals were collected by filtration and washed with methanol and diethyl ether to obtain the desired compound (170 mg). ¹ H-NMR (400 MHz, DMSO-d ₆ ) 3.60 (3H, s), 3.65 (3H, s), 4.08 (1H, d, J = 16.1 Hz), 4.29 (1H,
d, J = 16.1Hz), 6.87 (1H, d, J = 7.8Hz), 7.10-6.95 (3Hm), 7.25
-7.11 (3H, m), 7.42 (2H, d, J = 7.8Hz), 7.75-7.61 (2H, m), 8.6
0 (2H, d, J = 6.2Hz), 11.50 (1H, s).

Example 58 (E) -4- (2- (2-
(N- (hydroxylaminocarbonylmethyl) -N-
(4-nitrobenzenesulfonyl) amino) phenyl)
Vinyl) pyridine 1-oxide (Exemplary Compound No. 1-
49) (58-1) (E) -4- (2- (2- (4-nitrobenzene)
P-Nitrobenzenesulfonyl chloride (2.48 g) was added to a solution of ( nzenesulfonyl) amino) phenyl) vinylpyridine (E) -4- (2- (2-aminophenyl) vinyl) pyridine (2.00 g) in pyridine (50 ml). ,
Stirred at room temperature for 30 minutes. Pyridine was distilled off under reduced pressure, the residue was extracted with ethyl acetate, washed with water and then with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained compound is washed with diethyl ether,
The desired compound (2.26 g) was obtained. ^{1 H-NMR (270MHz, DMSO} -d 6) 7.12 (1H, d, J = 15.7Hz), 7.28-7.21 (1H, m), 7.50-7.34 (2H,
m), 7.85-7.74 (4H, m), 7.91 (2H, d, J = 7.7Hz), 8.17 (2H, d,
J = 7.8Hz), 8.83 (2H, d, J = 6.0Hz) (58-2) (E) -4- (2- (2- (N- (t-bu
Toxylcarbonylmethyl) -N- (4-nitrobenzene
A solution of ( sulfonyl) amino) phenyl) vinyl) pyridine (E) -4- (2- (2- (4-nitrobenzenesulfonyl) amino) phenyl) vinylpyridine (2.26 g) in dimethylformamide (DMF) (30 ml) was added with carbonic acid. Calcium (2.35 g) and then t-butyl bromoacetate (1.33 g) were added, and the mixture was stirred at room temperature for 15 minutes. The insolubles were filtered through celite, and DMF was distilled off under reduced pressure. The residue was extracted with ethyl acetate, washed with water and then with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained compound was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10 to 1: 1) to obtain the desired compound (830 mg). ¹ H-NMR (400 MHz, CDCl ₃ ) 1.41 (9 H, s), 4.23 (1 H, d, J = 14.4 Hz), 4.41 (1 H, d, J = 14.4 H
z), 6.85 (1H, d, J = 16.4Hz), 7.16 (1H, d, d, J = 8.0Hz, 1.2Hz),
7.31-7.26 (3H, m), 7.44-7.40 (1H, m), 7.58 (1H, d, J = 16.4H
z), 7.75 (1H, d, d, J = 8.0Hz, 1.4Hz), 7.89 (2H, d, J = 9.0Hz),
8.23 (2H, d, J = 9.0Hz), 8.58 (2H, d, J = 6.2Hz) (58-3) (E) -4- (2- (2- (N- (t-bu
Toxylcarbonylmethyl) -N- (4-nitrobenzene
Sulfonyl) amino) phenyl) vinyl) pyridine 1
-Oxide (E) -4- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-nitrobenzenesulfonyl))
To a solution of (amino) phenyl) vinyl) pyridine (830 mg) in dichloromethane (40 ml) was added m-chloroperbenzoic acid (mCPBA) (607 mg), and the mixture was stirred at room temperature for 1 hour.
The reaction solution was washed successively with a 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution, water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was purified by silica gel chromatography (dichloromethane: methanol = 100: 1 to 20: 1) to obtain the desired compound (750 mg). ¹ H-NMR (270 MHz, CDCl ₃ ) 1.44 (9 H, s), 4.44 (2 H, s), 7.17 (1 H, d, J = 16.0 Hz), 7.43-7.2
0 (1H, d, J = 5H, m), 7.53 (1H, d, J = 16.0Hz), 7.77-7.72 (1H,
m), 7.90 (2H, d, J = 8.6Hz), 8.24 (2H, d, J = 8.5Hz), 8.28 (2H,
d, J = 6.2Hz) (58-4) (E) -4- (2- (2- (N- (carbo
(Xymethyl) -N- (4-nitrobenzenesulfonyl)
Amino) phenyl) vinyl) pyridine 1-oxide (E) -4- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-nitrobenzenesulfonyl)
To a solution of (amino) phenyl) vinyl) pyridine 1-oxide (750 mg) in dichloromethane (25 ml) was added trifluoroacetic acid, and the mixture was stirred at room temperature for 4 hours. Under reduced pressure,
The residue obtained by distilling off the solvent was crystallized from dichloromethane to obtain the desired compound (300 mg). ¹ H-NMR (270 MHz, DMSO-d ₆ ) 4.50 (1 H, br), 7.10 (1 H, d, J = 16.1 Hz), 7.24-7.21 (1 H, m), 7.
49-7.33 (4H, m), 7.51 (1H, d, J = 16.1Hz), 7.94-7.83 (3H, m),
8.23 (2H, d, J = 7.8 Hz), 8.30 (2H, J = 6.1 Hz) (58-5) (E) -4- (2- (2- (N- ( hydro-
Xylaminocarbonylmethyl) -N- (4-nitrobe
Nzensulfonyl) amino) phenyl) vinyl) pyridi
1-oxide (E) -4- (2- (2- (N- (carboxymethyl)
-N- (4-nitrobenzenesulfonyl) amino) phenyl) vinyl) pyridine In a suspension of 1-oxide (300 mg) in dichloromethane (20 ml), N-methylmorpholine (200 mg), water-soluble carbodiimide hydrochloride (189 m
g), hydroxybenzotriazole (134 mg) and O-tetrahydropyranylhydroxylamine (71 m
g) was added and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, ice water was added to the reaction solution, and the mixture was directly extracted with dichloromethane,
After washing with saturated saline, drying over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (dichloromethane: methanol = 100: 1 to 1).
10: 1). The obtained white powder was dissolved in methanol (45 ml), p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, water and ethyl acetate were added, and the resulting crystals were collected by filtration and washed with methanol and tetrahydrofuran (THF) to obtain the desired compound (120 mg). ¹ H-NMR (400 MHz, DMSO-d ₆ ) 4.50 (1 H, br), 7.10 (1 H, d, J = 16.1 Hz), 7.24-7.21 (1 H, m), 7.
49-7.33 (4H, m), 7.51 (1H, d, J = 16.1Hz), 7.94-7.83 (3H, m),
8.23 (2H, d, J = 7.8Hz), 8.30 (2H, J = 6.1Hz).

(Example 59) (E) -4- (2- (2-
(N- (hydroxylaminocarbonylmethyl) -N-
(P-toluenesulfonyl) amino) phenyl) vinyl
Pyridine) 1-oxide (Exemplified Compound No. 1-51) (59-1) (E) -4- (2- (2- (p-toluene)
A solution of ( sulfonylamino) phenyl) vinyl) pyridine (E) -4- (2- (2-aminophenyl) vinyl) pyridine (4.00 g) in pyridine (150 ml) was added with p-
Toluenesulfonyl chloride (4.27 g) was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, pyridine was distilled off under reduced pressure, the residue was extracted with ethyl acetate, washed with water and then with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained compound was washed with diethyl ether to obtain the desired compound (6.20 g). ¹ H-NMR (270 MHz, CDCl ₃ ) 2.13 (3H, s), 7.20-7.11 (3H, m), 7.37-7.22 (5H, m), 7.58 (2
(H, d, J = 8.0Hz), 7.72-7,65 (1H, m), 8.55 (2H, d, J = 5.9Hz), 9.
82 (1H, s) (59-2) (E) -4- (2- (2- (N- (t-
Toxylcarbonylmethyl) -N- (p-toluenesulfo
Nyl) amino) phenyl) vinyl) pyridine (E) -4- (2- (2- (4-toluenesulfonylamino) phenyl) vinyl) pyridine (6.00 g) in dimethylformamide (DMF) solution (100 ml) Calcium (4.73 g) followed by t-butyl bromoacetate (3.67 g)
g) was added and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, insolubles were filtered through celite, and DMF was distilled off under reduced pressure. The residue was extracted with ethyl acetate, washed with water and then with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained compound was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10-1: 1) to obtain the desired compound (6.37 g). ¹ H-NMR (400 MHz, CDCl ₃ ) 1.38 (9 H, s), 2.36 (3 H, s), 4.15-4.09 (1 H, m), 6.82 (1 H, d, J =
15.5Hz), 7.26-7.08 (5H, m), 7.40-7.35 (1H, m), 7.49 (1H, d,
J = 15.5Hz), 7.60 (1H, d, J = 7.8Hz), 7.77 (1H, d, J = 7.5Hz), 8.
59 (2H, d, J = 5.9Hz) (59-3) (E) -4- (2- (2- (N- (t-
Toxylcarbonylmethyl) -N- (p-toluenesulfo
Nyl) amino) phenyl) vinyl) pyridine 1-oxo
To a solution of side (E) -4- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (p-toluenesulfonyl) amino) phenyl) vinyl) pyridine (6.37 g) in dichloromethane (70 ml) m-chloroperbenzoic acid (mCPB
A) (5.96 g) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was washed successively with a 10% aqueous solution of sodium thiosulfate, a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel chromatography (dichloromethane: methanol = 100: 1 to 10:
Purification in 1) gave the desired compound (4.93 g). ¹ H-NMR (400 MHz, CDCl ₃ ) 1.38 (9 H, s), 2.39 (3 H, s), 4.09 (1 H, d, J = 16.7 Hz), 4.38 (1 H,
d, J = 16.7Hz), 6.83 (1H, d, J = 15.7Hz), 6.99 (1H, d, J = 7.2H
z), 7.26-7.20 (3H, m), 7.38-7.32 (3H, m), 7.60-7.57 (2H,
m), 7.76-7.63 (2H, m), 8.18 (2H, d, J = 6.2 Hz) (59-4) (E) -4- (2- (2- (N- (carbo
(Xymethyl) -N- (p-toluenesulfonyl) ami
(No) phenyl) vinyl) pyridine 1-oxide (E) -4- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (p-toluenesulfonyl) amino) phenyl) vinyl) pyridine 1- Oxide (4.93
Trifluoroacetic acid was added to a solution of g) in dichloromethane (150 ml), and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the residue obtained by evaporating the solvent under reduced pressure was crystallized from dichloromethane to obtain the desired compound (3.00 g). ^{1 H-NMR (270MHz, DMSO} -d 6) 2.50 (3H, s), 4.45 (1H, br), 7.18-7.05 (2H, m), 7.43-7.25 (7
H, m), 7.53 (1H, d, J = 7.6Hz), 7.82 (1H, d, J = 7.8Hz), 8.20 (2
(H, d, J = 7.0Hz) (59-5) (E) -4- (2- (2- (N- ( hydro-
Xylaminocarbonylmethyl) -N- (p-toluene
Sulfonyl) amino) phenyl) vinyl) pyridine 1
-Oxide (E) -4- (2- (2- (N- (carboxymethyl)
-N- (p-toluenesulfonyl) amino) phenyl)
Vinyl) pyridine 1-oxide (1.0 g) in dichloromethane (20 ml) was suspended in N-methylmorpholine (525 ml).
mg), water-soluble carbodiimide hydrochloride (679 mg),
Hydroxybenzotriazole (334 mg) and O-tetrahydropyranylhydroxylamine (304 mg) were added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (dichloromethane: methanol = 100: 1-10:
Purified in 1). The obtained white powder was treated with methanol (45 m
1), p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, water and ethyl acetate were added, and the resulting crystals were collected by filtration and washed with methanol and tetrahydrofuran to obtain the desired compound (400 mg). ¹ H-NMR (400 MHz, DMSO-d ₆ ) 2.35 (1 H, s), 3.98 (1 H, d, J = 15.5 Hz), 4.24 (1 H, d, J = 15.5 H)
z), 6.92 (1H, d, J = 8.0Hz), 7.03 (2H, d, J = 8.8Hz), 7.14 (1H,
d, J = 16.5Hz), 7.32-7.28 (1H, m), 7.43-7.38 (3H, m), 7.59 (2H
H, d, J = 8.8Hz), 7.78 (1H, d, J = 16.5Hz), 7.87 (1H, d, J = 7.4H
z), 8.56 (1H, d, J = 6.0 Hz), 8.93 (1H, s), 10.52 (1H, s).

(Example 60) (E) -4- (2- (2-
(N- (hydroxylaminocarbonylmethyl) -N-
(P-toluenesulfonyl) amino) phenyl) vinyl
B) pyridine (Exemplified Compound No. 1-52) (60-1) (E) -4- (2- (2- (N- (carbo)
(Xymethyl) -N- (p-toluenesulfonyl) ami
(No) phenyl) vinyl) pyridine hydrochloride (E) -4- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (p-toluenesulfonyl) amino) phenyl) vinyl) pyridine (300 mg) ) Was added to a dioxane (20 ml) solution, and concentrated hydrochloric acid (5 ml) was added, followed by heating under reflux for 2 hours. After completion of the reaction, the mixture was cooled, the solvent was distilled off under reduced pressure, and the obtained residue was washed with diethyl ether to obtain the desired compound (210 mg). (60-2) (E) -4- (2- (2- (N- (hydro-
Xylaminocarbonylmethyl) -N- (p-toluene
Sulfonyl) amino) phenyl) vinyl) pyridine (E) -4- (2- (2- (N- (carboxymethyl)
-N- (p-toluenesulfonyl) amino) phenyl)
To a suspension of vinyl) pyridine / hydrochloride (210 mg) in dichloromethane (10 ml) was added N-methylmorpholine (239 m).
g), water-soluble carbodiimide hydrochloride (136 mg), hydroxybenzotriazole (96 mg), and O-tetrahydropyranylhydroxylamine (61 mg) were added, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, ice water was added to the reaction solution, and the mixture was extracted with dichloromethane as it was, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel chromatography (dichloromethane: methanol = 100: 1).
〜１０10: 1). The obtained white powder was dissolved in methanol (20 ml), p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, water and ethyl acetate were added, and the resulting crystals were collected by filtration, suspended in methanol, added with a saturated aqueous solution of sodium hydrogen carbonate, and subjected to ultrasonic waves. Filter the remaining powder,
After washing with methanol and ethyl acetate, the target compound (5 m
g) was obtained. ^{1 H-NMR (400MHz, DMSO} -d 6) 2.31 (3H, s), 4.00 (1H, d, J = 15.8Hz), 4.25 (1H, d, J = 15.8H
z), 6.92 (1H, d, J = 7.8Hz), 7.13 (1H, d, J = 8.2Hz), 7.43-7.26
(6H, m), 7.56-7.46 (3H, m), 7.82 (1H, d, J = 7.8Hz), 8.23 (2H,
d, J = 6.9Hz), 8.95 (1H, s), 10.54 (1H, s).

Example 61 (E) -4- (2- (2-
(N- (cyanomethyl) -N- (p-toluenesulfoni
L) amino) phenyl) vinyl) pyridine (Exemplary Compound No. 1-34) Sodium hydride (60% in mineral oil, 238m)
g) in a suspension of DMF (10 ml) under ice-cooling and (E)-
4- (2- (2- (4-methoxybenzenesulfonyl))
A solution of (amino) phenyl) vinyl) pyridine (1.82 g) in DMF (20 ml) was added, and the mixture was stirred at room temperature for 30 minutes. Under ice cooling, iodoacetonitrile (0.43 ml) was added, and the mixture was stirred for 3 hours, and then sodium hydride (60% in
Mineral oil, 119 mg) and iodoacetonitrile (0.22 ml) were added, and the mixture was further stirred for 15 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 3-0: 3), and then purified by Me.
The product was purified by rck's rover column (dichloromethane: methanol = 49: 1) to give the target compound (501 mg).
I got ¹ H-NMR (400 MHz, CD ₃ OD) 3.76 (3 H, s), 4.70 (1 H, br d, J = 16.0 Hz), 4.78 (1 H, br d, J = 1
6.0Hz), 6.99 (2H, d, J = 8.8Hz), 7.11 (1H, d, J = 16.4Hz), 7.1
6 (1H, d, J = 8.0Hz), 7.35-7.42 (2H, m), 7.43 (2H, d, J = 6.0H
z), 7.49 (1H, t, J = 8.0Hz), 7.67 (2H, d, J = 8.8Hz), 7.90 (1H,
d, J = 8.0Hz), 8.48 (2H, d, J = 6.0Hz).

(Example 62) (E) -4- (2- (2-
(N- (cyanomethyl) -N- (p-toluenesulfoni
Ru) amino) phenyl) vinyl) pyridine 1-oxy
De (Compound No. 1-33) (E) -4- (2- (2- (N- ( cyanomethyl) -N
-(P-toluenesulfonyl) amino) phenyl) vinyl) pyridine (150 mg) in dichloromethane (3 m
l) The solution was cooled with ice and m-chloroperbenzoic acid (128 m
g) was added and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 2 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. Wash the organic layer with saturated saline,
It was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel thin-layer chromatography (ethyl acetate: methanol = 4: 1) to obtain the desired compound (103 mg). ¹ H-NMR (400 MHz, CD ₃ OD) 3.80 (3 H, s), 4.72 (1 H, br d, J = 16.0 Hz), 4.77 (1 H, br d, J = 1
6.0Hz), 7.00 (2H, d, J = 8.9Hz), 7.10-7.16 (2H, m), 7.31-7.4
0 (2H, m), 7.49 (1H, t, J = 7.3Hz), 7.56 (2H, d, J = 7.1Hz), 7.66
(2H, d, J = 8.9Hz), 7.89 (1H, d, J = 8.0Hz), 8.27 (2H, d, J = 7.1H
z).

Example 63 (E) -4- (2- (2-
(N-((O-tetrahydropyran-2-yl) hydro
Xylaminocarbonylmethyl) -N- (4-methoxy
Benzenesulfonyl) amino) phenyl) vinyl) pyri
Gin (Exemplified Compound No. 1-22) (E) -4- (2- (2- (N-carboxymethyl)-
N- (4-methoxyphenoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine hydrochloride (300 m
g) in dichloromethane (30 ml) suspension, N-methylmorpholine (329 mg), water-soluble carbodiimide hydrochloride (187 mg), hydroxybenzotriazole (132 m2)
g) and O-tetrahydrofuranylhydroxylamine (70 mg) were added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, ice water was added to the reaction solution, and the mixture was extracted with dichloromethane as it was, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel chromatography (dichloromethane: methanol = 10
0: 1 to 10: 1). The obtained white powder was washed with ether to obtain the desired compound (180 mg). ¹ H-NMR (400 MHz, DMSO-d ₆ ) 1.91-1.66 (4H, m), 3.75-3.73 (5H, m), 4.28 (1H, d, J = 15.3H
z) 5.15-5.04 (1H, m), 6.95-6.91 (1H, m), 7.04 (2H, d, J = 8.8H
z), 7.19 (1H, d, J = 16.5Hz), 7.33 (1H, m, J = 7.5Hz), 7.41 (1H,
t, J = 7.5Hz), 7.47 (2H, d, J = 5.3Hz), 7.59 (2H, d, J = 8.6Hz),
7.75-7.71 (1H, m) .7.89 (1H, d, J = 7.8Hz), 8.61 (2H, d, J = 5.
2Hz), 11.07 (1H, d, J = 8.6Hz).

(Example 64) (E) -4- (2- (2-
(N-((O-tetrahydropyran-2-yl) hydro
Xylaminocarbonylmethyl) -N- (4-methoxy
Benzenesulfonyl) amino) phenyl) vinyl) pyri
Gin 1-oxide (Exemplified Compound No. 1-21) (E) -4- (2- (2- (N-carboxymethyl)-
N- (4-methoxybenzenesulfonyl) amino) phenyl) vinyl) pyridine In a suspension of 1-oxide (200 mg) in dichloromethane (20 ml), N-methylmorpholine (138 mg), water-soluble carbodiimide hydrochloride (131 m)
g), hydroxybenzotriazole (92 mg) and O
-Tetrahydrofuranylhydroxylamine (49mg)
Was added and stirred at room temperature for 3 hours. After completion of the reaction, ice water was added to the reaction solution, and the mixture was extracted with dichloromethane as it was, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel chromatography (dichloromethane: methanol = 100: 1 to 1).
0: 1). The obtained white powder was washed with diethyl ether to obtain the desired compound (60 mg). ¹ H-NMR (400 MHz, DMSO-d ₆ ) 1.93-1.70 (4H, m), 3.75-3.71 (5H, m), 4.03 (1H, d, J = 15.5H
z), 4.29 (1H, d, J = 15.5Hz), 5.16-5.10 (1H, m), 6.96-6.90 (1
H, m), 7.07 (2H, d, J = 8.9Hz), 7.16 (1H, d, J = 16.5Hz), 7.36-
7.29 (1H, m), 7.45-.39 (1H, m), 7.50 (2H, d, J = 5.2Hz), 7.61
(2H, d, J = 8.6Hz), 7.73 (1H, d, J = 16.5Hz), 7.89 (1H, d, J = 7.9
Hz), 8.22 (2H, d, J = 5.3Hz), 11.00 (1H, d, J = 8.6Hz).

(Example 65) (E) -4- (2- (2-
(N- (hydroxylaminocarbonylmethyl) -N-
(4-cyanobenzenesulfonyl) amino) phenyl)
Vinyl) pyridine (Exemplified Compound No. 1-72) (65-1) (E) -4- (2- (2- (4-cyanobe)
4-Cyanobenzenesulfonyl chloride (3.39 g) was added to a pyridine (150 ml) solution of (sensulfonylamino) phenyl) vinyl) pyridine (E) -4- (2- (2-aminophenyl) vinyl) pyridine (3.0 g). In addition,
Stirred at room temperature for 30 minutes. Pyridine was distilled off under reduced pressure, the residue was extracted with ethyl acetate, washed with water and then with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained compound is washed with diethyl ether,
The target compound (3.62 g) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 7.15 (1H, d, J = 15.9 Hz), 7.28-7.25 (1H, m), 7.49-7.30 (2H,
m), 7.88-7.70 (4H, m), 7.92 (2H, d, J = 7.9Hz), 8.20 (2H, d, J =
(7.7 Hz), 8.79 (2H, d, J = 5.8 Hz) (65-2) (E) -4- (2- (2- (N- (t-b)
Toxylcarbonylmethyl) -N- (4-cyanobenzene
Sulfonyl) amino) phenyl) vinyl) pyridine (E) -4- (2- (2- (4-cyanobenzenesulfonylamino) phenyl) vinyl) pyridine (1.5 g) in dimethylformamide (DMF) solution (60 ml) Calcium carbonate (1.72 g) and then t-butyl bromoacetate (0.87 g) were added, and the mixture was stirred at room temperature for 3 hours. The insolubles were filtered through celite, and DMF was distilled off under reduced pressure. The residue was extracted with ethyl acetate, washed with water and then with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained compound was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 10 to 1: 1) to obtain the desired compound (1.02 g). ¹ H-NMR (400 MHz, CDCl ₃ ) 1.40 (9 H, s), 4.24 (1 H, d, J = 15.0 Hz), 4.44 (1 H, d, J = 15.0 H)
z), 6.90 (1H, d, J = 16.4Hz), 7.20-7.10 (1H, m), 7.31-7.22 (3
H, m), 7.40-7.35 (1H, m), 7.60 (1H, d, J = 16.4Hz), 7.75 (1H,
d, J = 8.0Hz), 7.90 (1H, d, J = 8.8Hz), 8.20 (2H, d, J = 8.8Hz),
8.70 (2H, d, J = 5.8Hz) (65-3) (E) -4- (2- (2- (N- (carbo
(Xymethyl) -N- (4-cyanobenzenesulfonyl)
(Amino) phenyl) vinyl) pyridine hydrochloride (E) -4- (2- (2- (N- (t-butoxycarbonylmethyl))-N- (4-cyanobenzenesulfonyl)
Concentrated hydrochloric acid (10 ml) was added to a dioxane (50 ml) solution of (amino) phenyl) vinylpyridine (1.02 g), and the mixture was heated under reflux for 2 hours. After completion of the reaction, the reaction solution was cooled, the solvent was distilled off under reduced pressure, and the obtained residue was washed with diethyl ether to obtain the desired compound (950 mg). (65-4) (E) -4- (2- (2- (N- (hydro
Xylaminocarbonylmethyl) -N- (4-cyanobe
Nzensulfonyl) amino) phenyl) vinyl) pyridi
Emissions (E) -4- (2- (2- (N- ( carboxymethyl)
To a suspension of -N- (4-cyanobenzenesulfonyl) amino) phenyl) vinyl) pyridine hydrochloride (100 mg) in dichloromethane (50 ml), N-methylmorpholine (111 mg), water-soluble carbodiimide hydrochloride (63 m
g), hydroxybenzotriazole (44 mg) and O
-Tetrahydropyranylhydroxylamine (27mg)
Was added and stirred at room temperature for 5 hours. Ice water is added to the reaction solution,
The mixture was directly extracted with dichloromethane, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane: methanol = 100: 1 to 10: 1). The obtained white powder was dissolved in methanol (15 ml), p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, water and ethyl acetate were added, the resulting crystals were collected by filtration, suspended in methanol, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was subjected to ultrasonic waves. The remaining powder was collected by filtration and washed with methanol and ethyl acetate to obtain the desired compound (35 mg). ^{1 H-NMR (400MHz, DMSO} -d 6) 2.31 (3H, s), 4.00 (1H, d, J = 15.8Hz), 4.25 (1H, d, J = 15.8H
z), 6.92 (1H, d, J = 7.8Hz), 7.13 (1H, d, J = 8.2Hz), 7.43-7.26
(6H, m), 7.56-7.46 (3H, m), 7.82 (1H, d, J = 7.8Hz), 8.23 (2H,
d, J = 6.9Hz), 8.95 (1H, s), 10.54 (1H, s).

(Example 66) (E) -4- (2- (2-
(N-hydroxylaminocarbonylmethyl) -N-
(4- (methanesulfonylamino) benzenesulfoni
L) amino) phenyl) vinyl) pyridine (Exemplary Compound No. 1-80) (66-1) (E) -4- (2- (2- (N- (t-bu)
Toxylcarbonylmethyl) -N- (4-aminobenzene
Sulfonyl) amino) phenyl) vinyl) pyridine (E) -4- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-nitrobenzenesulfonyl)
Amino) phenyl) vinyl) pyridine (720 mg) was dissolved in ethanol (30 ml) and water (5 ml).
mg) and then ammonium chloride (7.8 mg)
added. The reaction was warmed to 120 ° C. and stirred for 3 hours.
After the completion of the reaction, the mixture was allowed to cool at room temperature and filtered. The filtrate was concentrated, diethyl ether was added to the residue, and the precipitate was collected by filtration to obtain the desired compound (600 mg). (66-2) (E) -4- (2- (2- (N- (t-
Toxylcarbonylmethyl) -N- (4- (methanesulfo
Nilamino) benzenesulfonyl) amino) phenyl)
Vinyl) pyridine (E) -4- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4-aminobenzenesulfonyl)
Triethylamine (392 mg) and methanesulfonyl chloride (162 mg) were added to a dichloromethane solution (60 ml) of (amino) phenyl) vinyl) pyridine (600 mg) under ice-cooling.
mg) were added sequentially. After stirring at room temperature for 2 hours, the mixture was extracted with dichloromethane. After washing with water and then with saturated saline,
It was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane: methanol = 100: 1 to 10: 1) to obtain the desired compound (250 mg). ¹ H-NMR (400 MHz, DMSO-d ₆ ) 1.40 (9 H, s), 2.91 (3 H, s), 4.11 (1 H, d, J = 16.6 Hz), 4.23 (1 H,
d, J = 16.6Hz), 6.96 (1H, d, J = 15.4Hz), 7.35-7.01 (4H, m), 7.
50-7.41 (4H, m), 7.63 (1H, d, J = 15.4Hz), 7.80 (2H, d, J = 8.1H
z), 8.50 (2H, d, J = 5.7 Hz) (66-3) (E) -4- (2- (2- (N- (carbo
Xymethyl) -N- (4- (methanesulfonylamino)
Benzenesulfonyl) amino) phenyl) vinyl) pyri
Gin hydrochloride (E) -4- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (4- (methanesulfonylamino))
Concentrated hydrochloric acid (3 ml) was added to a solution of benzenesulfonyl) amino) phenyl) vinyl) pyridine (250 mg) in dioxane (25 ml), and the mixture was refluxed for 1 hour. After cooling, the solvent was distilled off under reduced pressure, and the obtained residue was washed with diethyl ether to obtain the desired compound (130 mg). (66-4) (E) -4- (2- (2- (N- hydroxy
Silaminocarbonylmethyl) -N- (4- (methanes
Ruphonylamino) benzenesulfonyl) amino) phenyl
Ru) vinyl) pyridine (E) -4- (2- (2- (N- (carboxymethyl)
To a suspension of -N- (4- (methanesulfonylamino) benzenesulfonyl) amino) phenyl) vinyl) pyridine hydrochloride (130 mg) in dichloromethane (30 ml) was added N
-Methylmorpholine (125 mg), water-soluble carbodiimide hydrochloride (71 mg), hydroxybenzotriazole (50 mg) and 28% aqueous ammonia (23 mg) were added,
Stirred at room temperature for 4 hours. After completion of the reaction, ice water was added to the reaction solution, and the mixture was extracted with dichloromethane as it was, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane: methanol = 100: 1 to 10: 1). The obtained white powder was dissolved in methanol (10 ml), p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, water and ethyl acetate were added, the resulting crystals were collected by filtration, suspended in methanol, a saturated aqueous sodium hydrogen carbonate solution was added, and ultrasonic waves were applied. The remaining powder was collected by filtration and washed with methanol and ethyl acetate to obtain the desired compound (10 mg). ¹ H-NMR (400 MHz, DMSO-d ₆ ) 2.82 (3 H, s), 4.05 (1 H, d, J = 16.0 Hz), 4.24 (1 H, d, J = 16.0 H)
z), 6.90 (1H, d, J = 15.6Hz), 7.47-7.10 (5H, m), 7.65-7.50 (3
H, m), 7.70 (1H, d, J = 15.6Hz), 7.77 (2H, d, J = 8.0Hz), 8.62 (2
H, d, J = 5.6Hz).

(Example 67) (E) -4- (2- (3-
(N- (aminocarboxymethyl) -N- (4-methoxy
Sibenzenesulfonyl) amino) thienyl) vinyl) pi
Lysine (Exemplified Compound No. 6-2) (E) -4- (2- (3- (N- (t-butoxycarbonylmethyl) -N- (4-methoxybenzenesulfonyl) amino) thienyl) vinyl) pyridine (1 .23
g), concentrated hydrochloric acid (31 ml) and dioxane (12 ml)
In the same manner as in Example 2-1, 1.15 g of powder was obtained. The obtained powder (0.23 g), water-soluble carbodiimide hydrochloride (0.28 g), hydroxybenzotriazole (0.15 g), aqueous ammonia (6 ml), N
Using -methylmorpholine (0.76 ml) and dichloromethane (5.0 ml), the target compound (73 mg) was obtained in the same manner as in Example 9. ¹ H-NMR (400 MHz, CDCl ₃ ) 3.75 (3H, s), 4.16 (2H, s), 5.58 (1H, br, s), 6.48 (1H,
br, s), 6.66 (1H, d, J = 5.2Hz), 6.76 (1H, d, J = 16.2H
z), 6.92 (2H, d, J = 8.8Hz), 7.14-7.19 (4H, m), 7.64 (2H,
d, J = 8.8Hz), 8.56 (2H, d, J = 4.8Hz).

(Example 68) (E) -4- (2- (2- (2-
(N- (hydroxylaminocarbonylmethyl) -N-
(4-cyanobenzenesulfonyl) amino) phenyl)
Vinyl) pyridine (Exemplified Compound No. 1-72) (E) -4- (2- (2- (N- (carboxymethyl)
N-methylmorpholine (111 mg) was added to a suspension of -N- (4-cyanobenzenesulfonyl) amino) phenyl) vinyl) pyridine hydrochloride (100 mg) in dichloromethane (50 ml),
Water-soluble carbodiimide hydrochloride (63 mg), hydroxybenzotriazole (44 mg) and O-tetrahydropyranylhydroxylamine (28 mg) were added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, ice water and dichloromethane were added to the reaction solution for extraction. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue
Purification was performed by silica gel chromatography (dichloromethane: methanol = 100: 1 to 10: 1). The obtained white powder is dissolved in methanol (10 ml), and a catalytic amount of p
-Toluenesulfonic acid monohydrate was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, water and ethyl acetate were added, and the resulting crystals were collected by filtration. The obtained crystals were suspended in methanol, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was washed with ultrasonic waves. The remaining powder was collected by filtration and washed with ethanol and ethyl acetate to obtain the desired compound (15 mg). ¹ H-NMR (400 MHz, DMSO-d ₆ ) 4.35-4.02 (2H, m), 7.17-7.11 (3H, m), 7.45-7.32 (3H, m),
7.66 (1H, d, J = 16.6Hz), 7.83 (2H, d, J = 8.6Hz), 7.89-7.
87 (1H, m), 7.94 (2H, d, J = 8.6Hz), 8.57 (2H, s), 8.99 (1H,
s), 10.60 (1H, s).

Example 69 (E) -4- (2- (2-
(N- (hydroxylaminocarbonylmethyl) -N-
(Phenylsulfonyl) amino) phenyl) vinyl) pi
Lysine (Exemplified Compound No. 1-88) (69-1) (E) -4- (2- (2- (phenylsulfur)
To a solution of ( honylamino) phenyl) vinyl) pyridine (E) -4- (2- (2-aminophenyl) vinyl) pyridine (2.50 g) in pyridine (50 ml) was added benzenesulfonyl chloride (2.47 g), and the mixture was added at room temperature for 30 minutes. For a minute. After completion of the reaction, pyridine was distilled off under reduced pressure. Ethyl acetate was added to the residue, washed with water and then with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained compound is washed with diethyl ether to give the desired compound
(3.82 g) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) 6.65 (1H, d, J = 16.6 Hz), 7.42-7.23 (9H, m), 7.58-7.53 (1
H, m), 7.62 (2H, d, J = 8.5Hz), 8.55 (2H, d, J = 6.2Hz), 9.
41 (1H, s) (69-2) (E) -4- (2- (2- (N- (t-
Toxylcarbonylmethyl) -N- (phenylsulfoni
L) amino) phenyl) vinyl) pyridine (E) -4- (2- (2- (phenylsulfonylamino) phenyl) vinyl) pyridine (3.16 g) in dimethylformamide (DMF) solution (100 ml) was added to calcium carbonate ( 3.82
g) Then, t-butyl bromoacetate (2.16 g) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, insolubles were filtered through celite, and DMF was distilled off under reduced pressure. Ethyl acetate was added to the residue, washed with water and then with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained compound was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 10 to 1: 1) to obtain the desired compound (2.62 g). ¹ H-NMR (400 MHz, CDCl ₃ ) 1.39 (3H, s), 4.21 (2H, d, J = 9.2Hz), 6.92 (1H, d, J = 16.5
Hz), 7.19-7.12 (1H, m), 7.28-7.22 (1H, m), 7.57-7.30 (1
H, m), 7.73-7.68 (3H, m), 8.58 (2H, d, J = 6.8 Hz) (69-3) (E) -4- (2- (2- (N- (carbo
(Xymethyl) -N- (phenylsulfonyl) amino)
(Dienyl) vinyl) pyridine hydrochloride (E) -4- (2- (2- (N- (t-butoxycarbonylmethyl) -N- (phenylsulfonyl) amino) phenyl) vinyl) pyridine (2.62 g) dioxane (75ml)
To the solution was added concentrated hydrochloric acid (20 ml), and the mixture was heated under reflux for 2 hours. After completion of the reaction, the mixture was cooled, the solvent was distilled off under reduced pressure, and the obtained residue was washed with diethyl ether to obtain the desired compound (2.10 g). (69-4) (E) -4- (2- (2- (N- (hydro
Xylaminocarbonylmethyl) -N- (phenylsulfur
(Honyl) amino) phenyl) vinyl) pyridine (E) -4- (2- (2- (N- (carboxymethyl)
-N- (phenylsulfonyl) amino) phenyl) vinyl) pyridine hydrochloride (1.00 g) in dichloromethane (50 ml)
To the suspension, N-methylmorpholine (1.17 g), water-soluble carbodiimide hydrochloride (667 mg), hydroxybenzotriazole (477 mg) and O-tetrahydropyranylhydroxylamine (299 mg) were added, and the mixture was stirred at room temperature for 5 hours. . After completion of the reaction, ice water was added to the reaction solution, and dichloromethane was further added for extraction. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The residue was purified by silica gel chromatography (dichloromethane: methanol = 100: 1 to 10: 1).
The obtained white powder was dissolved in methanol (30 ml), p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, water and ethyl acetate were added, and the resulting crystals were collected by filtration. The obtained crystals were suspended in methanol, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was washed with ultrasonic waves. The remaining powder was collected by filtration and washed with methanol and ethyl acetate to obtain the desired compound (350 mg). ¹ H-NMR (400 MHz, DMSO-d ₆ ) 4.11 (1 H, d, J = 16.1 Hz), 4.30 (1 H, d, J = 16.1 Hz), 6.99 (1
H, d, J = 16.0Hz), 7.11 (1H, d, J = 8.1Hz), 7.40-7.29 (6H,
m), 7.60-7.43 (4H, m), 7.79 (1H, d, J = 8.2Hz), 8.17 (2H,
d, J = 6.6Hz), 8.90 (1H, s), 10.55 (1H, s).

(Example 70) (E) -4- (2- (2-
(N- (aminocarbonylmethyl) -N- (phenyl
Nzensulfonyl) amino) phenyl) vinyl) pyridi
Down (Compound No. 1-86) (E) -4- (2- (2- (N- ( carboxymethyl)
-N- (phenylsulfonyl) amino) phenyl) vinyl) pyridine hydrochloride (1.00 g) in dichloromethane (50 ml)
To the suspension were added N-methylmorpholine (1.17 g), water-soluble carbodiimide hydrochloride (667 mg), hydroxybenzotriazole (477 mg) and 28% aqueous ammonia (211 mg),
Stirred at room temperature for 4 hours. After completion of the reaction, ice water was added to the reaction solution, and dichloromethane was further added for extraction. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with dichloromethane to obtain the desired compound (800 mg). ¹ H-NMR (400 MHz, DMSO-d ₆ ) 4.21 (1 H, d, J = 15.9 Hz), 4.29 (1 H, d, J = 15.9 Hz), 6.98 (1
H, d, J = 16.2Hz), 7.12 (1H, d, J = 8.2Hz), 7.41-7.28 (6H,
m), 7.55-7.45 (4H, m), 7.81 (1H, d, J = 8.6Hz), 8.23 (2H,
d, J = 6.3 Hz), 8.58 (2H, d, J = 5.8 Hz).

(Formulation Example 1) (Tablets) According to a conventional method, 100 mg of the compound of Example 2 was added in an amount of 0.2 mg.
mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 m
Produced using g starch and 98.8 mg lactose.

(Test Example 1) Cancer cell proliferation inhibitory activity The human colon cancer cell line KM12-HX used in the experiment was provided by Professor Tatsuro Irimura, Faculty of Pharmaceutical Sciences, the University of Tokyo. KM-12-HX cells containing 10% FCS D
The cells were suspended in a MEM / F12 medium and seeded on a 96-well plate at 2 × 10 ⁴ cells / well. At the same time, the sample was added to the target concentration. After culturing for 72 hours, add an MTT solution (5 mg / ml) at 10 μl / well.
And incubated for a further 4 hours. Thereafter, the supernatant was removed, and the formazan precipitate was washed with DMSO (150 μl / we
ll), and the absorbance at 540 nm was measured. An IC ₅₀ value was calculated based on the measured absorbance.

[0240]

[Table 7]

[0241]

Industrial Applicability The compounds of the present invention have excellent cell cycle inhibitory activity and are useful as antitumor agents.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/4406 A61K 31/4406 31/4409 31/4409 (72) Inventor Keisuke Suzuki Hiromachi, Shinagawa-ku, Tokyo 1-258, Sankyo Co., Ltd. (72) The inventor, Hayato Iwatari 1-2-58 Sankyo Co., Ltd., Hiromachi, Tokyo 1-58-2, Inventor Yasaku Fujiwara, Yasaku Fujiwara, 1 No. 2-58 Sankyo Co., Ltd. F term (reference) 4C055 AA01 AA17 BA01 BA02 BA27 BB16 CA01 CA02 CA27 CB16 DA01 DA27 DB16 4C063 AA01 BB03 CC92 DD12 EE01 4C086 AA03 BC17 GA04 GA08 NA14 ZB26

Claims (14)

[Claims] 1. A compound of the general formula (1) (In the formula, ring A may have a substituent selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms and a halogeno group, a benzene ring or X represents a thiophene ring, and X represents a formula —CH ＝ CH—, a formula —CH ₂ CH ₂ —, a formula —CO
NR ^7a — (wherein, R ^7a is a hydrogen atom or a group having 1 to 6 carbon atoms)
Alkyl groups. ) Or a formula -NR ^7b CO- (wherein R ^7b represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms) (provided that the right end of the formula is bonded to a pyridine ring). 0 or 1, and R ¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkylsulfonylamino group having 1 to 6 carbon atoms, a halogeno group, a nitro group. , An amino group or a cyano group, R ² represents an alkylene group having 1 to 6 carbon atoms, Y is a cyano group, a formula —CONR ³ R ⁴ (wherein R ³ and R ⁴
May be the same or different and include a hydrogen atom, a hydroxy group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, and 3 to 8 cycloalkyl groups; An alkyloxy group, an aryl group having 6 to 10 carbon atoms, an aryloxy group having 6 to 10 carbon atoms,
An arylalkyl group having 7 to 16 carbon atoms, an arylalkyloxy group having 7 to 16 carbon atoms, and 4 to 1 carbon atoms
It represents four cycloalkylalkyl groups, cycloalkylalkyloxy groups having 4 to 14 carbon atoms or tetrahydrofuranyloxy group. Or a formula —SO ₂ NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ are the same or different and each represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms). ) And pharmacologically acceptable salts thereof. 2. The method according to claim 1, wherein ring A is unsubstituted benzene, methylbenzene, ethylbenzene, methoxybenzene, ethoxybenzene, unsubstituted thiophene, methylthiophene, ethylthiophene, methoxythiophene or ethoxythiophene. Compound. 3. The compound according to claim 1, wherein ring A is an unsubstituted benzene ring or an unsubstituted thiophene ring. 4. The compound according to claim 1, wherein ring A is an unsubstituted benzene ring. 5. X is a compound of the formula -CH = CH-, -CH ₂ CH ₂
The compound according to claim 1, wherein the compound is of formula —NHCO— or formula —CONH—. 6. The compound according to claim 1, wherein X is a formula —CH ＝ CH— (trans form) or a formula —NHCO—. 7. The compound according to claim 1, wherein n is 0. 8. The compound according to claim 1, wherein R ¹ is a methyl, ethyl, methoxy or ethoxy group. 9. The compound according to claim 1, wherein R ¹ is a methoxy group. 10. The compound according to claim 1, wherein R ² is a methylene or ethylene group. 11. The compound according to claim 1, wherein R ² is a methylene group. 12. Y is a group represented by the formula -CONHR ^{3a wherein} R is
^3a represents a hydrogen atom, a hydroxy group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or a tetrahydrofuranyloxy group) or a formula -CONCH ₃
^12. The compound according to claim 1, wherein R ^3b is a compound represented by the formula: wherein R ^3b represents an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms. 13. The method according to claim 13, wherein Y is of the formula --CONHR ^3c
3c represents a hydrogen atom, a hydroxy group, a methyl group, a methoxy group or a benzyl group) or a formula -CONCH ₃ R ^3d (where R ^3d represents a methyl group or a methoxy group),
The compound according to claim 1. 14. Y is a compound of the formula —CONH ₂ , —CONHC
H _3, a formula -CONHOH or Formula -CONCH ₃ OCH _3, A compound according to claim 1 to 11.